Chemical Design and Synthesis of Functionalized Probes for Imaging

Review pubs.acs.org/CR

Chemical Design and Synthesis of Functionalized Probes for Imaging and Treating Tumor Hypoxia Jia-nan Liu,*,† Wenbo Bu,*,†,‡ and Jianlin Shi*,† †

State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, P.R. China ‡ Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, P.R. China ABSTRACT: Hypoxia development in tumor is closely associated with its increased aggressiveness and strong resistance to therapy, leading to the poor prognosis in several cancer types. Clinically, invasive oxygen microelectrode and high dosage radiotherapy are often utilized to accurately detect and effectively fight hypoxia. Recently, however, there has been a surge of interdisciplinary research aiming at developing functional molecules and nanomaterials that can be used to noninvasively image and efficiently treat hypoxic tumors. In this review, we will provide an overview of the reports published to date on the imaging and therapy of hypoxic tumors. First, we will present the design concepts and engineering of various hypoxia-responsive probes that can be applied to image hypoxia noninvasively, in an order of fluorescent imaging, positron emission tomography, magnetic resonance imaging, and photoacoustic imaging. Then, we will summarize the up-to-date functional nanomaterials which can be used for the effective treatments of tumor hypoxia. The well-established chemical functions of these elaborately designed nanostructures will enable clinicians to adopt specific treatment concepts by overcoming or even utilizing hypoxia. Finally, challenges and future perspectives facing the researchers in the field will be discussed.

CONTENTS 1. Introduction 2. Hypoxia-Sensitive Fluorescent Probes 2.1. Sensing of Redox State 2.1.1. Nitro Group As a Hypoxia-Sensitive Moiety 2.1.2. Quinone Groups as a Hypoxia-Sensitive Moiety 2.1.3. Azo Group As Hypoxia-Sensitive Moiety 2.1.4. Reversible Sensing between Normoxia and Hypoxia 2.2. Sensing of Oxygen Molecules 2.2.1. Ratiometric Sensing by Combining Oxygen-Insensitive Dyes with Oxygen-Sensitive Indicators 2.2.2. Ratiometric Sensing by Forming FRET Pairs 2.2.3. Phosphorescence Lifetime Imaging 2.3. Simultaneous Sensing of Oxygen and pH 3. Hypoxia-Sensitive PET Probes 3.1. Nitroimidazole Analogues 3.2. Non-Nitroimidazole Agents 4. Hypoxia-Sensitive MRI Probes 4.1. T2-MRI Probes 4.2. T1-MRI Probes 4.2.1. T 1 Agents Based on Redox-Active Ligands © 2017 American Chemical Society

4.2.2. T1 Agents Based on Redox-Active Metal Ions 4.2.3. Ratiometric MRI Sensing 4.3. 19F MRI Probes 4.4. PARACEST Probes 4.4.1. Change of Water or Proton Lifetime τM 4.4.2. Change of T1 Relaxation Time 4.5. Hypoxia-Sensitive Dual-Mode Imaging Probes 5. Hypoxia-Sensitive Photoacoustic Probes 6. Therapeutic Agents for Treating Tumor Hypoxia 6.1. Therapeutic Agents for Hypoxic Microenvironment Overcoming 6.1.1. Therapeutic Agents for Oxygen Generation 6.1.2. Therapeutic Agents for the Oxygen Concentration Monitoring 6.1.3. Therapeutic Agents Providing Effective Synergetic Effect 6.1.4. Therapeutic Agents of Less Dependence on Oxygen Concentrations 6.2. Therapeutic Agents Enabled by Hypoxic Microenvironment

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Received: August 8, 2016 Published: April 20, 2017

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DOI: 10.1021/acs.chemrev.6b00525 Chem. Rev. 2017, 117, 6160−6224

Chemical Reviews 6.2.1. Nitroaromatic-Containing Nanocomposites 6.2.2. Azo-Containing Nanocomposites 6.2.3. Hypoxia-Generating and Subsequently Activatable Nanocomposites 7. Conclusions and Future Perspectives Author Information Corresponding Authors ORCID Notes Biographies Acknowledgments Abbreviations References

Review

As a negatively predictive factor, tumor hypoxia will inevitably lead to therapeutic problems since they make solid tumors highly resistant to the conventional chemotherapy and radiotherapy (RT).11,12 Because hypoxic tumor cells are nearly isolated from blood supply, most of anticancer drugs can hardly reach hypoxic regions.13 Though a small amount of the given drugs may finally reach the hypoxic tumors, most anticancer drugs may show much lowered efficacy under hypoxic conditions due to the reduced generation of reactive species14 and the decreased affinity with DNA olecules.15 Moreover, hypoxic tumors are unable to supply enough O2 which are necessary to fix the DNA damage during RT.16−18 In addition to these direct mechanisms involved in the process of therapeutic resistance, a number of derived factors may further increase hypoxic resistance to therapy, including hypoxia-driven angiogenesis,19 mutation,20,21 invasiveness,22 metastasis,23,24 and altered metabolism. As a result, hypoxia must be vigorously combated in the treatment of tumor given its central role in tumor progression.25 In the past decade, great efforts have been made to develop powerful and hypoxia-specific theranostics which can be well-applied to deal with such an extremely dangerous and intractable issue in tumor therapy.26 By making use of the functionalized nanomaterials with special chemical properties, hypoxic tumor cells can be effectively killed due to the powerful therapeutic effect created. This review, aiming to describe the latest investigations in the noninvasive imaging and treatment of tumor hypoxia by using chemistry-oriented nanotechnologies, will be presented in the following order. First, we present various probes for the sensitive and accurate imaging of hypoxic microenvironment by using optical, PET, MRI, and photoacoustic techniques (Table 1). Then, we discuss the recently developed functional nanotheranostics that can treat hypoxic tumors by using strategies of overcoming or utilizing hypoxia (Table 2). Since most of the current treatment strategies are heavily dependent on hypoxic degree, one of the hypoxia-overcoming strategies relies on transporting hypoxic cell sensitizers such as O2 to the tumor areas, while the other aims at developing novel treatment strategies that are less dependent on the O2 level. To utilize hypoxia, some recently developed nanoagents can even employ hypoxic microenvironment as an advantageous factor to trigger efficient therapy. Finally, we will discuss and provide our perspectives on the future clinical use of these nanoprobes in biomedicine. We hope that this review will stimulate new ideas to explore the potentials of functional molecules and nanoparticles for imaging and treating hypoxic tumors.

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1. INTRODUCTION As tumors grow in an exaggerated way, the interior of the tumor will become far beyond blood supply, leading to the largely suppressed delivery of oxygen (O2). Such an insufficient O2 supply can hardly meet the ever-increasing metabolic demands by the aggressively proliferating tumor cells, leaving the intratumor microenvironment significantly hypoxic.1 Hence, hypoxia is a common feature in all solid tumors. In the past two decades, considerable amounts of research have demonstrated that hypoxic tumor-bearing patients frequently have decreased overall survival rates.2,3 To fight hypoxia, effective approaches are critically needed to reliably detect or even image hypoxia in tumors.4 Accurate hypoxia imaging will allow clinicians not only to find those hypoxic tumor-bearing patients and position the hypoxia but also formulate suitable treatment strategies, thus contributing to the improvement of therapeutic outcomes.5−7 Clinically, O2 needle electrode method, as the gold standard by inserting a fine needle electrode into the readily accessible tumor sites, has enabled investigators to make accurate measurements of local O2 concentrations along with several specific tracks quantitatively but invasively.8−10 However, it will be more favorable that noninvasive approaches can be employed to accurately map the heterogeneous distribution of hypoxia in the interested regions. For this reason, the research interest of this field has been transferring from the direct but invasive O2 needle measurements to the noninvasive imaging by developing hypoxiasensitive probes whose signal intensity varies along with the hypoxic level fluctuations. Though various conventional dyes can be used to detect hypoxia thanks to their sensitive response to the change of O2 concentrations, they suffer from numbers of limitations such as low penetration depth of ultraviolet or visible excitation light, low photostability, and possible toxicity to biological tissues, making them difficult for the on-site and real-time detections of hypoxia. With the significant progress made in chemistry and nanotechnology, various fluorescent nanoprobes have shown enhanced penetration depth, brightness, and biocompatibility. Some nanoprobes are even capable of quantitative and reversible O2 imaging with enhanced resolution. Apart from optical hypoxia-sensitive probes, researchers are focusing more and more attention on the exploration of hypoxia-sensitive probes for clinically available imaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET). In these cases, three-dimensional (3D) information about hypoxic degree can be anticipated without the restriction of imaging depth in vivo.

2. HYPOXIA-SENSITIVE FLUORESCENT PROBES Optical imaging has become a powerful tool for visualizing morphological details of cells/tissues with subcellular resolution and high detection sensitivity.27−29 To achieve satisfactory optical imaging of hypoxia, there are two intrinsic analysts available: redox degree and O2 concentration.30 Herein, we will summarize the optical probes developed for either the indirect imaging of redox microenvironment or direct detection of O2 concentration. 2.1. Sensing of Redox State

It has been reported that low O2 concentration under hypoxic microenvironment can trigger the accumulation of various reductive species such as flavin adenine dinucleotide (FADH2) and nicotinamide adenine dinucleotide (NADH). These substances will lead to the reduction of the remaining O2, 6161


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therapeutics enabled by hypoxic microenvironment

hypoxic microenvironment overcoming

moderate

minimized oxygendependent therapy

chemotherapy/radiotherapy: MSNs, UCNPs, and UCNP@mSiO2 composites

combined therapy

nanocomposites containing nitroaromatic or azo derivatives

refs

in laboratories, both in vitro and in vivo

In Laboratories, both in vitro and in vivo preclinical

in laboratories, both in vitro and in vivo in laboratories, both in vitro and in vivo

therapeutic application

339, 340, and 344

301−303, and 305

264, 276, 277, and 281

555, 560, 570, 588, and 593

543−546

527, 531, and 539

441, 462, 468, and 471 493, 509, and 510

375, 388, 394, and 395 417 and 432

refs

44, 50, 55, 62, 90, 100−103, 105, 107, 115, 122, 133, 145, 171, 173, 182, 188, 200, 202, 203, 209, and 210 224, 232, 241, and 244 253−255

thermotherapy/photodynamic therapy: Ce6 conjugated gold nanostars, endoperoxide anchored nanorods, and polymers encapsulated with both photosensitizers and Fe3O4. photothermal therapy/radiotherapy: 64CuS, 131I-labeled CuS, CuS-decorated UCNPs, two-dimensional nanomaterials (such as WS2, MoS2, et al.) containing high-Z elements PDT agents which undergo type I (electron transfer) reaction such as photosensitizers-conjugated chondroitin sulfate hypoxia prodrugs: tirapazamine, apaziquone, banoxantrone, caricotamide, et al.

hemoglobin, perfluorocarbon compounds, manganese dioxide (MnO2) nanoparticles, et al.

oxygen generation

therapy strategy

in laboratories, both in vitro and in vivo in laboratories, both in vitro and in vivo in laboratories, in vivo

high high

in laboratories, both in vitro and in vivo in clinics in clinics

tested level

extremely low low low

detection limit

materials

redox-triggered changes in fluorescent intensity of exogenous probes; oxygen-induced quenching of phosphorescence of exogenous probes detection of radioisotope-labeled markers which are selectively trapped in hypoxic tumors blood oxygen level-dependent MRI (BOLD-MRI): the water relaxation behavior (particularly T2*) is determined by deoxyhemoglobin concentrations in bloodstream T1-MRI: hypoxia-induced change of relaxivity based on the altered number of inner-sphere water molecules (q) or the electronic relaxation time CEST: hypoxia-induced change of CEST effect based on the changed proton lifetime τM or T1 relaxation time the outputs of ultrasound signal determined by oxyhemoglobin and deoxyhemoglobin

hypoxia-sensitive mechanisms

Table 2. Summary of Various Strategies for Treating Tumor Hypoxia

photoacoustics

PET MRI

optical

modality

Table 1. Summary of Various Imaging Strategies for Detecting Tumor Hypoxia

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thus producing excessive reactive oxygen species (ROS).31,32 In addition, “normal” tumor cells often produce lactate from glucose since they undergo aerobic glycolysis,33 while the lack of O2 in hypoxic tumors will induce an anaerobic glycolytic behavior in cells for energy preservation.34 This process will result in the increased production of lactic acid and acidosis, leading to the acidic extracellular microenvironment (pH: 6.5− 6.9).35 As a result, hypoxia microenvironment possesses enhanced levels of redox, ROS, and acidosis. Generally, hypoxia degree is closely related to the local concentrations of reductive species such as nitroreductase (NTR) and azoreductase.36 Hence, a number of optical probes have been developed by employing nitroaromatic, quinone, or azobenzene (azo) derivatives as hypoxia-sensitive moieties based on the hypoxia-triggered molecular cleavage character of these derivatives. These hypoxia-sensitive probes are often constructed based on fluorescence resonance energy transfer (FRET), in which FRET donors and FRET acceptors are linked together by hypoxia-cleavable groups. FRET on and off states respectively between hypoxia and normal conditions can therefore be adopted to reflect the degree of hypoxia. 2.1.1. Nitro Group As a Hypoxia-Sensitive Moiety. In as early as 1991, Hodgkiss et al. developed several heteroaromatic nitro-compounds,37 whose fluorescence was extremely weak due to the quenching effect by nitro groups. When incubated in hypoxic microenvironment, fluorescence can be recovered due to the bioreduction of the nitro groups. Thus, hypoxia-sensitive nitroaromatic compounds become a promising candidate as fluorescent probes for hypoxia imaging. However, such probes usually suffer from low sensitivity to hypoxia as they could only respond to severe hypoxia. Taking this into consideration, Ma et al. designed a sensitive fluorescent probe which adopted 5-nitrofuran and resorufin as a hypoxia-sensitive moiety and the fluorescent dye, respectively.38 Upon the treatment of the developed probes with nitroreductase, 5-nitrofuran will be reduced, triggering the subsequent release of the colored resorufin by a 1,6rearrangement-elimination reaction. The detection limit of the probe was as low as 0.27 ng mL−1 for nitroreductase. It was also proven that the hypoxic and normoxic cancer cells can be distinguished by measuring endogenous nitroreductase levels. However, both the absorption and excitation wavelengths of these probes are within the ultraviolet or visible region, which is unfavorable when performing the in vivo experiments due to the easy tissue damages and extremely quick attenuation of these excitation lights.39,40 As a result, it is highly attractive to develop hypoxia probes whose absorption and excitation peaks are within the near-infrared (NIR) region of around 650−900 nm.41 For example, Nagasawa’s 42 and Tang’s group 43 developed hypoxia-sensitive NIR fluorescent probes independently. Both probes (λex = 753 nm/ λem = 778 nm and λex = 695 nm/ λem = 750 nm) comprised 2-nitroimidazole and tricarbocyanine dye (Cy7). The excellent fluorescence quencher nitroimidazole moiety works as a reporter for NTR. Unfortunately, the only moderate fluorescence enhancement (4-fold) after reduction makes these probes difficult for in vivo animal bioimaging of hypoxia. Very recently, Li et al. developed an improved Cy7-based NIR fluorescent probe with longer excitation and emission wavelengths (λex = 769 nm and λem = 788 nm), greatly favoring in vivo imaging in tumor.44 The developed probe can sensitively respond to NTR with an as high as 110-fold enhancement in fluorescent intensity (Figure 1, panels a−c).

Figure 1. (a) Schematic illustration of the enzyme-catalyzed luminescence of the obtained probes activated with nitroreductase. (b) The absorption and (c) fluorescence spectra of the probes before and after reaction with NTR. (d) In vivo fluorescent imaging (730 nm irradiation/800 ± 12 nm emission) of the A549 tumor-bearing mouse models in 5 min postintratumor injection of the probes. The tumor sizes are 7 mm (left tumor 1) and 12 mm (right tumor 2), respectively. (e) PET/CT imaging (1: coronal plane; 2: sagittal plane) of an A549 tumor-bearing mouse in 90 min postintravenous injection of the 18FFMISO. Reprinted from ref 44. Copyright 2015 American Chemical Society.

The fluorescent intensity of the probe is linearly related to the NTR concentration between 0.15 and 0.45 μg mL−1. In addition, the detection limit of the probe is calculated to be 1.14 ng mL−1 for NTR. Furthermore, the authors demonstrated the capability of the probes in monitoring overexpressed NTR in hypoxic cells and even tumors. They constructed different levels of hypoxia by implanting different-sized tumors to the mice since the increase in tumor sizes will result in an elevated degree of hypoxia. It was demonstrated that the fluorescence signal intensity was enhanced by around 3- and 8-fold in the hypoxic tumor regions for mice with 7 and 12 mm sized tumors, respectively (Figure 1d). These distinctive fluorescence enhancements reflect the varied degrees of hypoxia, which were further confirmed by PET imaging (Figure 1e). 2.1.2. Quinone Groups as a Hypoxia-Sensitive Moiety. The quinone group has been chosen for the hypoxia-sensitive moiety because it can be converted into the hydroquinone form under a hypoxic microenvironment. Quinones, as favorable electron acceptors,45 can efficiently quench the emission of various fluorophores. Conversely, hydroquinones are known as effective donors. Thus, the linked fluorophores will not be quenched by hydroquinones.46 Nishimoto et al. synthesized a hypoxia-specific fluorescence probe containing a hypoxia sensing moiety indolequinone and 6163


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fluorescent coumarin dye (Figure 2a).47 Under hypoxic conditions, the probes will be efficiently decomposed via

linked with a NIR cyanine dye and a black hole quencher (BHQ) to form the probes. The azo group remains untouched in normoxic conditions. As a result, the cyanine dyes are on the off state owing to the quenching effect of BHQ. Under hypoxic conditions, however, the azo group would be readily reduced. Consequently, the quenching effect of BHQ would be no longer present, resulting in the remarkable enhancement of fluorescence. These probes could be used to distinguish hypoxia from normoxia with a rapid response in vivo. Since azo group shows high sensitivity to hypoxic microenvironment, they further improved the probes by conjugating rhodamine directly to an azo group (Figure 3a).55 Upon light

Figure 2. (a) Schematic illustration of the reduction of the probes by NADH. (b and c) The time- and dose-dependent fluorescence intensities of the probe in the presence of varied concentrations of NADH (0, 0.25, 0.5, 1.0, 2.5, 5, and 10 mM). Reproduced with permission from ref 50. Copyright 2014 Wiley-VCH.

reducing reactions. As a result, the probes will generate intense fluorescent emission due to the release of coumarin-3carboxylic acid. However, their low solubility in water and relatively short excitation and emission wavelengths restricted further applications in cellular imaging. Alternatively, to make the probes applicable to the cellular imaging, they constructed a hydrophilic probe by conjugating rhodol48 with indolequinone since the rhodol is highly soluble in water.49 Under the regulation of the hypoxia-sensitive indolequinone, the fluorescent emission of the probes exhibited a favorable on/off switching property in normoxia/hypoxia conditions. They further designed a ubiquinone-rhodol conjugate by integrating NADH-responsive ubiquinone group and a rhodol fluorophore into one system (Figure 2a).50 Following the reduction by 0.5 mM (η5-C5Me5)Ir(phen)(H2O)]2+, the probes’ fluorescent intensity showed an 8.6-fold decrease in 10 min (Figure 2b). Such a decrease in the fluorescent intensity may be resulted from the photoinduced intramolecular electron transfer51 between hydroquinone and rhodol. By calculating the fluorescent intensity with the added amount of NADH in the presence of 0.5 mm (η5-C5Me5)Ir(phen)(H2O)]2+, a linear relation between them was established in the concentration range from 0.5 to 5 mM NADH (Figure 2c). As a result, the developed probes show the capability of quantitatively monitoring NADH concentrations. 2.1.3. Azo Group As Hypoxia-Sensitive Moiety. Generally, azo derivatives can be reduced stepwise by various reductases into aniline derivatives. Such a reduction process is highly dependent on the degree of hypoxia.52 Thus, apart from nitroaromatic and quinone moiety, azo derivative can be another type of potential hypoxia sensing moiety.53 In the past few years, Nagano et al. reported numbers of azocontaining probes which are sensitive to the hypoxic microenvironments.54 For example, two ends of azo group can be

Figure 3. (a) Proposed detection mechanism and chemical structure of azo-based probes (MAR and MASR) for hypoxia sensing. (b) Cellular hypoxia can be produced by a cover glass. (c) CLSM images of A549 cells incubated with MAR or MASR under the cover glass for 3 h. (d) Magnified images of A549 cells with different hypoxic degree. The areas near the boundary of the cover glass (periphery) are a little hypoxic, while severe hypoxia existed in the central part of the cover glass (center). Scale bar: 100 μm. Reproduced with permission from ref 55. Copyright 2013 Wiley-VCH.

excitation, no fluorescence can be emitted due to the conformational variation of the NN double bond existing in the azo group. Once the NN double bond was reductively cleaved by hypoxia, the probe will emit strong fluorescence thanks to the released fluorescent rhodamine dye. This probe featured even higher sensitivity while the fluorescence intensity increased dramatically by 630-fold under hypoxic conditions. In addition, the probes exhibit the capability to detect hypoxia in living cells because the fluorescent intensity varied significantly 6164


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Figure 4. (a) Design strategy of the reversible fluorescence probe for hypoxia. (b) Time-dependent fluorescence intensity of the probes under normoxic and hypoxic conditions. Ex/Em = 650/670 nm. (c) CLSM images of probes-containing A549 cells under cyclic conditions of normoxia/ hypoxia. (1) Cells were first incubated under normoxic conditions for 1 h. (2) Then, the cells were coverd with a glass to generate hypoxic conditions for another 1 h. (3) After removing the cover glass, the cells were incubated under 5% CO2 in air for 10 min. (4) Subsequently, cells were incubated under a cover glass for 1 h. (5) After removing the cover glass, the cells were incubated under 5% CO2 in air for 10 min. (6) Finally, the cells were incubated under a cover glass for 1 h after (5). Scale bar: 50 μm. Reprinted from ref 62. Copyright 2012 American Chemical Society.

Figure 5. Schematic illustration of the main energy transition pathways during the process of O2-induced phosphorescence quenching. S0, S1, and S2 represent the ground state and first and second excited singlet states of the indicator, respectively. T1 means the excited triplet state of the indicator. IC: internal conversion; ISC: intersystem crossing. Reprinted with permission from ref 78. Copyright 2013 Royal Society of Chemistry.

fluorescence probes for visualizing the dynamics of cycling hypoxia in the real time. Hanaoka et al. found that a dark quencher QSY-2161 shows different absorption peaks between its normal and reduced forms.62 Briefly, under normal conditions, QSY-21 molecules show a strong absorbance at 660 nm, while under hypoxic condition, this absorbance will be largely weakened because of the one-electron bioreduction of the molecules to the radical form (Figure 4a). More importantly, the reduced form will be easily reoxidized to QSY-21 once recovering to normoxia. On the basis of this finding, they constructed a reversible hypoxia probe by employing cyanine dye Cy5 and QSY-21 as FRET donor and acceptor, respectively. Under normoxia conditions, the designed probe showed extremely weak fluorescence, which, however, increased by 7- to 8-fold under hypoxia because the FRET from Cy5 to QSY-21 could no longer act. After re-exposure to air, the signal intensity rapidly decreased to the original level and subsequently remained invariant (Figure

in different conditions of hypoxia degree (Figure 3, panels b− d). Using this strategy, Sun et al. also presented a series of mononuclear Ir3+ complexes containing the azo group as the bioreducible moiety for the successful hypoxia detection in 3D multicellular spheroid models.56 2.1.4. Reversible Sensing between Normoxia and Hypoxia. All of the above probes measure a downstream consequence of hypoxia, and they usually can not correspondingly recover to the original state once the interested region returns back to normoxia. However, it has been suggested that tumor hypoxia is featured with tissue homeostasis between redox state and oxygenation because anoxia may be reoxygenated.57 Such repeated cycles of hypoxia-reoxygenation, as a well-recognized hallmark of solid tumors,58,59 can induce the accumulation of HIF-1α in tumor cells. Therefore, cancer cell phenotypes will exhibit enhanced prosurvival pathways and thus acquire resistance to therapy with increased malignant potential.18,60 As a result, it is better to develop reversible 6165


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can only be changed by O2 concentrations. Thus, such a lifetime signal will not be influenced by the heterogeneous distribution of luminescent molecules inside cells, organ, or even bodies.89 In this section, we will summarize the recently developed probes which are capable of providing more accurate measurements of O2 concentration in the biological environment than the simple luminescent intensity imaging. 2.2.1. Ratiometric Sensing by Combining OxygenInsensitive Dyes with Oxygen-Sensitive Indicators. In principle, ratiometric sensing probes should exhibit an O2sensitive phosphorescent emission and an O2-independent fluorescent emission at two separate emission wavelengths, and thus the intensity ratio between phosphorescence and fluorescence can be used to quantify the O2 concentration. Ideally, the ratiometric O2 probes are anticipated to possess the following two prerequisites. First, the fluorescent and phosphorescent spectra are clearly separated. Second, only phosphorescence can be quenched by O2 while both the phosphorescent and fluorescent emissions are not influenced by other biological substances and ambient physical conditions such as pH value. Most of the reported ratiometric O2 probes adopted the first strategy, and these composite materials are often in the forms of films and nanoparticles. For example, Chen et al. achieved colorimetric O2 determination by combining together a cadmium telluride quantum dots (QDs) with [meso-tetrakis(pentafluorophenyl)-porphyrinato]platinum2+ (PtF20TPP).90 As shown in Figure 6a, the reversible O2-sensitive probe

4, panels b and c). They further showed that this probe was applicable of monitoring repeated normoxia-hypoxia cycles in living cells. 2.2. Sensing of Oxygen Molecules

By developing hypoxia probes containing redox-sensitive groups, theoretically it is possible to monitor the degree of hypoxia. However, when it comes to specific applications, such strategies may be greatly influenced by other redox substances (such as glutathione and cysteine widely existed in cancer cells)63−65 because they do not directly measure cell pO2. Hence, it is much more important to develop hypoxia-sensitive probes which can directly image pO2 values within clinically relevant regions (0−15 mmHg) and even accurately map O2 distribution in vitro and in vivo if possible. Fortunately, luminescent probes which can be quenched by O2 molecules have long been explored.66 Photoluminescent O2sensitive molecules are usually based on those dyes with relatively long-decay emissions and lifetimes, such as Ru2+ complexes,67−70 Ir2+ complexes,71−75 and recently developed porphyrin-based phosphors.76,77 As shown in Figure 5, under light irradiation, the indicators quickly relax to an excited triplet state through the internal conversion and intersystem crossing processes. Once in contact with O2 molecules, part of excited dye molecules will undergo quenching through collisional interaction with O2 molecules because the emission intensity from the triplet state is generally low. As a result, the yield of the phosphorescence will decrease along with the increase of O2 concentration in a concentration-dependent manner.78 Such an O2-induced phosphorescence quenching effect can be used for the direct and reversible sensing of O2. By utilizing these O2 indicators, there have been numbers of optical probes developed for the “ON-OFF” detection of O2 based on the variation in single phosphorescent emission intensity.79 Though attractive, such single intensity-based reporting signals based on the individual use of one O2sensitive dye can easily be interfered by probe concentration, light scattering, and external environment variations such as temperature or pH value in practical applications. Without the assistance of complicated data processing, it will be highly difficult to determine O2 concentration accurately and quantitatively since the actual relationship between O2 concentration and fluorescent intensity is always not linearly dependent. In the past decade, researchers have developed at least three strategies to overcome the above-mentioned drawbacks. One effective strategy relies on the development of composite probes comprising with O2-insensitive dyes and O2-sensitive indicators. Such probes can realize ratiometric O2 measurement by simultaneously recording the fluorescence intensities at two wavelengths, thus providing a correction chance for the environmental effects by correlating the intensity ratio to the O2 concentration. A more efficient way to achieve ratiometric detection is the development of FRET-based dual-emissive nanoprobes.80−82 Typically, these nanoprobes consist of a fluorescent dye/nanoparticle acting as both a FRET donor and a fluorescent reference and an O2-sensitive organic dye serving as an acceptor emitting sensing signal. The relatively shortwavelength emission of the donor is anticipated to activate the acceptor to emit longer wavelengths, thus the ratio between these two emissions can be modulated by the O2 concentration. The third one is phosphorescence lifetime imaging.83−88 As an intrinsic property of the fluorophore, phosphorescence lifetime

Figure 6. (a) Schemetic illustration of the ratiometric optical O2 probe by developing a QDs-decorated film. (b) Color changes of the film probes, with (bottom) and without (top) an internal fluorescence standard QDs, at varied O2 concentrations. Highly sensitive red to green color change (bottom) can be observed in comparison with the less sensitive red fluorescent intensity variation (top). Reproduced with permission from ref 90. Copyright 2008 Wiley-VCH.

PtF20TPP91 was incorporated into a silica matrix while greenlight-emitting QDs were located underneath the O2-sensitive layer.92,93 Surprisingly, the probes exhibited well-distinguishable color changes visible with the naked eye under varied O2 concentrations. In sharp contrast, it was very difficult to detect the fluorescence intensity change of PtF20TPP if green-lightemitting QDs layer was extracted (Figure 6b). As a result, with the assistance of an internal fluorescence standard QDs, the 6166


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Besides MOFs, polymers have been widely used as matrices thanks to their outstanding water solubility. In addition, their O2-penetrable and hydrophobic core can be efficiently embedded with hydrophobic O2-sensitive dyes. For example, Wolfbeis et al. integrated two hydrophobic dyes into the hydrophobic polystyrene matrix, one is Pt(II)-5,10,15,20tetrakis(2,3,4,5,6-pentafluorophenyl)-porphyrin (PtTFPP) for O2 sensing and the other is N-(5-carboxypentyl)-4-piperidino1,8-naphthalimide butyl ester as an internal reference (Figure 8).101 Using this strategy, the optical signal about intracellular O2 distribution can be exported by either a standard RGB digital camera or a conventional wide-field microscope. More attractively, the designed probes are compatible with other O2 indicators if only their emission can be detected by the red channels of RGB cameras.

probes can rapidly image O2 concentration using a colorimetric method. Though this strategy is promising, the large size of these film materials is unfavorable for their applications in biomedicine. In the past decade, there have been growing interests in the development of “fusion technologies”, combining both O2sensitive dye and O2-insensitive dye into a nanoskeleton such as metal−organic frameworks (MOFs) or polymers, to sense O2 in a ratiometric way. MOFs, an emerging class of porous materials composed of transition metal ions and organic linkers, have been widely explored as chemical probes.94,95 Nanoscale MOFs (NMOFs) exhibit more interesting characteristics that make them desired nanomaterials for biosensor applications. First, NMOFs with reasonable crystallinity and structural tunability are highly porous, which enables them to accommodate high loadings of imaging agents, quick diffusion of small molecules such as analytes in their pore networks, and the dye self-quenching prevention. Second, NMOFs are intrinsically biodegradable in long terms due to their relatively labile metal−ligand bonds.96 As a result, NMOFs have also been used for small molecule sensing.97−99 Lin et al. first designed a NMOF-based O2 sensor by choosing Pt-5,15-di(p-benzoato)porphyrin (DBP-Pt) as an O2-sensitive bridging ligand and rhodamine-B isothiocyanate (RITC)-conjugated quaterphenyldicarboxylate as an O2independent luminescent ligand (Figure 7a).100 Under an

Figure 7. (a) Synthetic scheme of ligand-mixed NMOF and its postsynthesis modification to afford NMOF colabeled with DBP-Pt and RITC. (b) Emission spectra (λex = 514 nm) of the probe under varied oxygen partial pressures. (c) Plots of RI0/RI as a function of oxygen pressure. Reprinted from ref 100. Copyright 2016 American Chemical Society.

oxygen-free atmosphere, the probes exhibited a weak 570 nm emission from RITC and a strong 630 nm emission from DBPPt, respectively (Figure 7b). When the probes were exposed to aerated atmosphere, the phosphorescent intensity from DBP-Pt decreased significantly while the fluorescent intensity from RITC remained unchanged as expected. In addition, RI0/RI changed linearly with pO2 within a range from 0 to 80 mmHg on exposure to O2. Attractively, the ratio between RITC fluorescent intensity and DBP-Pt phosphorescent intensity can be regulated by changing the proportion of two dyes during MOF synthesis and postsynthesis modification, respectively.

Figure 8. (a) Schematic illustration of the polystyrene-matrix ratiometric O2 probe consisting of two luminophores. The red emission from PtTFPP is significantly sensitive to O2 levels while the green light emitted from the reference dye is constant under varied O2 concentrations. (b) Chemical structure of the O2-sensitive PtTFPP and (c) the reference dye N-(5-carboxypentyl)-4-piperidino-1,8naphthalimide butyl ester. (d) RGB image and (e) ratiometric image of the intracellular O2 distribution. Ratios between the red and green channels were calculated to obtain the brightness values for each pixel in the pseudocolor image. Reprinted with permission from ref 101. Copyright 2011 Royal Society of Chemistry. 6167


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Figure 9. (a) Chemical structure of the PVP-conjugated Ir3+ complex probe. An internal standard (R group) is linked to the end of the PVP chain for ratiometric O2 measurement. (b) Emission spectra of the probes at varied O2 concentrations (0, 2.5, 5, 7.5, 10, 20, 40, 60, 80, and 100%). (c) CLSM images of probes-containing SH-SY5Y cells (0.2 mg mL−1). The two signals (540−610 nm and 670−750 nm) were simultaneously obtained when incubating cells at varied O2 levels. Adapted from ref 102. Copyright 2015 Nature Publishing Group. (d) Optical whole-body imaging of the lung metastases-bearing mice from different angles. (e) Optical images of organs dissected from the lung metastases-bearing mice. (f) Whole-body optical imaging of the H22 tumor-bearing mice from two angles. Two phosphorescent signals can be detected while one is from the original tumor in the right rear paw and the other is from the metastasis in the right groin. (g) Optical imaging of the mice with the local skin removed. The location of an inguinal lymph node can be clearly indicated by the amplified images. Reproduced with permission from ref 103. Copyright 2015 Wiley-VCH.

penetrate into metastatic tumor cells after intravenous administration and subsequently light up metastatic tumors with hypoxia microenvironment. Compared with composite materials integrating two independent dyes into one system, single component materials of dual emissions will be more desirable for ratiometric O2 sensing due to their minimized dye leakage possibilities and the enhanced homogeneity of the probes. However, when both fluorescent and phosphorescent emissions come from one dye molecule, it will be a great challenge to regulate the ratio between fluorescent and phosphorescent intensities to facilitate the practical applications. Fraser et al. did pioneering work by developing a ratiometric probe for hypoxia imaging in vivo, which contained an iodide-substituted difluoroboron dibenzoylmethane-poly(lactic acid) (Figure 10).105 Difluoroboron dibenzoylmethanepoly(lactic acid) of varied molecular weights (P1 = 2700 Da, P2 = 7300 Da, and P3 = 17 600 Da) were synthesized by a controlled ring-opening polymerization route

Jiang et al. synthesized a poly(N-vinylpyrrolidone) (PVP) polymer-based probe for ratiometric imaging of hypoxic degree.102 The Ir3+ complex-conjugated PVP polymer was used not only to sense O2 level with prolonged intratumor retention of the probe, but also to provide a platform to link an internal standard (“R” group in Figure 9a), thus ensuring ratiometric O2 measurements (Figure 9, panels b and c). Using the developed nanoprobes, the same group further delivered them to the lung/lymph node noninvasively and detected cancer cell metastasis with high sensitivity and specificity (Figure 9d-g).103 This strategy to detect metastasis of cancer cell is dependent on the recovery of the nanoprobes photoluminescence under hypoxia conditions, thus effectively screening off nonspecific signals from normal organs. It is widely known that hypoxic cancer cells tend to metastasize and migrate to other organs through bloodstream, resulting in the poor patient outcome.104 As a result, it will be of great significance to explore such optical probes that can specifically 6168


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construct efficient FRET-based ratiometric sensing systems, it is usually a prerequisite that the donor emission matches well with the acceptor absorption bands. 2.2.2.1. Molecular Dyes As Donors. For example, Yoshihara et al. chose coumarin 343 (C343) fluorescent group as the donor and red-emitting iridium complex [(btp)2Ir(acac)] phosphorescent group as the receptor.107 To spatially separate these two luminophores, a tetraproline linker was used to connect them. Upon 405 nm light excitation, the C343 moiety in the probes can absorb the excitation photons, and then the partial electronic energy from C343 will be transferred to the iridium complex via energy transfer. The red phosphorescence of iridium complex is sensitive to O2 concentration while the blue fluorescence of C343 is insensitive to O2 (Figure 11, panels a and b). Under vacuum conditions (pO2: 0 mmHg), the probes emitted strong red light due to the domination of phosphorescence from iridium complex over fluorescence from C343. Whereas under aerated conditions (pO2: 160 mmHg), the probes emitted blue fluorescence from C343 because red phosphorescence has been almost completely quenched by O2 (Figure 11c). Subsequent experiments on HeLa cells cultured with the probes further indicated that the ratiometric probe can map local O2 concentrations in living cells (Figure 11d). Though such probes based on molecular dyes exhibit the advantages of better affinity to biological cells and less impact on living cells compared to big ones, ratiometric O2 probes based on nanoparticles are more attractive because they show better photostability and brighter emission due to the highdensity chromophores loaded in nanoparticles.108 Semiconducting polymer dots,109 based on various polymer backbone, have been widely used as fluorescent chemosensors110 due to several important advantages, such as exceptionally high brightness,111 narrow-band emission,112 and long circulation time.113 In addition, their compact structure will contribute to the effective suppression on luminescent quenching resulting from intermolecular aggregation which has been frequently found in linear conjugated polymers.114 Huang et al. constructed a kind of polymer dots with dual fluorescent/phosphorescent emissions by combining O2sensitive phosphorescent Pt2+ porphyrin with O2-insensitive fluorene-conjugated polyelectrolyte. These two moieties can self-assemble into polymer dots in the phosphate buffer saline (PBS). Such a self-assembly process originated from their amphiphilic structure composed of hydrophobic backbone and hydrophilic side chain (Figure 12a).115 Upon light excitation, the polymeric host will efficiently transfer photoenergy to the phosphorescent dye, resulting in the phosphorescent emission that is highly dependent on O2 levels (Figure 12b). The calculated energy transfer efficiency for such polymer dotsbased probes reached around 80%.116 To further confirm the potential application of the probes, they evaluated the performance of the probes for hypoxia imaging in vitro. As shown in Figure 12c, the fluorescence from the donor (420− 460 nm) remains unchanged, while the phosphorescence from the acceptor (630−680 nm) is highly sensitive to O2. These results indicated that the developed probes may be useful for ratiometric O2 sensing in the cells or tissues. It will be highly attractive if one can nonperturbatively measure the intracellular O2 tension deep within tissues because the intracellular hypoxia microenvironment is always complicated in both spatial and temporal distributions at widely varied locations,117 which, however, remains to be challenging

Figure 10. (a) Ring-opening polymerization of difluoroboron dibenzoylmethane-poly(lactic acid) with different molecular weights. Emission spectra of P1−P3 polymers in (b) air and (c) N2 conditions, respectively. (d−g) Optical imaging of a 4T1 breast tumor-bearing mouse with P2 nanoparticles, which show the (d) bright-field and (e) fluorescence/phosphorescence ratio imaging when breathing carbogen-95% O2, (f) room air-21% O2 and (g) nitrogen-0% O2. The fluorescent and phosphorescent emissions were collected from 430 to 480 nm and 530 to 600 nm, respectively. Reproduced with permission from ref 105. Copyright 2009 Nature Publishing Group.

(Figure 10a).106 The singlet−triplet energy gap of the probes can be modulated by changing the polymer-chain molecular weights. As a result, samples with relatively lower molecular weight exhibit red-shifted fluorescence, while materials with higher molecular weight show blue-shifted emission (Figure 10b). The low-molecular-weight component (P1) with negligible fluorescence (430 to 480 nm) and meanwhile strong phosphorescence (530 to 600 nm) can act as “turn-on” probes that lighten tissues in hypoxic environments. In contrast, the probes such as P2 with comparable intensities of fluorescent and phosphorescent emissions are more suitable for the ratiometric hypoxia imaging (Figure 10c). By using a single P2 nanomaterial, the ratiometric variations can be determined by the relative changes in fluorescence and phosphorescence intensities, which are dependent on the variations in O2 level. The ratio signal is well-related to O2 concentrations in tumors, which endows the probes with great potential to be successfully used in imaging hypoxia (Figure 10, panels d−g). 2.2.2. Ratiometric Sensing by Forming FRET Pairs. The highly effective FRET plays a remarkable role in elevating the amount of the triplet excited states of the O2-sensitive acceptor, thus improving the sensitivity of the probes. As a result, to 6169


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Figure 11. (a) Design concept of a molecular probe for the ratiometric sensing of O2 concentrations in living cells. (b) Molecular structure of the ratiometric probes. (c) Emission images of the probes in CH3CN under different oxygen pressures by UV irradiation (λexc = 365 nm). (d) CLSM images of HeLa cells incubated in the conditions of 20% or 2.5% O2. The excitation wavelength was 400−410 nm. Emissions from C343 (460−510 nm) and iridium complex (above 610 nm) were detected as a reference and the sensing signal, respectively. Reproduced with permission from ref 107. Copyright 2012 Wiley-VCH.

hypoxia response of the nanoprobes stems from the fact that the emission of surface-linked dye is strongly quenched by O2, while the QDs’ emission will not. Under the guidance of this principle, Kim et al. designed a multifunctional O2 sensing platform based on QDs which were coated with cationic amphiphilic polymers (Figure 14).133 Such a platform presents two important partitions, a hydrophobic inside pocket and a positive outer surface. The inside hydrophobic compartment Ru dyes along with dozens of bright QDs were applied for O2 sensing. The QDs act as O2insensitive fluorophores that emit at 470 nm, and such an emission will excite the O2 sensitive phosphore Ru(dpp)32+ dye molecules, whose emission at 620 nm will become quenched upon binding O2 molecules. The surface of this nanoprobe was further modified with polyethylenimine as a polycationic polymer vehicle backbone for gene delivery134 and with hyaluronic acids as well for targeted labeling. Hence, in addition to the capability of reversible O2 sensing by detecting the ratiometric optical signals, this O2 sensing probe can also be applied for simultaneous targeted labeling and gene delivery. It is more preferred that the ratiometric nanoprobes are excitable by NIR light instead of UV−vis, and their spatial resolutions should be better than several microns to detect biological events at the subcellular levels.135 Fortunately, NIRexcited multiphoton laser scanning microscopy enables noninvasive 3D optical imaging with spatial resolution of about 1 μm and high penetration depth.136,137 However, few traditionally used phosphors have been successfully applied to twophoton O2 measurements because they show extremely low two-photon absorption cross sections (σ2).138 For example, it has been proven that σ2 value of free-base tetraphenylporphyrin is as low as 1−25 Göppert-Mayer (1 GM is equivalent with 10−50 cm4·s/photon).139 Hence, the direct usage of phosphorescent dyes in two-photon microscopy imaging become insignificant due to the extremely low two-photon absorption

mainly due to the difficulties in delivering hypoxia-sensitive probes through hundreds of micrometers of cellular layers to hypoxic tumor regions.118 It has been widely accepted that the surface charge of nanoparticles is a key parameter which will influence cellular uptake,119,120 and fortunately, the tunable overall charge and Zpotential is another important feature of copolymer nanoparticles.121 Dmitriev et al. reported a type of conjugated polymer that consists of polyfluorene backbone antenna and red-emitting Pt2+-porphyrin reporters for ratiometric sensing.122 At the same time, a variety of charged groups (+, −, or ± ) can be easily grafted onto the backbone copolymer nanoparticles to form cationic, anionic, or zwitter-ionic structures as shown in Figure 13 (panels a and b). 3D cell models such as spheroids are attractive in vitro models of cancer and stem cell developments, but their in-depth staining with probes is challenging.123 They found that the “zwitterionic” nanoparticles show a high cell-staining efficiency and a deep penetration across multiple cell layers in 3D models of PC12 cells (Figure 13c). In addition, stained cells showed efficient response to O 2 in a ratiometric manner of luminescence intensity (Figure 13d). Figure 13e shows the uniform staining of 50−300 μm sized spheroids with intracellular localization of nanoparticles, allowing much deeper staining than with small molecule Calcein Green. 2.2.2.2. Quantum Dots As Donors. Compared with molecular dyes, luminescent semiconductor nanocrystals such as QDs exhibit several attractive advantages such as broad and intense absorption spectra, intense and narrow emissions in the UV−visible-NIR range, and high photostability.124,125 Thanks to these attractive properties, QDs serving as donors have been widely used to construct FRET nanoprobes for imaging various analysts.126−131 In the application for hypoxia imaging, Credi et al. first reported an O2 nanoprobe by anchoring pyrenyl units on the surface of CdSe core/ZnS shell QDs.132 The ratiometric 6170


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Figure 13. (a) Schematic illustration of the O2-sensitive conjugated polymers in an organic solvent and their nanoparticle form after precipitation with water. (b) TEM image of the resulting nanoparticles (SI-0.15+/0.05−). (c) CLSM images of PC12 cell aggregates cultured with nanoparticles and costained with calcein green (1 μM, 0.5 h). Arrows indicate aggregates. (d) Ratiometric intensity imaging of mouse embryonic fibroblast cells treated with nanoparticles (SI-0.1+/ 0.1−) under different concentrations of O2. Combined polyfluorene (390−430, green) and Pt2+-porphyrin (390−650, red) intensity images are shown. (e) 3D reconstruction CLSM images of spheroids HCT116 cells treated with SI-0.1+/0.1−. Reprinted from ref 122. Copyright 2015 American Chemical Society.

Figure 12. (a) Schematic illustration of the chemical structure of fluorescent/phosphorescent conjugated polyelectrolyte by introducing O2-sensitive phosphorescent Pt2+ porphyrin into O2-insensitive fluorene-based conjugated polyelectrolyte and their self-assembly process into the polymer dots. (b) O2 sensing mechanism of the conjugated polyelectrolyte and the schematic illustrations of energy levels of the moieties in the probes. (c) Ratiometric CLSM imaging of HepG2 cells incubated with the probes at 21% or 2.5% O 2 concentrations. Reprinted with permission from ref 115. Copyright 2015 Royal Society of Chemistry.

cross sections of phosphorescent dyes, which required much enhanced excitation power, long irradiation durations, and exceedingly high concentration of probes. As an alternative approach, integrating the conventional O2 indicators with twophoton absorbing antenna chromophores to facilitate the energy transfer will result in amplified two-photon absorbing signals from the O2 indicators without directly altering their electronic properties. QDs exhibit high σ2 values of about 104 GM,140,141 which make them attractive two-photon absorbing donors for FRET imaging.142,143 Nocera et al. developed a series of two-photon absorbing probes which contain O2-insensitive QDs and O2sensitive indicators for ratiometric detection of O2.144−146 The QDs served as both a multiphoton absorption species for exciting indicators and an internal reference for the ratiometric O2 sensing. The O2-sensitive dye such as Os(II)PP exhibits a broad absorption that extends into the red spectral region, which matches well with the emission of QDs. Thus, FRET from the QDs to the Os(II)PP can be established under twophoton excitation conditions (Figure 15, panels a and b). In this probe, ratiometric O2 sensing can be achieved by calculating the ratio between two emissions from porphyrin

and QDs. A ratiometric calibration curve by plotting the intensity ratio (I682 nm/I528 nm) versus O2 concentration exhibits an exponential relation between them (Figure 15c). The authors further checked the performance of probes in vivo by using a brain vasculature model. As shown in Figure 15 (panels d and e) which were obtained from numbers of images taken at the step of 10 μm in up to 200 μm depth, the QDs emission reveals the evenly distributed probes throughout the whole vessels. In contrast, O2 levels from arteries and veins are significantly different since the red emission from O2 indicators is variable. This observation is consistent with the known fact that O2 concentrations in the veins are always lower than that in arteries.147 These properties taken together established the QDs-based O2-sensitive nanoprobe for competent ratiometric, two-photon O2 sensoring in the biological microenvironment. 2.2.2.3. Upconversion Nanoparticles As Donors. Besides using two-photon probes to achieve NIR excitation, lanthanidedoped upconversion nanoparticles (UCNPs)148,149 have recently attracted great attention thanks to their ability to emit upconverted UV, visible, and NIR light150−152 with excellent photostability153 upon 980 nm NIR exposure.154 6171


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Figure 14. Schematic illustration for the synthetic procedure of amphiphilic polyethylenimine derivatized polymer (amPEI) and the encapsulation of dozens of QDs in amPEI for QD-amPEI composite construction (top). The QD-amPEI platform can be exploited for various applications including cellular labeling, siRNA delivery for GFP gene silencing, hyaluronic acid tethering for cell-specific targeting, and ratiometric photoluminescence O2 sensing. Reprinted from ref 133. Copyright 2015 American Chemical Society.

main moieties in the designed nanoprobe, which are O2 indicator [Ru(dpp)3]2+Cl2174 and UCNPs, respectively. Upon 980 nm excitation, their upconverted emission can act as the excitation light for [Ru(dpp)3]2+Cl2 (Figure 17a). In order to combine these two materials together, hollow-structured nanomaterials with UCNP core and mesoporous silica shell were constructed via a “surface-protected etching” process.175,176 It has been reported that materials with small mesopores as gas sensors offer special advantages since such small mesopores combine the advantages of high gas accessibility and large specific surface areas.177 Furthermore, our results indicate that hollow-structured mesoporous silica shell in the nanoprobes can adsorb O2 molecules from solutions. Such a significantly higher O2 concentration in the local nanoprobes is very beneficial for the potential clinical hypoxia detection because it is possible to detect O2 with relatively lower concentration. More attractively, both the absorption (980 nm) and emission (613 nm) wavelengths are within the tissue transparent regions, thus allowing high penetration depth imaging of hypoxic regions. In vivo results indicate that such nanoprobes have the potential of detecting hypoxia in the brain of zebrafish, which is considered to be a multifaceted tool for chemical biologists thanks to its specific character of optical transparency (Figure 17b).178,179 The fluorescence in the zebrafish brain will alternatively become quenched or recovered upon normoxia or hypoxia treatments for three times (Figure 17c). Such promising results qualify the nanoprobe as a meaningful way to detect O2 with relatively low concentrations in biologial tissues. 2.2.3. Phosphorescence Lifetime Imaging. As for phosphorescent O2 indicators, in addition to the fact that the luminescent intensity can be quenched by O2, their decay lifetime is also dependent on the concentration of O2.180 The O2-dependent emission intensity or decay lifetime has been represented as the famous Stern−Volmer eq 1,181 where I0/I

Compared with dye molecules which exhibit extremely short lifetime resulting from the “virtual” intermediate state under two-photon excitation, UCNPs exhibit much longer lifetime (several milliseconds) due to the existence of the real intermediate excited state.155 As a result, only moderate excitation power can excite UCNPs while sufficiently high photon flux is required to excite two-photon dyes. Thanks to the attractive properties of UCNPs, a number of UCNPs-based FRET systems combining UCNPs (donors) and specific indicators (acceptors) have been developed to detect various analysts, such as DNA,156−158 glutathione,159 CN−,160,161 •OH,162 Ca2+,163 Zn2+,164 Hg2+,165,166 and some important disease markers.167−170 To sense O2 level under NIR light excitation, Wolfbeis et al.171 and Su et al.172 developed a rational strategy by using antennae species UCNPs (NaYF4: Yb,Tm) that absorb NIR light and emit two upconverted emissions at 455 and 475 nm to excite the highly efficient O2 indicators (Figure 16, panels a and b). Typically, either hybrid nanoparticles or polymer films have been constructed to combine UCNPs with O2 indicator together. Though the probes exhibit the capability of ratiometric sensing under the NIR excitation (Figure 16c), they are limited to O2 detection in the atmosphere because of the inadequate sensitivity. As shown in Figure 16d, when the film is excited by 980 nm NIR laser, the slopes of the Stern− Volmer plots (plot 2) are much lower than the ones directly excited by a conventional 475 nm xenon lamp (see plot 1). This insensitivity can be attributed to following two causes. First, only O2 indicators located close to the UCNP can be photoexcited. In addition, these O2 indicators are not freely accessible to O2 species because of the shielding by UCNPs, which leads to a distinct reduction in the quenching efficiency of these molecules by O2. Our group designed an O2-sensitive nanoprobe that exhibits enhanced sensitivity both in vitro and in vivo.173 There are two 6172


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to 19 μs in 30 min, and this value maintained up to 60 min. In addition, such a strategy features reversible phosphorescence quenching by O2, which can therefore be used to detect successive O2 concentration changes between normoxia and hypoxia. It has been demonstrated that compared with linear light excitation, two-photon protocols exhibit more advantages such as enhanced depth resolution for 3D imaging and reduced risk of photodamage.184 Vinogradov et al. did pioneering work on two-photon excited lifetime-based O2 imaging by integrating the two-photon absorption chromophores with metalloporphyrin into one system (Figure 19a).185 In their designed structure, two-photon absorbing antenna chromophores can convert the excitation energy to the low-energy fluorescences, which matched well with the absorption peaks of the metalloporphyrins, thus facilitating an efficient energy transfer to trigger its O2-sensitive phosphorescence (Figure 19b). On the basis of this work, they further constructed a phosphorescent probe (PtP-C343) which integrated Pt porphyrin (PtP) and C343 into one system. Many C343 moieties in the PtPC343 molecule as the two-photon absorbing antenna can convert the excitation energy to the PtP core.186 Thanks to both the high quantum yield (ϕf1 = 0.8−1.0) of C343 and the strong absorption of PtP, efficient FRET could occur between these two moieties.187 Two-photon phosphorescence lifetime measurements exhibit a distinctive feature of measuring tissue pO2 at variable depths. By using such a two-photon-enhanced phosphorescent nanoprobe, Boas and Vinogradov et al. first achieved the measurement of pO2 in rats’ cortical microvasculature and tissue with high spatial and temporal resolutions.188 In a typical case, the authors obtained about 100 pO2 data in as deep as 240 μm underneath the cortical surface in a mouse brain (Figure 19c). Their results indicate that the obtained pO2 measurements are consistent with the previously existed data in rat cortices.189 More attractively, this approach can be applied to measure tissue pO2. They first classified various locations based on their distance away from artery. Afterward, tissue pO2 levels were measured (Figure 19, panels d−i) at selected locations (Figure 19e) under hypoxia created by 30 s respiratory arrest. Under hypoxia conditions, all of the measured locations showed rapid O2 depletion. In addition, a clear correlation can be found between the locations and the temporal profiles of O2 level, which indicated that pO2 for most points far away from the artery decreased quickly upon respiratory arrest but recovered more slowly if returning to normal respiration (Figure 19, panels g and i), while pO2 at the locations closer to the artery decreased slowly and recovered more faster (Figure 19h). Apart from pO2, local blood flow is another parameter that is highly related to O2 levels in blood vessels. Charpak and Vinogradov et al. mapped pO2 and blood flow with high temporal and spatial resolutions.190 The strategy used for monitoring pO2 was the same as above, while the blood flow was measured by monitoring the absolute flow rate of RBCs. In our opinion, if combined with the measurements of blood flow, the simultaneous detection of pO2 in both blood vessels and tissues will enable the direct measurements of O2 extraction fraction, opening the possibilities for tumor hypoxia detections. Currently, decay lifetime of the state-of-the-art O2 indicators such as phosphorescent complexes often varies from microseconds to several milliseconds.191 Apparently, compared with those conventional phosphorescent complexes, the indicators with exceptionally longer lifetime are expected to have higher

Figure 15. (a) Schematic illustration of O2 sensing under the twophoton excitation using probes based on quantum dot-porphyrin assembly. Under NIR two-photon (700−1000 nm) excitation, the porphyrin is promoted to an excited electronic state through FRET from the QDs to porphyrin. O2 concentration can therefore be indicated by measuring the intensity of the porphyrin emission. (b) Emission spectra of the probes (λex = 450 nm) at varied O2 concentrations (from top to bottom: 0, 5, 20, 55, 145, and 260 μM O2). (c) In vitro ratiometric intensity calibration curve ploted from the data obtained in (b). (d) Green and (e) red channels of mouse brain vasculature under two-photon excitation. Reprinted from ref 145. Copyright 2015 American Chemical Society.

and τ0/τ represent the emission intensity and decay lifetime in the absence (I0 and τ0) or presence (I and τ) of O2, respectively. [O2] is the molar concentration of O2. KSV is the Stern−Volmer quenching constant while kq is defined as the quenching rate constant, respectively. I0 τ = 0 = 1 + KSV[O2 ] = 1 + kqτ0[O2 ] (1) I τ With the goal to accurately sense O2, studies have also been focused on the exploration of lifetime imaging by making use of phosphorescent O2 indicators. For example, Kamachi et al. achieved lifetime imaging of O2 concentration inside whole cells by combining a phosphorescent indicator with a lifetime imaging microscope on a laser scanning confocal microscope (Figure 18).182 After the addition of antimycin A183 which could reduce the O2 consumption rate inside cells, the mean phosphorescence lifetime inside cells gradually reduced from 23 6173


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Figure 16. (a) Schematic illustration of NaYF4:Yb,Tm UCNPs-based optical probe for O2. Upon 980 nm laser excitation, these UCNPs emit blue emission to excite the iridium complex dissolved in ethyl cellulose, while the green emission from such an iridium complex, in turn, can be reversibly quenched by O2. (b) Normalized emission spectra of UCNPs (solid line) and absorption spectra of the O2 probe [Ir(Cs)2(acac)] (dashed line on the left), which show the spectral overlap. Dashed line on the right shows the emission spectrum of [Ir(Cs)2(acac)]. (c) Under 980 nm photoexcitation, signals were obtained by recording the green emission from the iridium probe at 568 nm when cycling among argon, nitrogen with 20% O2, and pure O2. From top to bottom: emissions collected at 696 nm, 568 nm, and the ratio of the two signals (I568/I696) with much weakened noise. (d) Intensity ratio vs O2 concentration plots of the film upon 475 nm xenon lamp (plot 1) and 980 nm laser (plot 2) illuminations, respectively. Reproduced with permission from ref 171. Copyright 2011 Wiley-VCH.

sensitivities.192 Unfortunately, dyes with relatively longer decay lifetime are always limited to low-luminescent fullerenes193 and few phosphorescent BF2-chelates.194,195 What’s worse, both substances are not very compatible with highly O2-permeable polymers. Hence, despite using the probes based on these indicators,196 the detection sensitivity for O2 is not significantly enhanced compared with those conventional dyes-based probes.197 By combining phosphorescent aluminum- and boron-chelates with several 100 ms decaying lifetime, and highly O2-permeable perfluorinated polymers, Borisov et al. developed an O2-sensitive probe with unimaginable sensitivity, which was improved by up to 20-fold compared with conventional probes.198 The detection limits of the probes reached as low as 5 p.p.b.v. in gas phase and 7 pM in solution, respectively. Such a previously inaccessible detection limit will make the developed probes a highly valuable tool in monitoring O2 level. It is widely accepted that the photoluminescent hypoxia imaging is usually highly sensitive but is not as accurate as expected. In contrast, lifetime hypoxia imaging is markedly reliable; however, is time-consuming. Hence, the combination of photoluminescent and lifetime imaging will enable the qualitative distinguishing between hypoxia and normoxia by photoluminescent imaging and the subsequent report of hypoxic degree by lifetime imaging. Papkovsky et al. developed an intracellular O2 sensing probe made from cationic polymer Eudragit RL-100-formulated nanoparticles,199 the hydrophobic O 2 -sensitive in dicator platinum(II)-meso -tetrakis(pentafluorophenyl)porphyrin (PtPFPP), and an O2-insensitive fluorescent perylene dyes (Figure 20, panels a−c).200 The perylene dyes act as both a light harvesting antennae and a FRET donor for the PtPFPP dye. The resultant probes

exhibited both ratiometric and lifetime sensing capability (Figure 20, panels d and e). To monitor the dynamics of intracellular O2 and its concentration change during cellular respiration, mouse embryonic fibroblast cells loaded with the probes were treated with classical mitochondrial activators (carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone, FCCP) or inhibitors (AntiA), which led to the increased rate of O2 consumption or gradual dissipation of O2 gradients, respectively. In these situations, the lifetime of the probe differed from each other significantly, which was about 66 and 36 μs, respectively. As a result, reliable and accurate measurements of intracellular O2 concentration in adherent cell cultures can be ensured by using the developed probes since both signals changed correspondingly under the condition of cell stimulation or inhibition. In addition, net positively charged RL-100 as the backbone of the probes endows them with the function of interacting with negatively charged cell membrane and penetrating inside the cells.201 They further improved the sensing probes by using highly photostable dye poly(9,9-dioctylfluorene) (PFO) and PtTFPP served as FRET donor and O2 reporter, respectively. As shown in Figure 20f, compared with the inner neurosphere, the surface of the neurosphere showed weaker PtTFPP signals and higher PtTFPP/PFO ratio due to the intensified surface oxygenation and in the meantime unsufficient O2 supply to the interior. Upon the AntiA treatment which inhibits cell respiration, the signal ratio greatly decreased due to the diminished cellular O2 consumption. In sharp contrast, the signal ratio increased significantly after adding sodium sulfite which can efficiently deoxygenate the cultured medium (Figure 20g).202 Such promising results demonstrate that after the probes penetrate into the cells, they can map cellular O2 6174


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Figure 18. (a) Relationship between O 2 concentration and phosphorescence lifetime (left), phosphorescence intensity (middle), and luminescence intensity (right). Averaged lifetime and intensity data inside cells are given. (b) Stern−Volmer plots of phosphorescence lifetime (left), phosphorescence intensity (middle), and luminescence intensity (right). (c) Phosphorescence lifetime images in response to the antimycin A added in Colon26 cells. Reproduced with permission from ref 182. Copyright 2015 Nature Publishing Group.

Figure 17. (a) Schematic illustration of the nanoprobe structure and its sensing to O2 via the intensity changes in luminescent emission. (b) CLSM images of living zebrafish embryos after the injection of nanoprobes followed by adding 2,3-butanedione, which can trigger the cerebral anoxia by completely abolishing cardiac contractility. (c) After adding fresh water, red emission in the brain was quenched due to the recovered O2 concentration in brain. (d−f) Such a process can be repeated for at least three times. All images share the same scale bar (400 μm). Reprinted from ref 173. Copyright 2014 American Chemical Society.

2.3. Simultaneous Sensing of Oxygen and pH

The above-mentioned probes can only report one hypoxiarelated parameter. However, the physical and chemical behaviors of hypoxia are usually not determined by only one environmental factor but also by the mutual influence of two or more factors (such as O2 concentration and pH) together.204 Although hypoxia is closely relevant to low O2 concentration and acidosis, there is a lack of definite spatial correlation between extracellular pH value and O2 concentrations.205 Hence, to clarify the hypoxia microenvironment more precisely, it would be necessary to explore the multifunctionalized fluorescent probes which can detect several environmental parameters at the same time. To provide accurate measurement of the O2 concentration and pH value, it is attractive to develop high throughput luminescent probes with separable emission wavelengths when combining O2 and pH indicators into one system.206 From an application perspective, two fluorescent moieties in the probe must be excitable by a single light source. As a result, their absorption spectra have to overlap with each other to some extent while two emissions from the probe can be spatially separated from each other but do not undergo FRET.207 Paradoxically, gas sensors are often made from hydrophobic materials thanks to their gas permeability property, whereas hydrophilic materials are needed to sense pH. Therefore, the design and construction of such multiple nanoprobes for intracellular applications are highly challenging to meet the

concentrations using various sensing modalities such as ratiometric imaging and phosphorescence lifetime imaging. Huang, Li, and Zhang et al. developed a phosphorescent Ir3+ complex-modified nanoprobe to monitor O2 concentration and meanwhile suppress autofluorescence in either downconverted or upconverted channels.203 The nanoprobe was made from UCNPs coated with a layer of mesoporous silica shell, in which contains O2-sensitive Ir3+ complex (Figure 21, panels a and b). When using the downconversion channel to monitor O2 level, the lifetime of O2-sensitive Ir3+ complex increased from 0.8 to 4.0 μs along with the environment transformation from normoxia into hypoxia. By visualizing such a variation of phosphorescence lifetime, the O2 level could be readily determined (Figure 21, panels c−j). In the upconversion channel, UCNPs’ ultraviolet and blue emission can excite Ir3+ complex via energy transfer, triggering the emission of O2quenchable phosphorescence of Ir3+ complex. Therefore, such a single nanoprobe allows various strategies, for example, CLSM imaging (Figure 21, panels c, d, h, and i), phosphorescence lifetime microscopic imaging (Figure 21, panels e and j), and time-gated imaging (Figure 21, panels f, g, k, and l) to clearly detect the gradient O2 concentration, which will be valuable to O2 sensing in tissues with nonuniform O2 distribution. 6175


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Figure 19. (a) Schematic illustration of a two-photon absorbing phosphorescent O2 probe by coupling a two-photon absorbing antenna to a metalloporphyrin core. (b) After the two-photon states of the antenna (aS2P) are populated, their fluorescence matches well with the absorption bands of the core metalloporphyrin, ensuring an efficient antenna-core resonance energy transfer. Reprinted from ref 185. Copyright 2005 American Chemical Society. (c) Composite image showing a projection of the imaged vasculature stack. pO2 measurement locations in the capillary vessels at 240 μm depth are marked with red arrows. The consecutive branches of the vascular tree, from pial arteriole (middle-left arrowed) to the capillary and then to the connection with ascending venule (up-right arrowed) are marked with orange arrows. (d−i) The measurement of tissue pO2 values in 29 locations of a rat below the cortical surface (about 100 μm). (d) Volumetric image of the microvasculature in the rat cortex with a red-coded pial artery and two blue-coded pial veins. (e) An integrated phosphorescence intensity image at 100 μm depth. The pial artery is marked with arrows. Gray bar represents the average number of counts from single phosphorescence decay at each pixel. (f) Temporal pO2 profiles acquired at selected locations during hypoxia. (g−i) Temporal measurement of pO2 values at selected locations (white dots labeled in e) during hypoxia. The period of hypoxia is marked with gray shading. Reproduced with permission from ref 188. Copyright 2010 Nature Publishing Group.

image O2 and pH value in the wounded area of human skin.210 Three channels of optical signals will be readily read out by digital RGB color cameras. Subsequently, the signal intensities in each pixel from both the red and the green channel were divided by the intensity of corresponding blue pixel as the reference channel. Therefore, the R/B and G/B ratios of each pixel represent the referenced responses to O2 level and pH, respectively (Figure 22d). As a control, a largely homogeneous distribution of O2 level and pH value can be observed in the intact skin (Figure 22, panels e−g). In sharp contrast, when visualizing a heterogeneous chronic wound, the abnormal O2 level and pH values can be observed in a sustained inflammatory area (Figures 22, panels h−j). These results clearly prove the known fact that the wounded area is quite hypoxic resulting from the increased demand of O2 during inflammation and new tissue formation. On the basis of the above discussions, there have been a considerable amount of research on the development of optical probes for imaging hypoxia at the level of cells, tissues, and living animals. Compared with other common imaging modalities such as PET or MRI, optical techniques for hypoxia imaging exhibit various attractive advantages, such as high sensitivity, large numbers of available hypoxia-sensitive agents, and low cost. Nevertheless, a number of challenges remain to be overcome. One major challenge for optical hypoxia imaging is the limited penetration depth of both excitation and emission light in living organisms. Fortunately, recent progress has indicated that the penetration depth of NIR-II (1000−1700

multifaceted requirements of simultaneous while distinctive sensing of individual parameters. The first solution to this problem is to combine two microbeads with different permeation selectivities for simultaneous sensing of acidity value and O2 level.208 In this system, the pH indicator carboxyfluorescein was encapsulated in particles made from poly(hydroxyethyl methacrylate) that is permeable to hydrogen ions, whereas an O2 indicator ruthenium(II) complex was physically adsorbed in sol−gelbased beads. Afterward, both microparticles were dispersed into the matrix made from hydrogel, which finally allowed simultaneous optical sensing of pH and O2. As another solution, Wolfbeis et al. developed a polymerbased nanoprobe (Figure 22a).209 In detail, the highly biocompatible polymer Pluronic F-127 core were linked with poly(ethylene glycol) (PEG) to form the nanoprobe. Redemitting platinum(II) meso-tetraphenyltetrabenzoporphyrin (PtTPTBP) as a lipophilic O2-sensitive probe, and a reference dye, blue-emitting tetrakis(pentafluorophenyl) porphyrin (TFPP), are simultaneously encapsulated into the hydrophobic core. In addition, a pH sensitive probe, green-emitting fluorescein isothiocyanate (FITC), is covalently linked to the PEG group located on the shell. The red luminescent intensity from Pt-TPFPP decreases with the increase of pO2 (Figure 22b), meanwhile the green fluorescence from FITC intensifies along with the increase of pH values (Figure 22c). They further integrated this kind of polymer microparticles into a biocompatible polymer film, which can be applied to 6176


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Figure 21. (a) Schematic illustrations of O2-sensitive mechanisms in the downconversion and upconversion channels. (b) Synthetic procedure of the core−shell UCNPs@mSiO2−Ir. (c, d, h, and i) CLSM images, (e and j) phosphorescence lifetime imaging microscopy images, and (f, g, k, and l) time-gated luminescence images of HeLa cells incubated with the core−shell UCNPs@mSiO2−Ir (200 μg mL−1) under 2.5% and 21% O2 levels. All the images share the same scale bar of 30 μm. Images were taken under 405 nm excitation. Reproduced with permission from ref 203. Copyright 2015 WileyVCH.

Figure 20. (a) Normalized absorption (dashed) and emission (solid) spectra of the PtPFPP (black) and perylene (gray) nanoparticles; chemical structures of (b) PtPFPP and (c) perylene dyes. (d and e) Intraneurosphere intracellular O2 concentrations and their lifetime responses to 2 μM FCCP (◆), 10 μM AntiA (●), and carrier (Δ) at 10 kPa pO2. The addition of FCCP and AntiA will lead to the decreased/increased concentration of O2 in cells, respectively. Reprinted from ref 200. Copyright 2011 American Chemical Society. (f) Ratiometric images of resting and treated (AntiA, 5 μM; Na2SO3, 5 mg mL−1) neurospheres measured on a multiphoton microscope. (g) Wide-field fluorescence lifetime imaging microscopic images of mouse embryonic fibroblast cells cultured with the probes (10 μg mL−1, 16 h) at varied levels of atmospheric O2. Reproduced with permission from ref 202. Copyright 2012 Wiley-VCH.

radiotracer probes.213 Generally, hypoxia markers should be able to readily and nonspecifically enter cancer cells, staying only in hypoxic cells while not in normoxic cells.214 Typically, a PET radiotracer consists of a radioisotope and a hypoxiaresponsive molecule that is specific to the hypoxic microenvironment (e.g., reduction or glucose resulted from metabolism).215,64Cu, 18F, 11C, and 15O are often selected as popular radioisotopes due to their short half-lives.216 The hypoxia-responsive moieties of the probes can be categorized into two groups: nitroimidazole analogues and nonnitroimidazole agents. Once the hypoxia markers are administered to the patients and subsequently trapped by hypoxic tumors, the PET radioisotopes will decay in the body by positron emission (Figure 23a).217 The emitted positron will come into collision with a nearby electron, producing two oppositely directed γrays. The detectors can absorb such photon energy and release the aborbed energy by emitting visible light. The light signal can be further converted into electrical current, whose intensity is linearly related to the incident photon energy (Figure 23b). As a result, PET can quantitatively image cancer hypoxia since the tracer concentration trapped in hypoxic tumors is proportional to the hypoxic degree.

nm) light could reach as high as 4 mm with the resolution of sub-10 μm, which can not be achieved by MRI, PET, or photoacoustic imaging.211 As a result, further development of hypoxia-responsive probes which can be excited by NIR-II light may attract research attention. In addition, to achieve singlemolecule labeling and subcellular imaging, researchers must be able to synthesize high-performance hypoxia-sensitive probes with further enhanced sensitivity and selectivity. Furthermore, the exploration of multifunctional probes, which can either sense O2 with different optical imaging modalities or sense two and more hypoxia-related analysts, is suggested for more accurate hypoxia imaging.

3. HYPOXIA-SENSITIVE PET PROBES Although the optical imaging modality exhibits the advantages of single-cell sensitivity, its spatial resolution decreases rapidly with the increase of the imaging depth. Among the clinically available imaging methods, MRI, computed tomography (CT), PET, and single photon emission tomography (SPECT) are extremely attractive because of their independent character of tissue depth. Of these, PET212 displays a number of advantages for studying hypoxia by offering noninvasive and 3D assessments of hypoxic degree in tumors with the assistance of

3.1. Nitroimidazole Analogues

2-Nitroimidazole-based compounds were considered to be the first generation of molecular probes for PET hypoxia imaging.218 Nitroimidazoles can passively diffuse into tumor cells and subsequently undergo reductive reactions to form an intermediate product (Figure 24).219 Under normoxic conditions, these species can be rapidly reoxidized into their parent compounds, resulting in the diffusion out of the cells.220 Under 6177


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Figure 22. (a) Schematic illustrations of the chemical structures of the dual nanoprobe for O2 and acidity. (b) O2-dependent and (c) pH-dependent spectra of the fluorescence intensities of the dual nanoprobes. Reprinted from ref 209. Copyright 2012 American Chemical Society. (d) The ratio pictures of red or green to blue channel (R/B or G/B, displayed in pseudo colors) indicate the probes’ responses to O2 or pH value, respectively. Both channel pictures show the absence of cross-reactivity. (e−g) In vivo dual sensing on the plain skin surface of a volar forearm and (h−j) a chronic wound. From the left to right: digital pictures on the (e) skin and (h) wound surfaces; (f and i) distributions of O2 reflected by the R/B ratio; and pH distributions on the surface of (g) skin and (j) wound reflected by the G/B ratios. Reproduced with permission from ref 210. Copyright 2011 Wiley-VCH.

prototype tracer, is the most widely used biomarker for PET hypoxia imaging due to its hypoxic selectivity.223 Typically, the kinetic modeling approach by comparing the trapping rate of the tracer in many tumor subregions is often used to detect tumor hypoxia. As an example shown in Figure 26, by using this kinetic analysis approach, the PET signal from hypoxia-specific radiotracer binding can be easily separated from the signal of the freely diffused tracer.224 Several studies have tried to make

hypoxic conditions, nitro ion radical will continue to undergo the bioreduction process, leading to the sustained generation of nitrosoheterocycles. Such produced species will be finally trapped in the cells.221 In the past two decades, several fluorinated nitroimidazolebased markers, as summarized in Figure 25, have been explored for PET imaging.222 Among these markers, 18F-fluoromisonidazole (18F-FMISO), constituting a typical 2-nitroimidazole6178


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Figure 23. (a) Annihilation of a positron with an electron producing two 511 keV photons traveling in the opposite directions. (b) The generated photons are absorbed by the circular gamma ray detector array equipped in the PET camera. Reprinted with permission from ref 217. Copyright 2010 Elsevier Ltd.

Figure 26. Imaging results of a dynamic PET scan as a function of time after intravanous injection of 18F-FMISO. Single reconstructed PET slice is displayed through the center of head and neck tumor. The images were taken every 1 min for the first five frames, followed by 5 min duration for the subsequent five frames. At the 30th minute after injection, the patient was removed from the scanner and then reimaged at 90 and 180 min after injection. As depicted in the final image in the series, low-dose CT scan was used to coregister PET images. It can be clearly observed that 18F-FMISO was distributed from initial blood pool to selective sequestration within hypoxic tumor subvolume. Reprinted with permission from ref 224. Copyright 2012 the Society of Nuclear Medicine and Molecular Imaging, Inc.

observed to be capable of indicating hypoxia in gliomas,225 head-and-neck,226 breast,227 lung,228 and renal tumors.229 The development of 18F-FMISO was followed by another radiosensitizer, etanidazole (18F-EF5). The lipophilic nature of these two markers ensures their efficient penetration into both tissues and cell membrane. However, it is their high lipophilicity that simultaneously limited the clearance of the unbound tracer. The reluctant clearance of the probes from normal tissues will lead to the relatively low hypoxic-tonormoxic contrast.230 To distribute the X-ray radiation directly to the tumor hypoxia regions, it is highly desirable to obtain PET imaging results with high target-to-background contrast. The limited hypoxic contrast does not favor the visual detection of hypoxic regions, which will hinder their clinical applications. As a result, great efforts have been made to explore PET imaging probes exhibiting enhanced pharmacokinetic abilities which enabled fast clearance of the probes from normoxic tumors. The remaining fluorinated compounds in Figure 25, such as 18FFETNIM, 18F-FETA, 18F-FAZA, and 18F-HX4, are more hydrophilic than FMISO, resulting in their easy clearance from normal tissues. Take 18F-HX4 as an example, a 1,2,3antitriazole moiety was incorporated into 18F-FMISO using a click chemistry method to render the probes more hydrophilic, which endowed the probe with a favorable pharmacokinetic and clearance profile.231 After an uptake period of around 2 h, most of 18F-HX4 were located in the tumor regions and kidneys while the probes’ accumulation in liver and other normal organs were very low (Figure 27).232 In sharp contrast, 2 h later after the injection of 18F-FMISO, their accumulation in the tumor site is still low while significant accumulation of 18F-FMISO in liver can be observed. Hence, compared with traditional 18FFMISO, 18F-HX4 exhibits higher specificity in tumors and shorter injection-acquisition time thanks to their faster clearance capability, which guaranteed a much lower background for tumor hypoxia imaging.

Figure 24. Schematic illustration of the mechanism of nitroimidazoles trapped under hypoxic conditions. Once diffused into the cells, lipophilic nitroimidazoles will be reduced to anionic radical species. Under the condition of sufficient O2, they can be reoxidized and subsequently diffuse out of the cells or start the next round of reduction and reoxidation. Under hypoxic conditions, O2 is insufficient to reoxidize them. Hence, the reduction process continues until they form species which can covalently bind to intracellular macromolecules and subsequently become trapped. The green asterisk denotes the radiolabeled species. Reprinted with permission from ref 219. Copyright 2011 Elsevier Ltd.

Figure 25. Structures of the commonly used nitroimidazole compounds as hypoxia PET imaging agents.

direct O2 measurements in vivo by detecting the accumulated 18 F-FMISO, which demonstrated that a moderate O2 level less than 10 mmHg was required for the 18F-FMISO retention in hypoxic tumors. The 18F-FMISO accumulation has been 6179


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potential application of FDG as a specific hypoxia tracer seems to be limited.236 Recently, copper complex linked with diacetyl-bis(N4methylthiosemicarbazone) (ATSM) ligands has been developed as an alternative class of hypoxia imaging agents.237 CuATSM, characterized by its high membrane permeability thanks to its lipophilic property and relatively low molecular weight, can therefore rapidly diffuse into cells.238 The specificity of CuATSM for hypoxia detection is based on the intracellular reduction of Cu2+ to Cu+ combined with reoxidation by intracellular O2 (Figure 28a).239 Under hypoxic microenvironment, the reduced Cu+-ATSM composite will be further dissociated into Cu+ ion and ATSM ligand, resulting in the trapping of the Cu+. While under normoxic conditions, the [Cu+-ATSM]− complex will be reoxidized to its original form, leading to their effective efflux out of the cells.240 Typically, the half-lives of Cu (60Cu, 61Cu, 62Cu, 64Cu, and 67Cu) radioisotopes varied from 9.8 min to 61.9 h. Of these, 64Cu is the most commonly used copper radioisotope because it exhibits highly favorable physical properties for diagnostic purposes. It has been proven that 64Cu-ATSM can be served as a reliable probe that can be used to detect tumor hypoxia in human cancers. As a representative example, the hypoxic regions of the known cervical tumor can be labeled after the injection of 64CuATSM (Figure 28b,c).241 In conclusion, Cu-ATSM as the efficient PET imaging agent for tumor hypoxia exhibits several distinct advantages such as faster clearance from normoxic tissues and simpler synthesis/radiolabeling methodology, which allows higher hypoxic-to-normoxic contrast and shorter intervals between injection and imaging. Compared with other imaging modalities, PET has been playing much more important roles in clinical imaging of tumor hypoxia due to the unique advantages. First, it enables precise positioning of tumor hypoxia thanks to their special features of high target-to-background contrast ratios and high-resolution tomographic imaging, which will be further enhanced by the fusion of PET and CT imaging. Another important advantage of PET is that it provides quantitative information on hypoxia distribution in the interested areas. Furthermore, the total dosage of the injected PET tracers is as low as nanomolar-to-

Figure 27. 18F-FMISO and 18F-HX4 imaging in a patient with a huge abdominal tumor. A much lower liver-to-muscle ratio can be observed for 18F-HX4, indicating much less uptake of the probes in liver and gastrointestinal. Reprinted with permission from ref 232. Copyright 2012 Wolters Kluwer Health, Inc.

3.2. Non-Nitroimidazole Agents

As a most commonly used PET imaging agent, 2-fluoro-2[18F]deoxy-D-glucose ([18F]FDG) has been successfully used for hypoxia detection. The principle of FDG PET hypoxia imaging is based on the glucose metabolism by taking advantage of the upregulated glucose transporters and glycolytic enzymes in tumors, as widely known as the Warburg effect.233 Under hypoxia conditions, the amount of the synthesized ATP in the mitochondria will decrease, resulting in the stimulation of cellular glycolysis to compensate energy supply. Therefore, FDG-PET has been utilized as a tumor hypoxia marker because the amount of [18F]FDG uptake by tumors are directly correlated to the hypoxic degree.234 However, inaccurate correlations between FDG retention and the degree of tumor hypoxia have been found in many clinical studies because most nonhypoxic tumor cells also depend heavily on glycolytic ATP production.228,235 As a result, the

Figure 28. Schematics of the hypoxia-induced 64Cu-ATSM formation for PET imaging. (a) In hypoxic condition, the Cu2+-ATSM is reduced to Cu+ATSM then the complex became instable and free 64Cu is trapped and accumulated in intracellular copper chaperones proteins. Reprinted with permission from ref 239. Copyright 2015 Frontiers. (b) Transaxial CT images of the pelvis show the known cervical tumor at site of cervical mass. (c) PET images of the pelvis at the same level demonstrate markedly increased uptake of 64Cu-ATSM within known primary cervical tumor. Reprinted with permission from ref 241. Copyright 2008 Society of Nuclear Medicine and Molecular Imaging, Inc. 6180


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picomolar concentration, thus causing minimal side effect to the biological tissues. As a result, PET imaging is capable of quantitatively measuring the hypoxic degree without perturbing the biological system. Furthermore, as an important application of PET hypoxia imaging, PET image results will aid in the planning of suitable dose escalation or dose reduction since severe hypoxic areas can be separated from normoxic areas by PET imaging.242 For example, once hypoxic regions are identified, the clinicians can homogeneously increase the radiation dosage to the entire tumor regions. However, such a uniform dosage increase can greatly raise the risk of side effects because the surrounding normal tissues also received the increased radiation dosage. Unlike traditional 3D conformal radiotherapy approaches, recently developed intensity-modulated radiotherapy can be used to finely regulate dose distributions by delivering intensified dose only on the hypoxic focuses.243 Thus, extremely precise control of radiation dose delivery and localization can be performed on a patient at will. In this situation, the clinicians can raise the dosage only to the hypoxic regions with a corresponding reduced dosage to the nonhypoxic areas while keeping the overall radiation dosage unchanged (Figure 29).244 This approach has achieved some successes in studies for patients bearing hypoxic tumors in head and neck squamous-cell carcinoma.245 PET imaging, however, compared with fluorescent imaging, PET hypoxia imaging exhibits relatively low resolution, which remains to be a great challenge for their successful application in guiding specialized treatment. Busk et al. simulated 18FFAZA signal dilution at the resolution of standard clinical PET scanners and showed that this could result in hypoxic foci being misclassified as normoxic.230 This is due to the fact that each voxel of PET imaging may contain numerous independent hypoxic regions and necrotic/nonhypoxic tissues. As a result, PET imaging results do not definitely report the actual hypoxia heterogeneity. We think that both better isotopes and scan protocols developed in the future would enable better spatial definition of the interested regions. In summary, in the era of precision medicine, PET imaging will play more important roles in optimizing the outcome of the patients with hypoxic tumors by quantifying hypoxia degree and assessing therapy response.

Figure 29. 18F-FAZA-assisted PET image used for dose painting. Images were taken from a patient with head and neck squamous-cell carcinoma located in the oropharyngeal region. (a) With the aid of a 18 F-FAZA-PET image, hypoxia existing in a yellow-red area can be detected with the highest radioactivity. (b) CT scan was used for the subsequent treatment planning and dose calculation. The region marked with red is the gross tumor volume defined from the CT and clinical examination. (c) Merged images of the 18F-FAZA-PET and CT scans. (d) Dose distribution from a seven field dose-painting intensitymodulated radiotherapy plan. The direction of the seven intensity modulated radiation treatment fields was indicated by the white lines. The desired dose distribution in the patient can be achieved by modulating the complex radiation intensity patterns from the seven fields. Only treatment radiation doses from 63 Gy (blue) to the maximal 98 Gy (red) are shown; the average dose to the gross tumor volume was 70 Gy. Reproduced with permission from ref 244. Copyright 2012 Nature Publishing Group.

4. HYPOXIA-SENSITIVE MRI PROBES Due to the concerns about the inevitable radiation exposure during PET scanning,246 MRI, which can provide exquisite anatomical images with high spatial resolution, is expected to play a growing role in clinical hypoxia diagnosis.247 Typically, by making use of hypoxia-responsive MRI agents, the hypoxiainduced changes of the water proton relaxation rates (T1, T2, and T2*) or water proton intensities (chemical exchange saturation transfer and paramagnetic chemical exchange saturation transfer, designated as CEST and PARACEST) can be detected.248,249 Here, we will describe various MRI contrast agents that can potentially respond to the hypoxic microenvironment.

to trace blood oxygenation using gradient echo sequences.251 The principle of this method is based on the fact that the state of iron ions within heme subunit will change from a diamagnetic low spin status under high pO2 to a paramagnetic high spin status under low pO2.252 Therefore, the variations in deoxyhemoglobin content in bloodstream will change the water relaxation behavior (particularly T2*), enabling blood oxygenation levels to be measured by MRI. In the past decade, several studies have proven that BOLD effects exhibit close correlations with standard strategies for measuring pO2.253−255 Recent reports have also suggested the feasibility of BOLD-MRI technique for hypoxia imaging in patients, which offers the capability of monitoring the oxygenation fluctuations in tumors.256−259 Such a technique exhibits several advantages including its noninvasive nature and real-time detection of the variations in oxygenation level.

4.1. T2-MRI Probes

Until now, there has been no report about the hypoxia-sensitive T2-MRI contrast agent because the T2-MR effect of the current superparamagnetic agents is usually not related to the hypoxic microenvironment.250 Fortunately, blood oxygen level-dependent MRI (BOLD-MRI) as a hypoxia detection method is able 6181


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4.2. T1-MRI Probes

4.2.2. T1 Agents Based on Redox-Active Metal Ions. In practical applications, it is highly desirable that the original form of the hypoxia-responsive probes under normoxia exhibits a completely silent signal while the hypoxia-incubated form has a high relaxivity, thus, the occurrence of the MR image contrasts can be unambiguously attributed to the existence of hypoxia while not to the dynamic changes of probes concentration. Since the relaxivities of the complexes described above were tuned solely by modulating ligand structure, T1 relaxation from either the reduced or the oxidized forms was not ever completely silent under these conditions. Fortunately, redoxactive metal ions-based composites, whose reduction and oxidation forms exhibit completely different electronic structure and magnetic properties, can be used to develop hypoxiasensitive MRI contrast agents. In a number of metal ion redox systems, their relaxivities of the originally oxidized form and the reduced forms are zero/negligible and significant, respectively, in these cases on/off MR hypoxia probes can be designed. The Eu2+/Eu3+ redox couple has been frequently used to design hypoxia-responsive probe. Isoelectronic to Gd3+, Eu2+ also possesses seven unpaired electrons in an 8S7/2 ground state and thus is capable of efficiently enhancing proton relaxation.265 In sharp contrast, the paramagnetic relaxation effect of Eu3+ is negligible relative to Eu2+ because Eu3+ is diamagnetic based on its ground state (7F0). The potential uses of Eu2+ complexes as pO2-sensitive probes have been proposed.266,267 However, the required stability of most Eu2+ polyaminopolycarboxylate complexes against oxidation has not yet been fully achieved, which severely limits their potential applications in vivo.268 Fortunately, recent research have demonstrated that Eu2+ cryptates are more stable toward oxidation, which shed new light on the further development of hypoxia-sensitive Eu2+based MR contrast agents.269 Unlike gadolinium, manganese has several stable oxidation states such as Mn2+, Mn3+, Mn4+, Mn6+, and Mn7+. Of these, only Mn2+ can serve as contrast agents for MRI due to the five unpaired electrons with long electronic relaxation time,270−274 potentially providing a chance to develop hypoxia-sensitive probes based on the Mn complex.275 Aime et al. first proposed the use of a Mn2+/Mn3+-based contrast agent as an O2 probe (Figure 31a) by incorporating the manganese-porphyrin complex into a β-CD host via supramolecular interactions.276 As shown in Figure 29b, the nuclear magnetic resonance (NMR) dispersive profiles of Mn2+ and Mn3+ complexes are significantly different from each other. However, only in fields lower than 0.2 T, the r1 relaxivity of Mn2+ complex can be over 3-fold higher than that of the Mn3+ complex. This result indicates that the relaxivity differences are quite small within clinically relevant fields (1H frequency: 60−120 MHz). As an efficient solution, they encapsulated Mn2+/Mn3+-complex into poly-β-CD. In this situation, the difference between Mn2+ and Mn3+ complexes could be significantly amplified because only the r1 value of Mn2+-complex increased significantly as a result of increased τR (Figure 31b). Another type of hypoxia-activated Mn-based MR agent was reported by Caravan et al, recently.277 They utilized the ligand hydroxybenzylethylenediaminetriacetic acid to stabilize Mn atom in states of 2+ or 3+. Compare with Mn3+ complex, Mn2+ counterpart displayed a 3.3-fold higher relaxivity at 4.7 T. This is because Mn2+ complex has one inner-sphere molecule, while Mn3+ complex has none (Figure 31c). Under hypoxia conditions, the Mn3+ ions in Mn3+-complex can be readily reduced to Mn2+. As shown in Figure 31d, the time course

Although these strategies based on T2-MRI are able to differentiate hypoxia from normoxia, they are still unable to provide a quantitative measurement of pO2 because both the BOLD and T2-MRI effects are not straightforwardly correlated to tissue oxygenation. Worse still, T2-MRI-based measurements give a signal-decreasing effect by reducing the transverse spin− spin relaxation time of water.260 Such a signal darkening effect may be confused with other pathogenic processes, making the detection results less reliable. Fortunately, compared with T2*/ T2-weighted image, T1-weighted sequences are able to provide more convincing images of higher resolution and signal-tonoise ratio because they increase relaxivity from these protons by reducing the longitudinal spin−lattice relaxation time of nearby water molecules, leading to the concerned areas seeming “brighter”.261 In principle, T1-shortening agents enhance MR signals by changing the longitudinal relaxation time of water protons in tissues.262 As revealed by the classical Solomon-BloembergenMorgan theory,263 the 1H relaxivity (r1) of the probe is dependent on various parameters such as the number of innersphere water molecules (q), the water residence lifetime (τM = kex−1) of a metal ion-bound water molecule, the rotational correlation time (τR) of the complex, and the electronic relaxation time (T1e) of the metal ion. The variation of each parameter triggered by the hypoxia microenvironment can be utilized to develop hypoxia-sensitive MR probes. The most commonly used strategy relies on the alterations of q. In addition, Mn2+ and Eu3+ which have different valence states under the hypoxic environment can also be utilized to design hypoxia-sensitive MRI probes by changing their magnetic properties. 4.2.1. T1 Agents Based on Redox-Active Ligands. By modulating the hydration state of Gd3+, Nagano et al. developed numbers of hypoxia-sensitive Gd3+ complexes bearing a nitrobenzenesulfonamide moiety (Figure 30).264

Figure 30. (a) Design strategy of hypoxia-sensitive probe by modulating the T1-MR-related parameter q. Reprinted with permission from ref 264. Copyright 2012 Elsevier Ltd.

Under hypoxia conditions, the nitro group can be effectively reduced to an amino group. The nitro and amino groups are strong electron-withdrawing and electron-donating substituents, respectively. When this reaction takes place under hypoxia conditions, the number of Gd3+-bounded water molecules can be increased from q = 0 to q = 2 because Gd3+ center will not be accessible by the intramolecular sulfonamide nitrogen atom once protonated under hypoxic environment. Therefore, the relaxivity of the resulting product was found increased by about 80% from the starting Gd3+ complex, which will be easily detected in T1-weighted MR images. As a result, such a smart MRI contrast agent may be useful for the hypoxia detection. 6182


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Figure 31. (a) 1/T1 nuclear magnetic resonance dispersive profile of 1 mM aqueous solutions of Mn2+ and Mn3+ complexes at pH 7 and 25 °C. (b) Plot of the water proton relaxation rate of solutions (0.2 mM) of Mn2+ and Mn3+ complexes as a function of poly-β-CD concentration (20 MHz, 25 °C, pH 7). The probes bound with poly-β-CD can yield largely enhanced r1 values due to the enhanced τR values.276 Reproduced with permission from ref 276. Copyright 2000 Wiley-VCH. (c) T1-MRI of pure water, 0.5 mM Mn3+, and 0.5 mM Mn2+ complexes in the buffer at 4.7 T. (d) Liquid chromatography mass spectrometry monitoring of the GSH-triggered reduction of Mn3+ complexes, indicating the disappearance of Mn3+ and the concurrent emergence of Mn2+ in the time course of reduction. Reprinted from ref 277. Copyright 2013 American Chemical Society.

Figure 32. (a) Schematic illustration of the experimental procedures for MRI Gd-DOTP mapping. The ratios between two maps obtained by injecting Gd-DOTP- or Gd-HPDO3A-labeled RBCs could be used to report O2 concentration independently of vascular volume. (b) Relaxometric titration of Gd-DOTP with oxy- or deoxy-Hb (mean ± SD). (c) Vascular volume (top) and relative deoxygenation (bottom) maps of the central slice of tumor. Reprinted from ref 281. Copyright 2015 American Chemical Society.

32b). In addition, Gd-HPDO3A was used to report the local RBCs’ concentration because it does not bind to hemoglobin regardless of its oxygenation state. Hence, the combined use of these two signal responses would provide a ratiometric result on tissue hypoxic levels, which indicated that the tumor core is largely dominated by the hypoxic region (Figure 32c). Such a ratiometric MRI sensing can be used for the determination of the O2 level regardless of the probe concentrations.

experiment indicates that the Mn2+-complex emerges correspondingly with the consumption of Mn3+-complex, which appeared to take place directly without the formation of any byproduct. More importantly, the Mn2+/Mn3+-complex was proven to be fully reversible, which will allow clinicians to reversibly detect hypoxia/normoxia microenvironment. 4.2.3. Ratiometric MRI Sensing. The use of hypoxiaresponsive imaging agents alone in MRI experiments is sometimes not accurate enough for the determination of oxygenation state in tumors because MRI signal is highly dependent on the concentration of contrast agents. Ratiometric MRI contrast agents, first developed by Aime et al., could offer two signals with distinct responses to the environmental variables being probed.278 Once both signal responses to the analysts could be well detected, the ratio between the obtained signals can be used to quantitatively monitor the environmental variables such as pH279 or enzymes.280 Very recently, Aime et al. reported a ratiometric MRI probe for sensing O2 based on the usage of RBCs labeled with [Gd(10-(2-hydroxypropyl)1,4,7-tetraazacyclododecane-1,4,7-triacetate] (Gd-HPDO3A) or [Gd(1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetrakis(methylenephosphonate))]5− (Gd-DOTP), where the first probe reports the local RBCs’ concentration and the second one serves as an O2-responsive agent (Figure 32a).281 Of these two probes, Gd-DOTP have been proven to have different binding affinities to O2-deficit or O2-rich hemoglobin.282 Under hypoxia conditions, the relaxivity increases much more significantly due to much stronger binding of Gd-DOTP to O2-deficit hemoglobin than to O2-rich hemoglobin (Figure

4.3.

19

F MRI Probes

As discussed above, conventional clinical MRI detects the signal of 1H nuclei, a majority of which reside in water and fat within the human body.283 Other active nuclei, such as 13C,284,285 19 286,287 23 F, Na,288 and 129Xe,289,290 can also be used in MRI detections. Of these, 19F MRI is receiving great attention recently because it has NMR sensitivity similar to that of 1H (83% relative to 1H) and offers the highest sensitivity next to 1 291 H. More importantly, the endogenous 19F concentration in tissues, usually less than 10−3 μmol/g wet tissue weight, is generally below the detection limit of 19F MRI. Such a lack of background signal in body tissues endows 19F MRI with a high signal-to-noise ratio, contributing to much higher specificity when detecting 19F signals.292 Nishimoto and Tanabe et al. monitored the bioreductiontriggered change in 19F chemical shift by constructing a 19Flabeled indolequinone derivative (designated as IQ-F, Figure 33a).293 Both a hypoxia-responsive indolequinone parent unit and a nonafluoro-tert-butyl group were incorporated in this probe. Under hypoxia microenvironment, the probes will release nonafluoro-tert-butyl alcohol (F−OH) species via oneelectron reduction. Upon the supply of sufficient O2, the generation of F−OH can be efficiently inhibited. Fortunately, the chemical shifts between F−OH (Figure 33b) and IQ-F 6183


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Figure 34. Schematic illustration of two fluorinated, redox-active copper complexes, which can be potentially used as 19F MRI contrast agents for cellular hypoxia detection. Trifluorinated Cu2+-ATSM-F3 displays a completely quenched 19F NMR signal (“turning-off”). However, after reduction in hypoxic conditions, 19F NMR signal will be “turned on” following the Cu2+ reduction to Cu+ in normoxia. Consequently, the incubation of cancer cells with Cu-ATSM-F3 resulted in the selective detection of 19F signal in cells cultured under hypoxic conditions. Reprinted from ref 294. Copyright 2016 American Chemical Society.

Figure 33. (a) Bioreduction of the 19F-labeled indolequinone derivative (IQ-F) under hypoxic conditions to release F−OH. (b, c, and d) 19F chemical shifts indicating the one-electron reduction of the IQ-F monitored by 19F NMR. (b) IQ-F was incubated under hypoxic conditions and (c) aerobic conditions for 15 min, respectively, and that before (d) incubation. (e and f) 19F MR images of A549 cell lysate incubated with IQ-F for 0 (I), 6 (II and V), 12 (III and VI), and 24 h (IV and VII) under aerobic (II, III, and IV) or hypoxic (V, VI, and VII) conditions: (e) IQ-F signal selected image and (f) F−OH signal selected image. Reprinted from ref 293. Copyright 2009 American Chemical Society.

may enable their successful application for the in vivo 19F MRI of hypoxia. 4.4. PARACEST Probes

So far, MRI-detectable hypoxia probes have been largely limited to T1 relaxation agents, and these reporters have always been excessively utilized to achieve the required detection sensitivity. In the past decade, a new class of CEST-based contrast agents with high sensitivity has been discovered.296 Briefly, upon irradiation of selective radio frequency, mobile solute protons from a small proton pool are saturated, resulting in the subsequent transfer into the bulk water pool (the surrounding water molecules). Such a saturation transfer can trigger a decrease in bulk water signal, giving rise to the CEST-MRI contrast.297 To let CEST occur, the proton exchange rate (kex) between the two pools should be less than the chemical shift difference between the two pools (Δω). Considering this criterion, various labile proton-containing ligands such as −SH, −OH, and −NH,298 which were used to increase Δω value, have been integrated with paramagnetic lanthanide299 or transition-metal complexes to form most PARACEST agents. Thanks to the paramagnetic effect of such metal ions, the 1H NMR signals of these protons exhibit extremely large chemical shifts depending on the distance and geometric orientation between the metal ions and proton-containing ligands. Typically, the final CEST effect is dependent on numbers of parameters, including kex, the relaxation time of the exchanging pools, and power of the applied presaturation pulse (B1). Supposing that the exchangeable proton pool is completely saturated, the net magnetization of bulk water protons (Mz/ M0) at steady-state can be expressed as eq 2, in which c is the concentration of the contrast agent, q is the number of exchanging water molecules, and τM is the residence lifetime (τM = 1/kex). If the parameters included in the eq 2 differed in hypoxic and normoxic conditions, they can be used to design a hypoxia-responsive PARACEST agent. Typically, τM and T1 are the most commonly used hypoxia-sensitive parameters.297

(Figure 33c) are significantly different. As a result, the reduction microenvironment-triggered signal can be used to monitor the degree of hypoxia. And under normoxic conditions, the corresponding signal became hardly detectable, almost the same as without incubation (Figure 33d). To further demonstrate the potential application of the probes in vitro, they evaluated the reduction efficiency of the probes in a human cell line A549 cells. As shown in Figure 33 (panels e and f), upon normoxia treatment, no F−OH signal can be detected while an intense IQ-F signal emerged. In sharp contrast, upon hypoxic treatment, the F−OH signal increases continuously along with an obvious decrease in IQ-F signals. As a result, the reduced process of IQ-F in hypoxia conditions can be monitored by 19F MRI in the real time. Very recently, Que et al. designed a probe based on fluorinated Cu-ATSM scaffold for sensing cellular hypoxia using 19F MRI (Figure 34).294 Cu-ATSM is widely used as a radioactive complex for PET imaging of hypoxia since it is a cell permeable complex that will preferentially accumulate in hypoxic cells accompanied by the reduction of Cu2+ to Cu+. By incorporating fluorine atoms proximal to the Cu2+, they found that the NMR/MRI signal was turned off because the paramagnetic effect of Cu2+ will lead to the shortened T2 relaxation time of interacting 19F nuclei. Under hypoxia conditions, the T2 relaxation time will be prolonged along with the reduction of Cu2+ to Cu+ as well as further ligand dissociation, turning the signal “on” via a paramagnetic relaxation enhancement mechanism.295 Since Cu-ATSM scaffold had been approved by U.S. Food and Drug Administration for clinical applications, further improvements in the fluorine density and hypoxia targeting of these scaffolds

Mz /M 0 = (1 + c*q*T1/55.5*τM)−1 6184

(2) DOI: 10.1021/acs.chemrev.6b00525 Chem. Rev. 2017, 117, 6160−6224

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4.4.2. Change of T1 Relaxation Time. Apart from τM, T1 value of bulk water pool can also influence CEST signal intensity, which can also be utilized to design the hypoxiasensitive CEST probes. For example, Kovacs et al. designed a Eu3+-(DOTA-tetraamide) complex consisting of two nitroxide free radical groups.303 Nitroxides conjugation can shorten the T1 relaxation time of bulk water protons because they have only one unpaired electron.304 Under hypoxia conditions, the probes could be easily reduced to diamagnetic hydroxylamines, resulting in the restoration of the T1 signal, and in the meantime, the CEST signal was found to be greatly enhanced (Figure 36, panels a and b). Hence, such CEST signal changes

4.4.1. Change of Water or Proton Lifetime τM. Of all Ln3+ complexes, Eu3+ complexes linked with DOTA-tetraamide ligands have been commonly utilized to design PARACEST probes as they typically exhibit the slowest water exchange rates.300 The metal-bound water exchange rate is extremely sensitive to the electronic effects of the ligand pendant arms, providing a great chance for designing hypoxia-sensitive PARACEST probes. Sherry et al. demonstrated that the reduction of a Eu3+ complex bearing a p-nitro group to p-amino derivative will trigger the alteration of the water exchange rate (Figure 35a).301

Figure 35. (a) CEST images between the oxidized (p-NO2) and reduced (p-NH2) forms of EuDOTA-tetraamide complexes differentiated by MR imaging. Reprinted from ref 301. Copyright 2008 American Chemical Society. (b) CEST spectra of the oxidized (blue) and reduced (red) forms of the improved EuDOTA-tetraamide complexes with two quinolinium moieties. The inserted PARACEST images were acquired from a phantom containing four tubes: (A) 20 mM of the probes dissolved in the buffer, (B) the probes plus 2 equiv of NADH in the buffer, (W) water, and (H) the buffer at pH 7. Reprinted from ref 302. Copyright 2012 American Chemical Society.

Figure 36. (a) CEST spectra and (b) images of Eu complex Eu3+(DOTA-tetraamide) before (blue) and after (red) the reduction with L-ascorbic acid. (c−k) CEST images of the bladder from a female black mouse. Top row: preinjection spin−echo images with saturation at (c) −43 ppm and (d) + 43 ppm. (e) The CEST difference image was obtained by subtracting (d) on-resonance image from the (c) offresonance image. Middle row: similar (f) off-resonance, (g) onresonance, and (h) difference images of the same mouse in 10 min after intravenous injection of Eu complex. Bottom row: (i) offresonance, (j) on-resonance, and (k) difference image in 1 h after the intravenous injection of L-ascorbic acid. Reprinted from ref 303. Copyright 2013 American Chemical Society.

Their results indicated that compared with the reduced form (p-NH2), the oxidized form (p-NO2) exhibited 30% higher CEST signal intensity. The CEST signal intensity decrease by the reduction is due to fact that τM of an electron-withdrawing group p-NO2 was longer than that of an electron-donating group p-NH2. However, this proof-of-concept probe meets difficulties in hypoxia imaging in vivo because the detection range of this probe is out of the biologically relevant range. To make these probes more sensitive to hypoxia, the same group developed another PARACEST redox probe containing two functional N-methylquinolinium moieties as hypoxia-responsive groups.302 Under hypoxia conditions, quinolinium group will be reduced to the dihydroquinoline derivative, resulting in the increase of water exchange lifetime from 78 to 130 μs by changing the coordination environment around the lanthanide ion. As a result, the CEST signal intensity increased dramatically once in hypoxic conditions (Figure 35b).

modulated by T1 relaxation can be utilized to differentiate normoxia and hypoxia environments. When the probes were intravenously injected into healthy mice, they can be detected in the bladder very fast because of the efficient renal filtration. No CEST signal can be observed in the bladder despite the slightly brighter T1-MR images evidenced the presence of the oxidized agents (Figure 36, panels c−e). After the subsequent injection of reductive substance L-ascorbic acid, the complex was subsequently reduced in vivo, leading to the enhanced CEST in the bladder due to the generation of diamagnetic hydroxylamine (Figure 36, panels f−k). This work shed light on 6185


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atoms in MnO2 nanosheets are in the valence state of +4, making no contribution to both longitudinal and transverse relaxation of water protons. As a result, compared with free Mn2+ ions, the MnO2 nanosheet is a low-performance T1weighted contrast agent. In the meantime, the fluorescence emitted from the adsorbed aptamers can be largely quenched by the black MnO2 nanosheet. Therefore, in the absence of the hypoxia microenvironment, both the fluorescence and MRI contrast of the probes are quenched. However, in the presence of hypoxia, endocytosed MnO2 nanosheets can be reduced to transparent free Mn2+ ions in aqueous solutions, which activate the recovery of both fluorescent and T1-weighted MR signals. Such a platform facilitates the further exploration of the probes whose dual bimodalities (fluorescence/MRI) can be activated by hypoxia. Alternatively, it will be more desirable in certain cases to develop dual-mode hypoxia-sensitive imaging probes in which one contrast signal can be detected only after the disappearance of the other. In this case, the confusing effects of the unknown and often heterogeneous distributions of contrast agents during hypoxia detections can thus be greatly minimized. However, few literature has reported such hypoxia-activated dual-mode probes due to technical challenges. Louie et al. rationally designed and synthesized such a kind of activatable T1-weighted MRI/optical contrast agent (Figure 38a) containing a macrocycle-based gadolinium complex, in which the two modes are reversibly sensitive to hypoxic microenvironment.314 In the normal physiological environment, the open acyclic merocyanine isomer of the probe exhibits a strong visible fluorescence. While in the presence of hypoxia, the probe underwent isomerization to its closed spirocyclic isomer, which resulted in the disappearance of fluorescence because the extended π system was interrupted. In the meantime, r1 relaxivity increased by 54% because Gd3+ center was more accessible to water molecules, thus increasing the hydration number of Gd3+ to 2.01 ± 0.05.315 When the microenvironment was rich in hydrogen peroxide, the formerly reduced ring-closed form under hypoxia would be reoxidized to the initial ring-open merocyanine form. As a result, such signal changes could be reversible. Activatable fluorescent probes have been widely used for fluorescence-guided surgery,316−318 which enables the fast and accurate positioning of hypoxic tumors owing to its inherent advantages such as fast feedback and high sensitivity. Hence, for the convenience of surgery, it is more preferred that the optical signal from the dual-mode probes can be intensified in response to hypoxia, followed by the confirmation of hypoxic degree by MRI. Johnson et al. reported hypoxia-responsive branchedbottlebrush copolymer nanoparticles that possess a high density of nitroxide and a NIR dye for MRI and optical imaging, respectively (Figure 38b).319 These probes were prepared using ring-opening metathesis polymerization reactions between Cy5.5-conjugated macromonomers and spirocyclohexyl nitroxide.320 Nitroxides are widely known for the capability in quenching excited singlet states by catalyzing intersystem crossing reactions.321 In addition, nitroxides have also been proven to be effective “organic radical contrast agents” for MRI.322 Hence, the probe consisting of dense nitroxide backbone will exhibit high MRI performance and simultaneously quench the Cy5.5 fluorescent emission. In response to hypoxia-induced physiological reduction environment, the nitroxides can be quickly reduced to diamagnetic hydroxylamines,323 which leads to decreased MRI contrast and an

the design of hypoxia-sensitive PARACEST probes which can report the hypoxic degree of tissues and cells in vivo. From the viewpoint of clinical applications, it is more preferred that the developed probes are capable of imaging hypoxia-normoxia cycles reversibly. Bearing this in mind, Morrow et al. first reported a hypoxia-activated PARACEST agent, Co complex, that can generate PARACEST-on or PARACEST-off signals (Figure 37) when they are in the

Figure 37. Structures of Co2+/Co3+ complexes and CEST spectra recorded at 11.7 T of [Co(TPT)]2+ and [Co(TPT)]3+ solutions, respectively. Reproduced with permission from ref 305. Copyright 2013 Wiley-VCH.

paramagnetic or diamagnetic states.305 In detail, magnetic properties of Co2+/Co3+ metal redox couples varied substantially in hypoxia or normoxia conditions.306 Co2+ as a primary metal ion shift agent is very suitable for PARACEST imaging.307,308 Whereas Co3+ can not generate PARACEST effect due to its diamagnetic nature. Further conjugation of triazamacrocycle on Co species will not only offer an enhanced stability but also be beneficial for the construction of PARACEST agents because the pyrazole NH protons are away from the transition-metal center.309 Their results indicate that the paramagnetic Co2+ form can produce a highly shifted CEST signal at 135 ppm. Such a significant shift will contribute to the enhanced signal-to-noise ratio since the interference from tissues magnetization transfer effects can be largely minimized. Further efforts can be made to develop ratiometric PARACEST agents to overcome the dependence of CEST imaging contrast on the probe concentrations and distributions in tissues. 4.5. Hypoxia-Sensitive Dual-Mode Imaging Probes

Though the above-developed probes in response to hypoxia have great potentials in the future clinical applications, such signal intensity changes in response to hypoxia may not be one hundred percent reliable due to the possible false positive contrast caused by the fluctuations of the probe concentration and many other environmental variables. If one imaging probe can report the hypoxia degree by two imaging modes simultaneously, more convincing and accurate assessments of hypoxia can be achieved than a single imaging modality. In particular, dual-mode imaging agents capable of both anatomic and functional imaging will provide powerful and complementary information for reliable clinical diagnosis for hypoxia. 310,311 Taking into account of all the above considerations, MRI/fluorescence bimodal strategies can be an attractive combination because the disadvantages of each imaging mode can be offset by the companion.312 Tan et al. first developed a hypoxia-responsive fluorescence/ MRI bimodal platform by combining Cy5 photoluminecent molecules with manganese dioxide (MnO2) nanosheet.313 Mn 6186


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magnetic contribution of the agent to the water proton relaxation and chemical exchange saturation transfer.325 Terreno et al. reported the first T1-CEST liposomal dual mode agent by modifying a commonly used lipoCEST agent with paramagnetic Gd3+ complexes (Figure 39).326 Liposomes

Figure 39. (a) Schematic illustration of a dual-modality T1/CEST agent. The Gd-units can be rapidly washed out from the Gd3+ complexes under hypoxia microenvironment, which resulted in the disappearance of T1 signal and the simultaneous activation of CEST contrast. (b) MR images recorded at 7 T of (1) LipoCEST-PDP, (2) LipoCEST-SH, (3) LipoCEST−S−S-Gd, and (4) sample 3 after the reduction with TCEP and the removal of the detached Gd-DO3A-SH complex. Left: T1w image. Right: CEST map upon irradiation at 3.5 ppm overlaid to a T2w-image of the phantom. Reprinted with permission from ref 326. Copyright 2011 Royal Society of Chemistry.

Figure 38. Hypoxia detection by MRI/fluorescence bimodal imaging. (a) In the presence of NADH, a macrocycle-based gadolinium complex undergoes isomerization, resulting in an increase in r1 relaxivity by 54%, while the intense fluorescence disappeared. Reproduced with permission from ref 314. Copyright 2009 WileyVCH. (b) Schematic illustration of the dual-modality molecular imaging in response to nitroxide reduction. (c and d) Fluorescence images of a whole mouse (c) before and 30 min (d) after the probe injection, indicating the recovered fluorescence by surrounding nitroxides. (e and f) MR images of whole mouse (e) before and (f) 30 min after probe injection with specific organs/tissues outlined for reference. The low MRI contrast in liver could be ascribed to the ascorbate-induced nitroxide reduction, corresponding to a strong fluorescent emission observed in the liver. Reproduced with permission from ref 319. Copyright 2014 Nature Publishing Group.

themselves exhibit strong CEST effect because protons existed in liposomes are not exchangeable with water molecules due to the generated barrier from the lipid membrane. Once Gd-based reagents are loaded on the surface of liposomes, two water peaks can be generated in the water proton signal, which are from intraliposomal water and extraliposomal bulk water, respectively. The signal intensity of extraliposomal water will decrease due to the selective magnetization saturation of intraliposomal proton resonance, thus quenching or even silencing the CEST effect. Hence, T1-MR signal will be generated while the CEST contrast is silenced under normoxic conditions. Once under hypoxic microenvironment, the coated Gd3+ will be removed, resulting in the disappearance of T1-MR signal and the restoration of CEST contrast signal. As a result, this dual probe can report hypoxic degree by two MR signals, in which the CEST signal can only be detected after the disaperance of the T1-MR signal. Such a probe exhibits a distinctive advantage that the hypoxia will be quantitatively monitored by two different modes with high spatial and temporal resolutions on the same machine, which will be highly useful for the clinical application in the future. As an alternative noninvasive strategy, MRI has been increasingly used in clinical diagnostics thanks to their exceptional spatial resolution (80000 per particle). The absorbed energy will release as heat due to the highly self-quenching character of porphyrin excited states, which qualifies porphysomes as PTT agents with exceptional properties. As a result, the monomeric porphyrin photosensitizers useful for PDT can be assembled to porphysomes efficient for PTT enhancement. The in vivo results clearly indicate that porphysome-assisted PTT achieves the best therapeutic effect since such a strategy will treat tumors whether they are hyperoxic or hypoxic. In contract, either photofrin-assisted or porphysome-assisted PDT achieves poor treatment effect 6196


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excited by NIR light. These agents may play more and more important roles in the fight against hypoxic tumors in the future. As another rational strategy to combine PDT and PTT, Akkaya and Yoon et al. integrated gold nanorods and an anthracene endoperoxide derivative into one system (Figure 54).468 Endoperoxides were proven to be the reliable chemical

because they are therapeutically inactive under hypoxia microenvironment (Figure 52b-e). Since PDT and PTT are two major phototherapeutic approaches, it will undoubtedly be of significance to develop the therapeutic agents which can generate both PDT and PTT effects under light irradiation. In the past decade, various materials systems, such as plasmonic nanoparticles,444−447 carbon nanomaterials,448−451 single-layer two-dimensional nanomaterials,452−454 as well as organic nanoparticles encapsulated NIR-absorbing dyes 455−457 have been intensively investigated for hyperthermia agents. To achieve combined PTT/PDT, various nanoplatforms have been constructed by combining photosensitizers with photothermal components into one system. In these nanoplatforms, two different light sources are often utilized due to the absorption mismatch between photosensitizers and photothermal components.458−461 To perform simultaneous PTT/PDT treatments upon single laser irradiation, Chen et al. connected a traditional photosensitizer Chlorin e6 (Ce6) to the gold nanostar via covalent bond (Figure 53).462 They further tuned the localized surface

Figure 54. Photothermal-induced photodynamic concept. Top: Synthesis of gold nanorod functionalized with the anthracene endoperoxide derivative. Bottom: Upon NIR exposure, gold nanorods generate plasmonic heating, leading to thermal cycloreversion of the endoperoxides to yield singlet oxygen. Reproduced with permission from ref 468. Copyright 2016 Wiley-VCH.

sources which can generate singlet oxygen upon heating with high chemical yields.469 When gold nanorods tethered with endoperoxides were irradiated at 808 nm, local heat generated by gold nanorods could initiate thermal cyclo-reversion of the endoperoxides, resulting in the generation of singlet oxygen. The half-lives of endoperoxides can reach as long as several years at room temperature.470 However, they can be rapidly decomposed by cyclo-reversion when heated. The authors demonstrated that the produced singlet oxygen in this way was sufficient for triggering apoptosis in cell cultures. Such a thermally controlled generation of singlet oxygen via endoperoxide-based therapies is not O2-dependent, which can overcome the inherent limitations of PDT and may open a new avenue for the development of synergetic PTT/PDT therapeutic agents. It is anticipated that the continuous supply of O2 during the synergetic hypoxic cancer therapy will result in much enhanced therapy outcomes. For example, Chiu et al. encapsulated both photosensitizers and superparamagnetic iron oxide nanoparticles into the polymer O2 bubbles (Figure 55).471 Under the treatment of the high frequency magnetic field, hyperthermia from the iron oxide nanoparticles could activate the release of both O2 and photosensitizer from polymer bubbles. Subsequent irradiation with red light laser can trigger efficient PDT, thus achieving the O2 self-enriched synergetic magnetothermal/photodynamic therapy. After staining of tumor sections from tumor-bearing mice with hypoxia indicators, they found that therapeutic monocytes significantly accumulate in tumor hypoxia regions via chemotactic recruitment, which

Figure 53. Schematic illustration of Ce6-conjugated gold nanostars for the coordinated PDT/PTT treatment upon single laser irradiation. Reproduced with permission from ref 462. Copyright 2013 WileyVCH.

plasmon resonance of gold nanostar to make the absorption wavelength of gold nanostar and Ce6 overlap with each other. Upon NIR laser irradiation, the PDT efficiency of the anchored Ce6 component decreases over time due to the appearance of PDT-induced hypoxia environment, while the O2-independent PTT effect gradually intensifies upon irradiation because the stable gold nanostar in the nanoconjugates can enable photoinduced thermal accumulation over time. It has been confirmed that by varying irradiation time duration, the early phase PDT effect can be tuned to be well-coordinated with the late-phase PTT effect to achieve sustained synergetic cancer therapy efficacy. In recent years, we have witnessed the rapid development of theranostic agents which can perform simultaneous PDT and PTT treatments by loading photosensitizers on nanostructures,463−467 most of which can be 6197


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Figure 55. Schematic illustration of the delivery of O2-filled therapeutic bubbles to tumor hypoxia via tumor-tropic monocytes for simultaneous photodynamic and magnetothermal therapy. Both superparamagnetic iron oxide nanoparticles and photosensitizers were encapsulated in the polymer O2 bubbles. Under external high frequency magnetic field and red light excitation, significant apoptosis can be observed for therapeutic agents incubated cancer cells due to the combined effects of the O2 self-enriched PDT and magnetic hyperthermia. Reprinted with permission from ref 471. Copyright 2015 Elsevier Ltd.

functional theranostics by decorating silica-coated UCNPs with CuS nanodots (Figure 56a).493 The elements (such as Yb, Gd,

enabled the subsequent hyperthermia and PDT treatments to take place in the desired hypoxic tumor areas following the activations of both high frequency magnetic field and laser illumination. Since tumor hypoxic areas are always located in the deep tissues, the magnetic field-triggered synergetic therapy can be more promising compared with the phototriggered one because such an excitation source is virtually free from the restriction by penetration depth. Fortunately, various functional nanomaterials have been explored to convert the penetration-independent energy source such as magnetic field,472−476 radiofrequency,477−479 microwave,480−482 and ultrasound483,484 to heat, which have also been used to generate local heating for tumor repression. In the future, the development of nanoagents which can generate both heat and ROS under the trigger of these penetration-independent energy sources can be promising for the clinical applications. 6.1.3.3. Combined Photothermal Therapy with Radiotherapy. As another attractive strategy to achieve synergetic therapy, the combination of PTT with RT is particularly suitable for treating hypoxic tumors owing to the following advantages. First, high temperature heating generated by PTT can directly induce direct cell necrosis. More attractively, the mild PTT is able to improve oxygenation level by boosting the blood flow in the tumor, which can be very beneficial for the overcoming of hypoxia-associated radio-resistance.485,486 To achieve combined PTT/RT, the simplest way is to construct multifunctional composite nanomaterials by the integration of PTT agents and radiosensitizers into one composite. Since CuS nanoparticles have been widely used as photothermal agents because they can transfer NIR laser into the local heat for the effective ablation of cancer cell,487,488 recent research has been focused on the integration of CuS nanoparticles with radiosensitizers. For example, the development of radionuclide-labeled photothermal agents, such as recently reported 64CuS NPs489 and 131I labeled CuS490/reduced graphene oxide,491 can be an effective way to achieve combined PTT and RT in a single nanoplatform. Such radionuclides can generate high-energy Xray, which will kill cancer cells due to the radio ionization effect.492 As another example, our group constructed multi-

Figure 56. (a) Schematic illustration of the multifunctional core/ satellite nanotheranostic agent by decorating silica-coated UCNP with CuS nanodots to integrate PTT with RT for improved cancer therapy. (b) Time-dependent tumor growth curves of mice receiving varied treatments. (c) The photographs of mice after the treatment (group 7), which indicated that the tumor can be completely eradicated with no obvious recurrences in at least 120 days. Reprinted from ref 493. Copyright 2013 American Chemical Society.

and Er) with high atomic number existing in the theranostics can be served as radiosensitizers to cause a significant enhancement of local radiation dose around the theranostics. In addition, the upconverted UV/vis emissions from UCNP cores can excite the coated CuS nanoparticles outside, inducing a strong PTT effect. As shown in Figure 56 (panels b and c), after thorough eradication of the tumor in 4 days, they did not show subsequent recurrence within 120 days. Clearly, the hyperthermal effect-induced reoxygenation greatly contributed to this outstanding therapy outcome by mitigating possible hypoxia in the interior of solid tumors. As another advantage of this design, radioresistant S-phase cells, considered to be the 6198


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least sensitive to radiation in the cell replication cycle, can be effectively killed by the lethal effects of hyperthermia. As a result, such an integration between photothermal agents (CuS NPs) and radiosensitizers (UCNPs) can generate a powerful therapeutic effect, which may aid in the tumor eradication by making use of their respective advantages while avoiding their individual disadvantages. With the rapid developments in nanomaterial synthesis, researchers have explored various single nanosystems exhibiting both PTT and RT effect. As a representative example, Hu et al. synthesized ternary semiconductor Cu3BiS3 nanocrystals by a solvothermal route.494 Such a single nanocrystal inherited the features from their binary parents. CuS serves as an efficient NIR-triggered photothermal agent due to its strong NIR absorption, while Bi2S3 exhibits efficient radiosensitizing effect thanks to the enhanced X-ray attenuation coefficient of bismuth.495 Consequently, Cu3BiS3 nanocrystals alone showed responses to either NIR or X-ray excitation. Besides CuS, transition metal dichalcogenides such as WS2 and MoS2496 have also been utilized as novel NIR-responsive photothermal agents. As for WS2, apart from their PTT effect, the high-Z tungsten element could sensitize RT by concentrating the radiation dose in the tumor. Hence, Zhao et al.497 prepared ultrasmall WS2 QDs with an average diameter of 3 nm, which can be utilized for remarkable synergistic PTT/ RT tumor treatment. It is worth mentioning that ultrasmall WS2 QDs were synthesized by a facile and “green” method, which utilized physical grinding, ultrasonication, and H2SO4 intercalation to break the weak interlayer van der Waals interactions. After prolonging the ultrasonication process, the size of the products could be gradually reduced to a few nanometers. Thanks to their ultrasmall sizes, it was demonstrated that these nanoparticles could be excreted through the kidney, thus greatly minimizing the potential side effects of WS2 QDs. Compared to nanocrystals, two-dimensional nanomaterials such as WS2498 have been demonstrated to be more efficient photothermal agents for cancer treatment. For example, our group has recently synthesized two-dimensional Bi2S3/MoS2 composite nanosheets for combined tumor PTT and RT.499 MoS2 nanosheets have attracted great attention in tumor PTT due to the strong NIR absorbance,500−502 while Bi2S3 shows a dose-enhancement capability in tumor RT thanks to the high X-ray attenuation effect of Bi.503,504 In clinical applications, it will be more favorable if the theranostic agents can be simultaneously served as multimodal imaging agents, which could provide valuable information in guiding the cancer treatment. However, most of the previous transitional metal dichalcogenides-based nanoagents have fixed chemical compositions because they were often synthesized by the exfoliation of their bulk counterparts,505−508 which is unfavorable for their multifunctionalization via doping with other elements of interest. To solve this problem, Liu et al. developed a bottom-up method to prepare high-quality WS2 nanoflakes intrinsically doped with Gd3+, facilitating imagingguided combination therapy of cancer (Figure 57a).509 In this nanostructure, strong contrast in T1-weighted MR imaging can be obtained by the doped Gd3+ ions. In the meantime, both Gd and W elements can strongly attenuate X-ray irradiation, resulting in CT imaging. In addition, PA imaging can also be performed due to the strong NIR absorbance of WS2. Hence, single WS2 could serve as both therapeutic agents for combined PTT/RT and multimodal imaging agents for MR/CT/PA.

Figure 57. (a) Schematic illustration of Gd3+-doped WS2 nanoflakes for the synergistic cancer therapy and simultaneous multimodal bioimaging. (b) Representative immunofluorescence images of tumor slices. The nuclei, blood vessels, and hypoxic areas were stained with DAPI (blue), anti-CD31 antibody (red), and antipimonidazole antibody (green), respectively. Tumor hypoxia could be markedly alleviated by the mild PTT from Gd3+-doped WS2, particularly for tumor cells near blood vessels, which would be beneficial for the subsequent RT. Reprinted from ref 509. Copyright 2015 American Chemical Society.

After systemic administration of the nanotheranostics into tumor-bearing mice, the tumor could be accurately positioned under the assistance of trimodal MR/CT/PA imaging. Interestingly, it was found that the tumor treated with both WS2 and NIR showed a clearly weakened hypoxia compared to single WS2 treatment, proving that mild hyperthermia can effectively alleviate the tumor hypoxia by promoting tumor blood flow (Figure 57b). Such a phenomenon may subsequently contribute to the overcoming of hypoxiaassociated radio-resistance during the synegetic therapy. As another solution, Liu et al. proposed a new strategy for the synthesis of multifunctional MnSe@Bi2Se3 core−shell nanostructures via cation exchange (Figure 58a).510 First of all, MnSe nanocrystals were premade as templates. During the cation-exchange process, Mn species in the outer layer of MnSe can be replaced by Bi to form a Bi2Se3 shell based on the fact that manganese chalcogenides have a much higher solubility than bismuth chalcogenides.511 In such a system, the MnSe core functions as a contrast agent for T1-MRI because Mn2+ possesses five unpaired 3d electrons.270,272 In addition, the Bi2Se3 shell provides the nanotheranostic with the capability of enhanced RT and efficient PTT thanks to their high absorption of ionizing radiation and NIR (Figure 58, panels b−e). In a recent work, the same group further constructed hollowstructured Bi2Se3 nanoparticles, which can not only absorb both X-ray irradiation and NIR light but also load perfluorohexane compounds acting as an O2 reservoir.512 After being saturated with O2, the obtained nanoparticles can release O2 and 6199


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Figure 58. (a) Schematic illustration of the MnSe@Bi2Se3 core−shell nanoprobes by cation exchange and subsequent surface modification. (b) CT and MR imaging of the mouse bearing a tumor using MnSe@Bi2Se3−PEG. (c) IR thermal images of 4T1 tumor-bearing mice after the injection of PBS or MnSe@Bi2Se3−PEG under the 808 nm laser irradiation. (d) Tumor growth curves of mice after varied treatments. (e) Whole-body fluorescence imaging of tumor-bearing mice by intratumoral injection of hypoxia-sensitive fluorescence probe Ir-PVP or a mixture of MnSe@Bi2Se3− PEG and Ir-PVP. The images were taken before and after NIR irradiation. Reproduced with permission from ref 510. Copyright 2015 Wiley-VCH.

From the clinical view, it will be appealing that one can develop a photosensitizer which can also produce 1O2 species even in the tumor hypoxic microenvironment. The abovediscussed PDT mechanisms indicate that, compared to 1O2 generation from the type II mechanism, radical species produced from the type I mechanism will enable an enhanced PDT response in the hypoxia condition.523 As a result, it is apparent that the modulation of the PDT process from the type II to the type I mechanism will benefit the treatment of hypoxic tumors.524 For example, Gao et al. described a photosensitizer by incorporating 5,10,15,20-tetrakis(meso-hydroxyphenyl)porphyrin into a poly(2-(diisopropylamino)ethyl methacrylate) micelle serving as an electron reservoir, which can undergo type I photoactivation processes.525 The electron-rich micelles not only improve the biocompatibility of photosensitizer drugs526 but also facilitate type I reactions for PDT. As a result, though using a typical II photosensitizer agent, the domination in type I mechanism can still significantly intensify the production of O2•−, leading to the enhanced PDT efficacy in hypoxic microenvironments. Na et al. further designed a degradable photosensitizersconjugated chondroitin sulfate, which enabled type I PDTtriggered drug release (Figure 59a).527 The chondroitin sulfate528 composed of sulfate groups containing (β-1,3)-linked

simultaneously bring about significant DNA damage in cancer cells during synergetic RT and PTT. 6.1.4. Therapeutic Agents of Less Dependence on Oxygen Concentrations. Recently, PDT has received considerable attention due to their effectiveness in the treatment of tumor, cardiovascular, dermatological, and ophthalmic diseases.513−515 Traditionally used photosensitizers516 in PDT usually include porphyrin,517,518 5-aminolevulinic acid,519,520 and mono-L-aspartyl-chlorin e6, etc.521 In principle, upon specific light excitation, the sensitizers at the singlet state can be transformed into a relatively long-lived triplet state. Subsequently, the excited triplet can generate ROS via two kinds of reactions,522 which are type I (electron transfer) and/or type II (energy transfer) reactions. As for type I reaction, the excited triplet can react directly with a substrate such as cell membrane which offers a hydrogen atom or an electron, thus resulting in the formation of radical anion species (e.g., HO•, O2•−). Alternatively, the triplet can also transfer its energy to O2, forming activated singlet oxygen (type II reaction). Typically, conventional PDT process commonly undergoes type II reaction involving significant O2 consumption, which will inevitably lead to the drastically decreased antitumor therapeutic efficacy during continuous PDT treatment. 6200


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Figure 59. (a) Schematic illustration of chondroitin sulfate-based drug carriers comprising alternating units of (β-1,4)-linked D-glucuronic acid (GlcUA) and (β-1,3)-linked N-acetyl-galactosamine (GalNac). The electron-rich sulfate groups in chondroitin sulfate could elicit type I photochemical reaction of conjugated photosensitizers, and the generated ROS would further trigger the degradation of chondroitin sulfate. Therefore, under hypoxic tumor conditions, the ROS generated from light-irradiated photosensitizers in polysaccharide-based carrier can trigger the release of encapsulated drugs, thus enhancing the anticancer drug delivery efficiency. (b) Chemical structure of the drug carriers which could be depolymerized only under the conditions of both light irradiation and a hypoxic tumor environment. Reprinted with permission from ref 527. Copyright 2016 Elsevier Ltd.

N-acetyl-galactosamine as the carrier backbone and alternating units of (β-1,4)-linked D-glucuronic acid. The sulfate groups in chondroitin sulfate are rich in electrons, which will promote the type I photochemical reactions of the photosensitizers under hypoxic conditions. More importantly, the generated ROStype1 can efficiently trigger the degradation of chondroitin sulfate (Figure 59b).529,530 Such polysaccharide-based carriers will help to improve the drug delivery efficiency in tumor treatment thanks to their ROStype1-triggered degradation ability. To simultaneously overcome the O2-dependency of tumor therapy and limited penetration depth of light excitation, our group developed an X-ray-triggered PDT strategy through type-I pathway using H2O as the 1O2 source.531 In brief, octahedral Ce 3+-doped LiYF 4 scintillating nanoparticles (SCNP) and a semiconductor ZnO as an ionizing-radiationinduced PDT agent were integrated into one system by decorating ZnO nanoparticles on the surface of SCNP@dSiO2 (Figure 60a). Upon high-energy ionizing radiation, SCNPs can emit down-converted ultraviolet luminescence.532−534 Such an ultraviolet light can be immediately absorbed by the surfacebound ZnO nanoparticles because it matches well with the bandgap of ZnO nanoparticles. Subsequently, the excited ZnO nanoparticles535 can efficiently generate the hole (h+), which can further interact with the absorbed water molecules instead of O2 to form the highly reactive hydroxyl radicals (·OH) (Figure 60b). As shown in Figure 60 (panels c and d), under Xray irradiation alone, the viability of hypoxic cell remained unchanged in comparison to that of normoxic cells. In a sharp contrast, the treatment of the designed probes under X-ray irradiation can significantly kill both normoxic and hypoxic HeLa cells. As another attractive advantage of this therapy strategy, the excitation source X-ray completely overcomes the restriction of the penetration depth of visible or NIR light.536

However, generally speaking, the X-ray-triggered PDT modality is not satisfactory in terms of the 1O2 quantum yield, which generally results in the relatively lower efficiency of tumor inhibition compared to the distinct therapeutic responses induced from conventional PDT. Hence, the substantial enhancement of the scintillation quantum yield of SCNPs is a remaining challenge.537 Apparently, it will be more attractive to develop the smart photosensitizers which can switch between type I and II reactions during PDT depending on the hypoxic or normoxic microenvironment where the sensitizer is located. Rivarola et al. designed and synthesized a smart porphyrin-C60 dyad, which could generate biological photodamages through either type I reactions under low O2 concentration or type II reactions under sufficient O2 supplies.538 Inspired by this research, Shu et al. further designed an amphiphilic photosensitizer trismethylpyridylporphyrin-C70 (PC70) dyad539 via the coordination of “three-point” binding of C70 with D-TMPyP.540 Attractively, compared with D-TMPyP, PC70 can produce ROS more efficiently in hypoxia microenvironments. This phenomenon is due to the extremely long-life triplet state (211.3 μs) of PC70 under hypoxic condition, which provides long enough diffusion time for exiguous O2 to reach the activated (3P−C70)*. Subsequently, they can interact with each other to generate singlet state oxygen. As shown in Figure 61 (panels a and b), by monitoring the temporal decay of the triplet absorption band at 480 nm,541 the triplet lifetime of PC70 (1.86 μs) was found to be comparable to that of D-TMPyP (1.64 μs) under normoxic condition, which can result from the decay of the triplet states themselves. In a sharp contrast, a distinctive triplet decay behavior of much longer lifetime was observed for PC70 than DTMPyP under N2-saturated conditions. These results can be reasonably attributed to the formed exciplex due to energy 6201


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Figure 61. Transient absorption spectroscopic spectra of D-TMPyP and PC70 under (a) air-saturated and (b) nitrogen-saturated conditions, respectively. (c) The schematic illustration of the relaxation pathways of PC70 triplet state. The energy transfer between the excited D-TMPyP and the ground state C70 can form the exciplex which accounts for the longer lifetime of PC70. Though the diffusion rate of O2 was low under the hypoxia condition, the prolonged triplet lifetime of PC70 would still make it possible to photosensitize O2 in the ground state to generate singlet oxygen. Reprinted with permission from ref 539. Copyright 2015 Royal Society of Chemistry.

Figure 60. (a) Schematic illustration of the synthetic procedure for an ionizing-radiation-induced PDT agent by combining a scintillator and a semiconductor together. (b) Proposed mechanism for ionizing radiation-induced PDT. Under ionizing irradiation, the Ce3+-doped LiYF4 nanoscintillator emits the downconverted ultraviolet fluorescence, which can further excite ZnO nanoparticles to generate electron−hole (e−−h+) pairs, resulting in the production of biotoxic hydroxyl radicals. Viabilities of (c) normoxic and (d) hypoxic HeLa cells treated with ionizing-radiation-induced PDT agents for 24 h followed by various dosages of X-ray radiation (0, 2, 4, and 6 Gy). Reproduced with permission from ref 531. Copyright 2015 WileyVCH.

is important to explore functional nanoprobes that can selectively release therapeutic agents in hypoxia conditions. 6.2.1. Nitroaromatic-Containing Nanocomposites. As discussed in section 2.1, numbers of hypoxia-responsive moieties such as nitroaromatic or azo derivatives have been employed in the molecular design of diagnostic agents for hypoxia imaging. These hypoxia-sensitive groups can also be used for the development of hypoxia-triggered drug release systems. Of the derivatives investigated to date, 2-nitroimidazoles, which can be transformed to hydrophilic 2aminoimidazoles via a series of selective bioreductions under hypoxic conditions,553 have been the most widely utilized in the exploration of imaging agents and bioreductive prodrugs.554 By using hypoxia-sensitive group 2-nitroimidazoles, Park et al. prepared hypoxia-responsive nanoparticles composed of the polymeric backbones and 2-nitroimidazole derivatives, which enabled the release of anticancer drugs in hypoxic tumors (Figure 62).555 The selected polymeric nanocarriers can largely enhance the solubility and circulation durations of the loaded drugs.556 The 2-nitroimidazole derivative was chemically conjugated to the polymeric backbone through amide formation. Their cargoes can only be selectively released under hypoxic conditions since these carriers remain to be stable under normal physiological conditions. However, due to the insufficient sensitivity of these hypoxia-sensitive derivatives, it is difficult for these nanocarriers to be completely disassembled under hypoxia conditions. To surmount this issue, they further selected nitrobenzyl chloroformate as a hypoxia-sensitive molecule557 and prepared an amphiphilic block copolymer containing nitroaromatics, which will form micelles via self-assembly in normoxia but release anticancer

transfer from the excited DTMPyP to the ground state C70, as illustrated in Figure 61c. This clarifies why PC70 still remains the PDT capability to make cancer cells killed in the hypoxia microenvironment. 6.2. Therapeutic Agents Enabled by Hypoxic Microenvironment

Different from the above attempts to develop multifunctional probes which can overcome hypoxia microenvironment, the second approach in combating hypoxia is to develop hypoxiasensitive therapeutic agents by making use of the unique hypoxia microenvironment as an advantage for cancer treatment.542 Typically, significant advances have been made in the development of hypoxia-activated prodrugs,543 which can be selectively reduced to the desired cytotoxic species under hypoxic conditions while remaining inactive in normal tissues or tumors,544−546 and a number of them have now reached clinical trials.547 However, due to their limited ability in diffusing through tumor tissues to reach the hypoxic cells since hypoxic tumors are often hypoperfused, the efficacy of these developed prodrugs is rather limited548,549 though this barrier can sometimes be circumvented by antiangiogenesis-induced normalization of tumor vasculature.550,551 Fortunately, various nanoparticles acting as drug carriers can preferentially accumulate in tumor tissues via so-called enhanced permeation and retention (EPR) effect to different extents.552 Therefore, it 6202


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phototrigger that exhibits the capability of photodependent cleavage561 due to the high two-photon absorption cross section.562,563 Under normoxic conditions, any photoexcitation will be absorbed and relaxed to the nitroimidazole electron acceptor via photoinduced electron transfer, which will result in the quenched fluorescence and nontoxicity due to no photocleavage. Conversely, in hypoxic solid tumors, the coumarin phototrigger can be activated via hypoxia-specific nitro-to-amino reduction. Subsequent photoactivation will trigger the release of the caged anticancer drugs by waterassisted photoheterolysis of the C−O bond. In addition, blue fluorescence of the nanocarriers can be recovered. Such a careful design by using the internal stimulus (tumor hypoxia) to unlock the drug carriers and the external stimulus (photo irradiation) to release the loaded drugs, will shed some light on further development of hypoxia-specific drug delivery systems. 6.2.2. Azo-Containing Nanocomposites. In seeking for therapeutic agents for tumor treatment, a number of efficient drugs are hydrophobic, which greatly hindered their clinical applications.564 Recently, numbers of promising drug-delivery vehicles, such as liposomes,565 polymers,566 and hollowstructured nanoparticles,567−569 have successfully transported hydrophobic therapeutic agents into cancer cells. However, there are few examples which can release hydrophobic drugs in response to the hypoxic microenvironment to date. Zhang et al. developed azo-based micelles to release hydrophobic anticancer drugs quickly under hypoxia conditions (Figure 64).570 In

Figure 62. Schematic illustration of 2-nitroimidazole-containing drug carriers and in vivo tumor-targeting pathways. The nanoparticles could reach the tumor site via the EPR effect, followed by intracellular drug release at hypoxic tissue. Reprinted with permission from ref 555. Copyright 2014 Elsevier Ltd.

drugs in hypoxic conditions due to the complete disassembly of the nanocomposites. In clinical applications, effective chemotherapy should be able to differentiate and specifically kill hypoxic tumor cells. However, apart from tumor areas, many other biological tissues can also possess hypoxic regions.558,559 As a result, those hypoxia-responsive drug delivery systems may also release their cargoes during their ways to the hypoxic tumors. To achieve high therapy selectivity, it is more favorable that the carriers are able to release therapeutic drugs only at the desired hypoxic tumor areas rather than other hypoxic tissues. It is anticipated that combined internal (such as tumor hypoxia) and external (such as light illumination) stimuli can be an effective solution to this issue. Such a system can only be activated by both hypoxia activation and light irradiation. As a result, it may come true that anticancer drugs can be accurately released to hypoxic tumor tissues. For example, Zhu et al. constructed a smart nanocarrier for highly controllable release of anticancer drugs under both internal (hypoxia) and external (photo) controls (Figure 63).560 In their design, nitroimidazole, served as both an electron acceptor and a lock, was merged with a coumarin

Figure 64. Chemical structure of the PEG-C6-AZO-CA4 molecule and schematic illustration of PEG-C6-AZO-CA4/DOX micelle as a codelivery platform for CA4 and DOX. In hypoxic tumors, CA4 and DOX can be rapidly released from the PEG-C6-AZO-CA4/DOX micelles. CA4 can inhibit tubulin polymerization, while DOX can diffuse into the nucleus to kill cancer cells. Reprinted with permission from ref 570. Copyright 2015 Royal Society of Chemistry.

detail, an azo bond, as a linker which can be cut off under hypoxic environment, was used to conjugate with PEG and an anticancer drug combretastatin A-4. These molecules can form micelles via self-assembly with hydrophobic anticancer drugs encapsulated. They further demonstrated that two kinds of hydrophobic drugs (combretastatin A-4 and DOX) could be simultaneously loaded into the micelles and subsequently released under hypoxia microenvironment. As one of the promising strategies, gene therapy aims to treat diseases at the genetic level by introducing genetic therapeutic agents such as oligonucleotides, RNA, or DNA into their intracellular target site.571−575 To achieve efficient gene therapy, the clinicians are facing a number of principal

Figure 63. Schematic illustration of hypoxia-activated and phototriggered drug release system based on chitosan nanoparticles. Only under unique tumor-hypoxia conditions, the locked probes would be reduced and unlocked. Thus, upon subsequent visible light or twophoton NIR excitation, the caged drug can be triggered to release. Reproduced with permission from ref 560. Copyright 2013 WileyVCH. 6203


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challenges such as (1) possible degradation of the delivered genetic therapeutic agents during their way to the target, (2) undesired prerelease of genetic therapeutic agents into endosomes or lysosomes, and (3) biological obstacles faced by genetic therapeutic agents when they cross the cytoplasm and penetrate the nuclear membrane barrier to enter the nucleus. In the past decade, various nonviral gene nanocarriers such as liposomes,576 polymer,577,578 and inorganic-based nanoparticles (e.g., silica-based nanoparticles,579,580 gold nanorods,581 metal oxide nanoparticles,582 and QDs583) with appropriate surface modification have been developed to overcome these challenges. It should be mentioned that such a gene expression system is an inducible system but not an on/off one. This fact suggests that side effects can always happen due to a possibility of leaky expression. Therefore, it will be more promising to develop stimuli-responsive systems that can release the genetic therapeutic agents only in the target site.316−318,584,585 In the past decade, various hypoxia-sensitive gene delivery systems, which can respond to the unique characteristics of tumor hypoxia microenvironments, have been well-established.586,587 Such hypoxia-inducible regulatory systems may be useful techniques to enhance the efficacy of gene therapy. However, delivery of siRNA to hypoxic tumor regions is very challenging since they are isolated from blood vessels. Recently, Torchilin et al. developed a gene nanocarrier consisting of 1,2dioleyl-sn-glycero-3-phosphoethanolamine (DOPE) units, azo, PEG2000, and PEI for the hypoxia-triggered uptake of siRNA.588 The two ends of azo were anchored with a PEIDOPE conjugate and PEG2000, respectively (Figure 65a). The formation of micellar nanoparticles can be achieved by the complexation of PEI-DOPE conjugate with siRNA. PEG2000 as the hydrophilic block can not only endow siRNA with enhanced stability but also protect siRNA from the nuclease attack.589 In the hypoxic tumor environment, PEG groups will detach from micellar nanoparticles due to the degradation of azo (Figure 65b). Therefore, the residual PEI-DOPE/siRNA complexes will be effectively taken up by the cells thanks to the exposure of PEI’s positive charge, thus achieving their silencing activity (Figure 65c). Such hypoxia-sensitive gene delivery systems will lead to the up-regulated gene expression with high specificity. Once blood supply is recovered, the O2 supply can down-regulate the expression of the therapeutic genes. As a result, the risk of of gene overexpression in normal tissues can be largely decreased, thus contributing to the reduction of side effects. However, the hypoxia-sensitive gene expression systems should be further improved to ensure their safe use because there are a number of other organs that also have regions of low O2 concentrations. In our opinion, the combination of hypoxia-targeting carriers590 with hypoxia inducible expression system may further enhance the specificity of gene therapy, thereby providing an exciting opportunity for tumor-specific gene therapy of cancer. 6.2.3. Hypoxia-Generating and Subsequently Activatable Nanocomposites. It is known that presently welldeveloped hypoxia-activatable prodrugs will become more toxic when the microenvironment becomes more hypoxic. By making use of the traditionally unwanted PDT-induced hypoxia microenvironment, our group combined PDT with bioreductive pro-drugs to achieve the synergetic therapeutic effect for hypoxic tumors.591 To achieve this, we first constructed a nanoplatform composed of UCNP core and double layers of silica shell (dense and mesoporous silica shells) (Figure 66a).

Figure 65. (a) Schematic illustration of the polymers structure and (b) internalization mechanism of the probes in hypoxic tumor microenvironment. The designed nanocarrier consisted of PEG 2000, azo, PEI, and DOPE units. The hypoxia-induced siRNA uptake could be realized with high sensitivity and specificity due to the degradation of the azo linker. (c) CLSM images of HeLa/GFP cells transfected with GFP siRNA, PEG-Rhodamine-PEI-DOPE (PRPD), and Rhodamine B labeled copolymers PEG-Azo-Rhodamine-PEI-DOPE (PARPD) under normoxia or hypoxia. Reproduced with permission from ref 588. Copyright 2014 Wiley-VCH.

The photosensitizers silicon phthalocyanine dihydroxide592 for NIR-triggered PDT were incorporated into the middle dense silica layer while pro-drugs TPZ were loaded in the mesoporous channels of the outer mesoporous silica layer. During PDT in response to 980 nm NIR excitation, a large amount of ROS can be generated to kill cancer cells. More importantly, the created hypoxic microenvironment due to photochemical O2 depletion of PDT can activate the cytotoxicity of TPZ (Figure 66b) to hypoxic cancer cells. Compared to tumors subjected to PDT alone, the growth of tumors treated with the nanoprobes plus NIR laser was far more remarkably suppressed. This result indicates that the released TPZ greatly contributes to the treatment outcomes thanks to the enhanced therapeutic effect of TPZ in hypoxia conditions (Figure 66c). Thus, such a PDTinduced intratumoral hypoxia will be a highly effective aid in potentiating the bioreductive therapy. This design concept can serve as a general strategy for the enhancement of O2dependent therapy effect. As an alternative example, Gu and Shen et al. designed a conjugated polymer which can make use of PDT-induced hypoxia to trigger anticancer drug release via the dissociation of 6204


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based on the thorough understanding of the behaviors of hypoxic tumors, various innovative strategies have been explored aiming at the effective hypoxic tumor treatment by taking advantages of functional nanomaterials. However, despite these recently significant progresses and promising results, most attempts still remain in the proof-of-concept stage. Before the successful translation of these concepts from the bench to the bedside, there have been great challenges facing the researchers in the field. Here, we outline several possible aspects in future research on the interface between materials chemistry and biology toward accurate imaging and effective treatment of hypoxia. (1) In optical hypoxia imaging, the intensity measurement at a single wavelength is the last and least preferred option for hypoxia imaging. In this situation, it is rather difficult to obtain quantitative information about hypoxic degree because signals produced by the probes will be highly influenced by a number of parameters including photobleaching, excitation intensity, and image acquisition settings, et al. More preferred mode for O2 quantification is the phosphorescence lifetime-based imaging since it can provide accurate signals through one-off calibration. However, special software and hardware are needed to support time-gated single photon counting detections, which is absent on commonly used live cell imaging systems. Alternatively, ratiometric detection based on dual-emissive probes is a more accessible and reliable method for hypoxia imaging, which can be readily enabled on standard live fluorescence imaging platforms. (2) Obviously, PET imaging will serve as a useful tool to detect hypoxia since numbers of the developed tracers have now been assessed in tumor patients. However, we must be aware that the current tracers are only capable of detecting very low pO2 levels. From clinical viewpoints, the tracers should report pO2 levels within the clinically relevant hypoxic range (e.g., 0−10 mmHg) because the cells with “intermediate” levels of hypoxia may be more important than the maximally hypoxic cells when assessing tumor responses to the conventional RT.597 Thus, further explorations of novel functional PET tracers capable of providing both qualitative and quantitative measurements for hypoxia are urgently required. (3) MRI technique remains to be the most suitable method for tumor hypoxia imaging because it offers unique penetration-independent, noninvasive, and highresolution tomographic imaging. In the past decade, a considerable amount of effort has been devoted to the design of responsive contrast agents which can be triggered by their local hypoxia environment. However, most of the currently available agents do not respond to the in vivo hypoxia microenvironments, so their response range must also be finely tuned in the biologically reasonable range. In addition, unlike T1- or T2-based agents, PARACEST agents featuring chemical exchange-mediated magnetization saturation transfer are arguably one of the most attractive platforms for hypoxia imaging. However, compared to T1- or T2-based agents, PARACEST agents often exhibit relatively lower sensitivity. Finally, such a limitation will be surmounted by the optimization of responsive CEST agents which can be activated by the hypoxia microenvironment. (4) While hypoxic microenvironment is very complicated, it will be impossible to accurately acquire all the hypoxia-related parameters using only one imaging modality. The combination of two different imaging techniques, which can provide simultaneous anatomic (e.g., MRI and CT) and functional (e.g., fluorescent imaging and PET) information, is undoubtedly highly desirable to accurately and quantitatively answer several biomedical

Figure 66. Combination of a PDT system with a hypoxia-sensitive drug-delivery system for enhanced anticancer therapy. (a) Representative TEM images of UCNPs, dense silica-coated UCNPs, and UCNPs coated with both dense and outer mesoporous silica shells. (b) A synergetic tumor therapeutic effect could be achieved by treating tumors with PDT under normal O2 environment and the subsequently enhanced cytotoxicity of activated TPZ thanks to the lowered oxygen concentration induced by PDT. (c) Time-dependent tumor volumes obtained by the indicated treatments. The synergistic therapeutic effects were confirmed by marked and sustained difference among different groups. Reproduced with permission from ref 591. Copyright 2015 Wiley-VCH.

drug carriers.593 The polymer-based nanocarrier consists of three important components: ROS-generating and hypoxiasensitive conjugated polymer, encapsulated drug DOX, and poly(vinyl alcohol) (PVA) surface coatings (Figure 67a). Upon light irradiation, the dithiophene-benzotriazole moiety incorporated in the conjugated polymer is able to produce 1O2, thus triggering cell apoptosis.594 Meanwhile, the rapid consumption of the dissolved O2 during PDT can result in a local hypoxic environment. Therefore, the other moiety 2-nitroimidazole grafted on the conjugated polymer will be reduced to 2aminoimidazoles, resulting in the dissociation of conjugated polymer and subsequent release of anticancer drugs (Figure 67b).595 Combined with the PDT effect, the DNA damagemediated cytotoxicity induced by the released DOX could contribute to an enhanced synergistic antitumor activity. Such strategies provide a design guideline for the improvement of PDT efficiency, which makes use of inevitable PDT-induced hypoxic microenvironment to activate other reactions for achieving enhanced treatment efficacy.

7. CONCLUSIONS AND FUTURE PERSPECTIVES In this review, the most recent progresses in design and construction of functional probes for the sensitive detection and effective treatment of cancer hypoxia have been summarized and discussed in detail. In efforts to detect hypoxia, the great advances achieved in the developments of various imaging probes have enabled the noninvasive imaging of hypoxia microenvironment using various techniques such as fluorescent imaging, PET, MRI, and PAT. Apparently, each of these modalities has its own specific advantages and disadvantages. It can be anticipated that, if right contrast agents are used, each noninvasive imaging modality can play their irreplaceable role in the clinical application.596 In addition, 6205


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Figure 67. (a) Schematic illustration of the hypoxia-responsive and light-activated drug delivery systems, which were comprised of three components: ROS-generating and hypoxia-responsive 2-nitroimidazole-grafted conjugated polymer, encapsulated drug DOX, and PVA surface coatings. Under PDT-induced hypoxic microenvironment, the nitroimidazole group could be reduced, which promoted the release of its cargoes via the disassembly of drug carriers. (b) A schematics illustrating that the designed polymer would first generate ROS under illumination, and then PDTresulted local hypoxic environment can trigger the dissociation of drug carriers for enhanced anticancer efficacy. Reproduced with permission from ref 593. Copyright 2016 Wiley-VCH.

translation of such nanomaterials is greatly challenging at present, but it is undeniable that nanomaterials possessing unusual and useful properties and features will provide opportunities for the exploration of new therapeutic venues. Continued innovations of the therapeutic concepts, nanotechnologies, and corresponding nanoprobes with ever more powerful and integrated functionalities to fully meet the requirements of hypoxic tumor treatments are the responsibilities of the researchers and engineers in the multidisciplinary fields such as medicine, biology, chemistry, and materials. In summary, the tumor hypoxia leaves us a great challenge to overcome and in the meantime great opportunities to intervene and make contributions. Undoubtedly, the use of the imaging probes and therapeutic agents in hypoxic tumor diagnosis and therapy will greatly aid our understanding and subsequent treatment of malignant tumors. One big challenge remaining for these theranostic agents is to address the stringent micropharmacokinetic requirements for their efficient targeting to hypoxic cancer cells distant from vasculature.549,606 This critical issue has not been addressed explicitly to date, which, however, is of vital significance in ensuring that constructed nanoprobers reach their full potentials in the human being’s combating tumor. Very recently, by taking advantage of the fact that magneto-aerotactic bacteria can preferentially migrate to

questions in one trial. Such a strategy may enable one to study hypoxia on the hybrid imaging platforms and at different scales by using a single imaging agent. Although we have witnessed the rapid development of hybrid imaging techniques such as PET-CT598,599 and SPECT-CT,600,601 we think that one of the most attractive approaches of multimodal hypoxia imaging is the integration of MRI with PET or SPECT.602−605 In such a PET/MRI system, the high sensitivity of PET could be used to determine the locations of the focal uptake of a hypoxiasensitive PET/MRI agent in the body. Subsequently, the highresolution MR images, acquired only in the localized regions where a PET signal is seen, can report hypoxic degree using the same agent. Unfortunately, there has been no report about hypoxia-responsive dual-mode PET/MRI agents until now. We believe that the research on this topic will start soon, and such agents are likely to play more important and attractive roles in the accurate imaging of hypoxic tumors than other combinations. (5) Hypoxic tumors as a formidable foe have protected themselves by showing powerful skills for survival and proliferation. Most of the conventional therapy strategies fail to meet the clinical expectations from patients and the medical communities. Fortunately, numbers of functional nanomaterials with specific chemical properties have been found to be effective in the treatment of hypoxic tumors. While the clinical 6206


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16XD1404000), and the Shanghai Yangfan Program (Grant 14YF1406400).

and remain at the regions of low O2 concentrations via geomagnetic-assisted aerotaxis, Martel et al. utilized magnetoaerotactic bacteria as drug carriers to successfully transport them into hypoxic regions of the tumor. This research may shed some light on the further development of therapeutic agents with the ability of hypoxia targeting.607 Moreover, the ever-restrictive demands for the diagnostic and therapeutic clinical applications of all the nanoagents should be seriously considered and treated. 608 For example, toxicity and immunogenicity of either molecules or nanomaterials must be comprehensively evaluated before clinical trials.609 In this process, detailed evaluations of every component and their biological responses of the agents, especially the correlation between the elaborately designed nanostructures with their biological responses, should be systematically studied to maximize their capabilities and in the meantime minimize their side effects. In addition, the degradability of the involved molecules and nanomaterials should be guaranteed, which will enable the body to clear them as soon as possible after performing their designated pharmacological functions. Once all these critical issues are satisfactorily solved, the successful translation of these theranostics to clinical applications can be anticipated in the near future.

ABBREVIATIONS 3D three-dimensional ATSM diacetyl-bis(N4-methylthiosemicarbazone) azo azobenzene BHQ black hole quencher BOLD-MRI blood oxygen level dependent-magnetic resonance imaging BTP [(btp)2Ir(acac)] β-CD β-cyclodextrin CEST chemical exchange saturation transfer CLSM confocal laser scanning microscope CPT camptothecin CT computed tomography Cy7 cyanine 7 DBP-Pt Pt-5,15-di(p-benzoato)porphyrin DOPE 1,2-dioleyl-sn-glycero-3-phosphoethanolamine DOTA 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid DOX doxorubicin EPR enhanced permeation and retention FADH2 flavin adenine dinucleotide FCM fluorescence confocal microscopy [18F]FDG 2-fluoro-2-[18F]deoxy-D-glucose 18 F-FMISO 18F-fluoromisonidazole FITC fluorescein isothiocyanate FRET fluorescence resonance energy transfer HIF hypoxia-inducible factors H2O2 hydrogen peroxide HSA human serum albumin LSPR localized surface plasmon resonance MMC mitomycin C MOFs metal−organic frameworks MRI magnetic resonance imaging MSN mesoporous silica nanoparticles NADH nicotinamide adenine dinucleotide NIR near-infrared NMR nuclear magnetic resonance NTR nitroreductase PALI photoacoustic lifetime imaging PAT photoacoustic tomography PBS phosphate buffer saline PDHF poly(9,9-dihexylfluorene) PDT photodynamic therapy PEG poly(ethylene glycol) PET positron emission tomography PFO poly(9,9-dioctylfluorene) PLGA poly(D,L-lactic-co-glycolic acid) pO2 partial pressure of oxygen PtP Pt porphyrin PtPFPP platinum(II)-meso-tetrakis(pentafluorophenyl)porphyrin PTT photothermal therapy PtTFPP Pt(II)-5,10,15,20-tetrakis(2,3,4,5,6-pentafluorophenyl)-porphyrin PtTPTBP platinum(II) meso-tetraphenyltetrabenzoporphyrin PVA poly(vinyl alcohol) PVP poly(N-vinylpyrrolidone) q the number of inner-sphere water molecules QDs quantum dots

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Wenbo Bu: 0000-0001-6664-3453 Jianlin Shi: 0000-0001-8790-195X Notes

The authors declare no competing financial interest. Biographies Jia-nan Liu received his Ph.D. from Shanghai Institute of Ceramics, Chinese Academy of Sciences (SICCAS) in 2013 under the supervision of Profs Jianlin Shi and Wenbo Bu. He is now an associate professor in SICCAS. His research is focused on the design and synthesis of functionalized nanoprobes for biomedical applications, especially in combating cancer hypoxia. Wenbo Bu received his Ph.D. degree from Nanjing Tech University (China) in 2002. He has been a full professor in SICCAS since 2008. In 2016, he moved from SICCAS to East China Normal University. His research mainly focuses on the design and synthesis of multifunctional rare-earth-based nanomaterials for future cancer imaging and therapeutic applications. Jianlin Shi received his Ph.D. degree in SICCAS. He has been a full professor at SICCAS since 1994. His research interests involve the synthesis of mesoporous silica nanoparticles and mesoporous silicabased nanocomposites for biomedical applications. He has published over 400 scientific papers which have been cited more than 20000 times by other scientists with an h-index of 75 (2017).

ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Grants 51372260 and 51402338), Youth Innovation Promotion Association CAS (2015201), the Shanghai Excellent Academic Leaders Program (Grant 6207


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(18) Dewhirst, M. W.; Cao, Y.; Moeller, B. Cycling Hypoxia and Free Radicals Regulate Angiogenesis and Radiotherapy Response. Nat. Rev. Cancer 2008, 8, 425−437. (19) Pugh, C. W.; Ratcliffe, P. J. Regulation of Angiogenesis by Hypoxia: Role of the HIF System. Nat. Med. 2003, 9, 677−684. (20) Semenza, G. L. HIF-1 Mediates Metabolic Responses to Intratumoral Hypoxia and Oncogenic Mutations. J. Clin. Invest. 2013, 123, 3664−3671. (21) Thienpont, B.; Steinbacher, J.; Zhao, H.; D’Anna, F.; Kuchnio, A.; Ploumakis, A.; Ghesquière, B.; Van Dyck, L.; Boeckx, B.; Schoonjans, L.; et al. Tumour hypoxia causes DNA hypermethylation by reducing TET activity. Nature 2016, 537, 63−68. (22) Pennacchietti, S.; Michieli, P.; Galluzzo, M.; Mazzone, M.; Giordano, S.; Comoglio, P. M. Hypoxia Promotes Invasive Growth by Transcriptional Activation of The Met Protooncogene. Cancer Cell 2003, 3, 347−361. (23) Subarsky, P.; Hill, R. The Hypoxic Tumour Microenvironment and Metastatic Progression. Clin. Exp. Metastasis 2003, 20, 237−250. (24) Lu, X.; Kang, Y. Hypoxia and Hypoxia-Inducible Factors: Master Regulators of Metastasis. Clin. Cancer Res. 2010, 16, 5928− 5935. (25) Harris, A. L. Hypoxia - A Key Regulatory Factor in Tumour Growth. Nat. Rev. Cancer 2002, 2, 38−47. (26) Pouysségur, J.; Dayan, F.; Mazure, N. M. Hypoxia Signalling in Cancer and Approaches to Enforce Tumour Regression. Nature 2006, 441, 437−443. (27) Xu, H.; Li, Q.; Wang, L.; He, Y.; Shi, J.; Tang, B.; Fan, C. Nanoscale Optical Probes for Cellular Imaging. Chem. Soc. Rev. 2014, 43, 2650−2661. (28) Yang, Y.; Zhao, Q.; Feng, W.; Li, F. Luminescent Chemodosimeters for Bioimaging. Chem. Rev. 2013, 113, 192−270. (29) Stephens, D. J.; Allan, V. J. Light Microscopy Techniques for Live Cell Imaging. Science 2003, 300, 82−86. (30) Chitneni, S. K.; Palmer, G. M.; Zalutsky, M. R.; Dewhirst, M. W. Molecular Imaging of Hypoxia. J. Nucl. Med. 2011, 52, 165−168. (31) Guzy, R. D.; Hoyos, B.; Robin, E.; Chen, H.; Liu, L.; Mansfield, K. D.; Simon, M. C.; Hammerling, U.; Schumacker, P. T. Mitochondrial Complex III is Required for Hypoxia-Induced ROS Production and Cellular Oxygen Sensing. Cell Metab. 2005, 1, 401− 408. (32) López-Lázaro, M. Dual Role of Hydrogen Peroxide in Cancer: Possible Relevance to Cancer Chemoprevention and Therapy. Cancer Lett. 2007, 252, 1−8. (33) Gatenby, R. A.; Gillies, R. J. Why do Cancers Have High Aerobic Glycolysis? Nat. Rev. Cancer 2004, 4, 891−899. (34) Chiche, J.; Brahimi-Horn, M. C.; Pouysségur, J. Tumour Hypoxia Induces A Metabolic Shift Causing Acidosis: A Common Feature in Cancer. J. Cell. Mol. Med. 2010, 14, 771−794. (35) Kato, Y.; Ozawa, S.; Miyamoto, C.; Maehata, Y.; Suzuki, A.; Maeda, T.; Baba, Y. Acidic Extracellular Microenvironment and Cancer. Cancer Cell Int. 2013, 13, 89. (36) Cui, L.; Zhong, Y.; Zhu, W. P.; Xu, Y. F.; Du, Q. S.; Wang, X.; Qian, X. H.; Xiao, Y. A New Prodrug-Derived Ratiometric Fluorescent Probe for Hypoxia: High Selectivity of Nitroreductase and Imaging in Tumor Cell. Org. Lett. 2011, 13, 928−931. (37) Hodgkiss, R. J.; Begg, A. C.; Middleton, R. W.; Parrick, J.; Stratford, M. R. L.; Wardman, P.; Wilson, G. D. Fluorescent Markers for Hypoxic Cells: A Study of Novel Heterocyclic Compounds that Undergo Bio-Reductive Binding. Biochem. Pharmacol. 1991, 41, 533− 541. (38) Li, Z.; Li, X.; Gao, X.; Zhang, Y.; Shi, W.; Ma, H. Nitroreductase Detection and Hypoxic Tumor Cell Imaging by a Designed Sensitive and Selective Fluorescent Probe, 7-[(5-Nitrofuran-2-yl)methoxy]-3Hphenoxazin-3-one. Anal. Chem. 2013, 85, 3926−3932. (39) Schwarz, A.; Stander, S.; Berneburg, M.; Bohm, M.; Kulms, D.; van Steeg, H.; Grosse-Heitmeyer, K.; Krutmann, J.; Schwarz, T. Interleukin-12 Suppresses Ultraviolet Radiation-Induced Apoptosis by Inducing DNA Repair. Nat. Cell Biol. 2002, 4, 26−31.

radiotherapy red blood cells rhodamine-B isothiocyanate reactive oxygen species scintillating nanoparticles selenoamino acid oxygen saturation of hemoglobin single photon emission tomography transmission electron microscope tetrakis(pentafluorophenyl) porphyrin tirapazamine upconversion nanoparticles the water residence lifetime the rotational correlation time

REFERENCES (1) Gatenby, R. A.; Gillies, R. J. A Microenvironmental Model of Carcinogenesis. Nat. Rev. Cancer 2008, 8, 56−61. (2) Bristow, R. G.; Hill, R. P. Hypoxia, DNA Repair and Genetic Instability. Nat. Rev. Cancer 2008, 8, 180−192. (3) Brahimi-Horn, M. C.; Chiche, J.; Pouysségur, J. Hypoxia and Cancer. J. Mol. Med. 2007, 85, 1301−1307. (4) Brown, J. M.; Le, Q.-T. Tumor Hypoxia is Important in Radiotherapy, But How Should We Measure It? Int. J. Radiat. Oncol., Biol., Phys. 2002, 54, 1299−1301. (5) Jubb, A. M.; Buffa, F. M.; Harris, A. L. Assessment of Tumour Hypoxia for Prediction of Response to Therapy and Cancer Prognosis. J. Cell. Mol. Med. 2010, 14, 18−29. (6) Minn, H.; Gronroos, T. J.; Komar, G.; Eskola, O.; Lehtio, K.; Tuomela, J.; Seppanen, M.; Solin, O. Imaging of Tumor Hypoxia to Predict Treatment Sensitivity. Curr. Pharm. Des. 2008, 14, 2932−2942. (7) Rajendran, J. G.; Hendrickson, K. R. G.; Spence, A. M.; Muzi, M.; Krohn, K. A.; Mankoff, D. A. Hypoxia Imaging-Directed Radiation Treatment Planning. Eur. J. Nucl. Med. Mol. Imaging 2006, 33, 44−53. (8) Vaupel, P.; Schlenger, K.; Knoop, C.; Höckel, M. Oxygenation of Human Tumors: Evaluation of Tissue Oxygen Distribution in Breast Cancers by Computerized O2 Tension Measurements. Cancer Res. 1991, 51, 3316−3322. (9) Höckel, M.; Schlenger, K.; Knoop, C.; Vaupel, P. Oxygenation of Carcinomas of the Uterine Cervix: Evaluation by Computerized O2 Tension Measurements. Cancer Res. 1991, 51, 6098−6102. (10) Höckel, M.; Knoop, C.; Schlenger, K.; Vorndran, B.; Bauβnann, E.; Mitze, M.; Knapstein, P. G.; Vaupel, P. Intratumoral pO2 Predicts Survival in Advanced Cancer of The Uterine Cervix. Radiother. Oncol. 1993, 26, 45−50. (11) Teicher, B. Hypoxia and Drug Resistance. Cancer Metastasis Rev. 1994, 13, 139−168. (12) Harrison, L.; Blackwell, K. Hypoxia and Anemia: Factors in Decreased Sensitivity to Radiation Therapy and Chemotherapy? Oncologist 2004, 9, 31−40. (13) Primeau, A. J.; Rendon, A.; Hedley, D.; Lilge, L.; Tannock, I. F. The Distribution of the Anticancer Drug Doxorubicin in Relation to Blood Vessels in Solid Tumors. Clin. Cancer Res. 2005, 11, 8782− 8788. (14) Cunningham, M. L.; Ringrose, P. S.; Lokesh, B. R. Inhibition of The Genotoxicity of Bleomycin by Superoxide Dismutase. Mutat. Res., Genet. Toxicol. Test. 1984, 135, 199−202. (15) Vaupel, P.; Thews, O.; Hoeckel, M. Treatment Resistance of Solid Tumors. Med. Oncol. 2001, 18, 243−259. (16) Gray, L. H.; Conger, A. D.; Ebert, M.; Hornsey, S.; Scott, O. C. A. The Concentration of Oxygen Dissolved in Tissues at the Time of Irradiation as a Factor in Radiotherapy. Br. J. Radiol. 1953, 26, 638− 648. (17) Fyles, A. W.; Milosevic, M.; Wong, R.; Kavanagh, M.-C.; Pintilie, M.; Sun, A.; Chapman, W.; Levin, W.; Manchul, L.; Keane, T. J.; et al. Oxygenation Predicts Radiation Response and Survival in Patients with Cervix Cancer. Radiother. Oncol. 1998, 48, 149−156. 6208


Chemical Reviews

Review

(40) Ichihashi, M.; Ueda, M.; Budiyanto, A.; Bito, T.; Oka, M.; Fukunaga, M.; Tsuru, K.; Horikawa, T. UV-Induced Skin Damage. Toxicology 2003, 189, 21−39. (41) Weissleder, R. A Clearer Vision for In Vivo Imaging. Nat. Biotechnol. 2001, 19, 316−317. (42) Okuda, K.; Okabe, Y.; Kadonosono, T.; Ueno, T.; Youssif, B. G. M.; Kizaka-Kondoh, S.; Nagasawa, H. 2-Nitroimidazole-Tricarbocyanine Conjugate as a Near-Infrared Fluorescent Probe for In Vivo Imaging of Tumor Hypoxia. Bioconjugate Chem. 2012, 23, 324−329. (43) Xu, K.; Wang, F.; Pan, X.; Liu, R.; Ma, J.; Kong, F.; Tang, B. High Selectivity Imaging of Nitroreductase Using a Near-Infrared Fluorescence Probe in Hypoxic Tumor. Chem. Commun. 2013, 49, 2554−2556. (44) Li, Y.; Sun, Y.; Li, J.; Su, Q.; Yuan, W.; Dai, Y.; Han, C.; Wang, Q.; Feng, W.; Li, F. Ultrasensitive Near-Infrared FluorescenceEnhanced Probe for in Vivo Nitroreductase Imaging. J. Am. Chem. Soc. 2015, 137, 6407−6416. (45) Scott, D. T.; McKnight, D. M.; Blunt-Harris, E. L.; Kolesar, S. E.; Lovley, D. R. Quinone Moieties Act as Electron Acceptors in the Reduction of Humic Substances by Humics-Reducing Microorganisms. Environ. Sci. Technol. 1998, 32, 2984−2989. (46) Nohl, H.; Jordan, W.; Youngman, R. J. Quinones in Biology: Functions in Electron Transfer and Oxygen Activation. Adv. Free Radical Biol. Med. 1986, 2, 211−279. (47) Tanabe, K.; Hirata, N.; Harada, H.; Hiraoka, M.; Nishimoto, S.-i. Emission under Hypoxia: One-Electron Reduction and Fluorescence Characteristics of an Indolequinone−Coumarin Conjugate. ChemBioChem 2008, 9, 426−432. (48) Whitaker, J. E.; Haugland, R. P.; Ryan, D.; Hewitt, P. C.; Haugland, R. P.; Prendergast, F. G. Fluorescent Rhodol Derivatives: Versatile, Photostable Labels and Tracers. Anal. Biochem. 1992, 207, 267−279. (49) Komatsu, H.; Harada, H.; Tanabe, K.; Hiraoka, M.; Nishimoto, S.-i. Indolequinone-Rhodol Conjugate as A Fluorescent Probe for Hypoxic Cells: Enzymatic Activation and Fluorescence Properties. MedChemComm 2010, 1, 50−53. (50) Komatsu, H.; Shindo, Y.; Oka, K.; Hill, J. P.; Ariga, K. Ubiquinone-Rhodol (UQ-Rh) for Fluorescence Imaging of NAD(P)H through Intracellular Activation. Angew. Chem., Int. Ed. 2014, 53, 3993−3995. (51) Miura, T.; Urano, Y.; Tanaka, K.; Nagano, T.; Ohkubo, K.; Fukuzumi, S. Rational Design Principle for Modulating Fluorescence Properties of Fluorescein-Based Probes by Photoinduced Electron Transfer. J. Am. Chem. Soc. 2003, 125, 8666−8671. (52) Zbaida, S.; Levine, W. G. A Novel Application of Cyclic Voltammetry for Direct Investigation of Metabolic Intermediates in Microsomal Azo Reduction. Chem. Res. Toxicol. 1991, 4, 82−88. (53) Uddin, M. I.; Evans, S. M.; Craft, J. R.; Marnett, L. J.; Uddin, M. J.; Jayagopal, A. Applications of Azo-Based Probes for Imaging Retinal Hypoxia. ACS Med. Chem. Lett. 2015, 6, 445−449. (54) Kiyose, K.; Hanaoka, K.; Oushiki, D.; Nakamura, T.; Kajimura, M.; Suematsu, M.; Nishimatsu, H.; Yamane, T.; Terai, T.; Hirata, Y.; et al. Hypoxia-Sensitive Fluorescent Probes for In Vivo Real-Time Fluorescence Imaging of Acute Ischemia. J. Am. Chem. Soc. 2010, 132, 15846−15848. (55) Piao, W.; Tsuda, S.; Tanaka, Y.; Maeda, S.; Liu, F.; Takahashi, S.; Kushida, Y.; Komatsu, T.; Ueno, T.; Terai, T.; et al. Development of Azo-Based Fluorescent Probes to Detect Different Levels of Hypoxia. Angew. Chem., Int. Ed. 2013, 52, 13028−13032. (56) Sun, L.; Li, G.; Chen, X.; Chen, Y.; Jin, C.; Ji, L.; Chao, H. AzoBased Iridium(III) Complexes as Multicolor Phosphorescent Probes to Detect Hypoxia in 3D Multicellular Tumor Spheroids. Sci. Rep. 2015, 5, 14837. (57) Clanton, T. L. Hypoxia-Induced Reactive Oxygen Species Formation in Skeletal Muscle. J. Appl. Physiol. 2007, 102, 2379−2388. (58) Matsumoto, S.; Yasui, H.; Mitchell, J. B.; Krishna, M. C. Imaging Cycling Tumor Hypoxia. Cancer Res. 2010, 70, 10019−10023. (59) Dewhirst, M. W. Relationships between Cycling Hypoxia, HIF1, Angiogenesis and Oxidative Stress. Radiat. Res. 2009, 172, 653−665.

(60) Moeller, B. J.; Cao, Y.; Li, C. Y.; Dewhirst, M. W. Radiation activates HIF-1 to Regulate Vascular Radiosensitivity in Tumors: Role of Reoxygenation, Free Radicals, and Stress Granules. Cancer Cell 2004, 5, 429−441. (61) Stabley, D. R.; Jurchenko, C.; Marshall, S. S.; Salaita, K. S. Visualizing Mechanical Tension across Membrane Receptors with A Fluorescent Sensor. Nat. Methods 2011, 9, 64−67. (62) Takahashi, S.; Piao, W.; Matsumura, Y.; Komatsu, T.; Ueno, T.; Terai, T.; Kamachi, T.; Kohno, M.; Nagano, T.; Hanaoka, K. Reversible Off−On Fluorescence Probe for Hypoxia and Imaging of Hypoxia−Normoxia Cycles in Live Cells. J. Am. Chem. Soc. 2012, 134, 19588−19591. (63) Liu, J.; Sun, Y. Q.; Huo, Y. Y.; Zhang, H. X.; Wang, L. F.; Zhang, P.; Song, D.; Shi, Y. W.; Guo, W. Simultaneous Fluorescence Sensing of Cys and GSH from Different Emission Channels. J. Am. Chem. Soc. 2014, 136, 574−577. (64) Jones, D. P. Redox Potential of GSH/GSSG Couple: Assay and Biological Significance. Methods Enzymol. 2002, 348, 93−112. (65) Lee, M. H.; Yang, Z.; Lim, C. W.; Lee, Y. H.; Dongbang, S.; Kang, C.; Kim, J. S. Disulfide-Cleavage-Triggered Chemosensors and Their Biological Applications. Chem. Rev. 2013, 113, 5071−5109. (66) Rumsey, W.; Vanderkooi, J.; Wilson, D. Imaging of Phosphorescence: A Novel Method for Measuring Oxygen Distribution in Perfused Tissue. Science 1988, 241, 1649−1651. (67) Dobrucki, J. W. Interaction of Oxygen-Sensitive Luminescent Probes Ru(phen)32+ and Ru(bipy)32+ with Animal and Plant Cells In Vitro: Mechanism of Phototoxicity and Conditions for Non-Invasive Oxygen Measurements. J. Photochem. Photobiol., B 2001, 65, 136−144. (68) Ji, J.; Rosenzweig, N.; Jones, I.; Rosenzweig, Z. Novel Fluorescent Oxygen Indicator for Intracellular Oxygen Measurements. J. Biomed. Opt. 2002, 7, 404−409. (69) Komatsu, H.; Yoshihara, K.; Yamada, H.; Kimura, Y.; Son, A.; Nishimoto, S.-i.; Tanabe, K. Ruthenium Complexes with Hydrophobic Ligands That Are Key Factors for the Optical Imaging of Physiological Hypoxia. Chem. - Eur. J. 2013, 19, 1971−1977. (70) Ozturk, O.; Oter, O.; Yildirim, S.; Subasi, E.; Ertekin, K.; Celik, E.; Temel, H. Tuning Oxygen Sensitivity of Ruthenium Complex Exploiting Silver Nanoparticles. J. Lumin. 2014, 155, 191−197. (71) Lowry, M. S.; Bernhard, S. Synthetically Tailored Excited States: Phosphorescent, Cyclometalated Iridium(III) Complexes and Their Applications. Chem. - Eur. J. 2006, 12, 7970−7977. (72) Zhang, S.; Hosaka, M.; Yoshihara, T.; Negishi, K.; Iida, Y.; Tobita, S.; Takeuchi, T. Phosphorescent Light−Emitting Iridium Complexes Serve as a Hypoxia-Sensing Probe for Tumor Imaging in Living Animals. Cancer Res. 2010, 70, 4490−4498. (73) Koren, K.; Dmitriev, R. I.; Borisov, S. M.; Papkovsky, D. B.; Klimant, I. Complexes of IrIII-Octaethylporphyrin with Peptides as Probes for Sensing Cellular O2. ChemBioChem 2012, 13, 1184−1190. (74) DeRosa, M. C.; Hodgson, D. J.; Enright, G. D.; Dawson, B.; Evans, C. E. B.; Crutchley, R. J. Iridium Luminophore Complexes for Unimolecular Oxygen Sensors. J. Am. Chem. Soc. 2004, 126, 7619− 7626. (75) Xie, Z.; Ma, L.; deKrafft, K. E.; Jin, A.; Lin, W. Porous Phosphorescent Coordination Polymers for Oxygen Sensing. J. Am. Chem. Soc. 2010, 132, 922−923. (76) Esipova, T. V.; Karagodov, A.; Miller, J.; Wilson, D. F.; Busch, T. M.; Vinogradov, S. A. Two New “Protected” Oxyphors for Biological Oximetry: Properties and Application in Tumor Imaging. Anal. Chem. 2011, 83, 8756−8765. (77) Dunphy, I.; Vinogradov, S. A.; Wilson, D. F. Oxyphor R2 and G2: Phosphors for Measuring Oxygen by Oxygen-Dependent Quenching of Phosphorescence. Anal. Biochem. 2002, 310, 191−198. (78) Papkovsky, D. B.; Dmitriev, R. I. Biological Detection by Optical Oxygen Sensing. Chem. Soc. Rev. 2013, 42, 8700−8732. (79) Tobita, S.; Yoshihara, T. Intracellular and in vivo Oxygen Sensing Using Phosphorescent Iridium(III) Complexes. Curr. Opin. Chem. Biol. 2016, 33, 39−45. 6209


Chemical Reviews

Review

Bimodal Imaging and Nitroaromatic Sensing. J. Phys. Chem. C 2014, 118, 12241−12249. (99) Yang, W.; Feng, J.; Song, S.; Zhang, H. Microwave-Assisted Modular Fabrication of Nanoscale Luminescent Metal-Organic Framework for Molecular Sensing. ChemPhysChem 2012, 13, 2734− 2738. (100) Xu, R.; Wang, Y.; Duan, X.; Lu, K.; Micheroni, D.; Hu, A.; Lin, W. Nanoscale Metal−Organic Frameworks for Ratiometric Oxygen Sensing in Live Cells. J. Am. Chem. Soc. 2016, 138, 2158−2161. (101) Wang, X.-d.; Gorris, H. H.; Stolwijk, J. A.; Meier, R. J.; Groegel, D. B. M.; Wegener, J.; Wolfbeis, O. S. Self-Referenced RGB Colour Imaging of Intracellular Oxygen. Chem. Sci. 2011, 2, 901−906. (102) Zheng, X.; Wang, X.; Mao, H.; Wu, W.; Liu, B.; Jiang, X. Hypoxia-Specific Ultrasensitive Detection of Tumours and Cancer Cells In Vivo. Nat. Commun. 2015, 6, 5834. (103) Zheng, X.; Tang, H.; Xie, C.; Zhang, J.; Wu, W.; Jiang, X. Tracking Cancer Metastasis In Vivo by Using an Iridium-Based Hypoxia-Activated Optical Oxygen Nanosensor. Angew. Chem., Int. Ed. 2015, 54, 8094−8099. (104) Erler, J. T.; Bennewith, K. L.; Nicolau, M.; Dornhofer, N.; Kong, C.; Le, Q.-T.; Chi, J.-T. A.; Jeffrey, S. S.; Giaccia, A. J. Lysyl Oxidase is Essential for Hypoxia-Induced Metastasis. Nature 2006, 440, 1222−1226. (105) Zhang, G.; Palmer, G. M.; Dewhirst, M. W.; Fraser, C. L. A Dual-Emissive-Materials Design Concept Enables Tumour Hypoxia Imaging. Nat. Mater. 2009, 8, 747−751. (106) Zhang, G.; Kooi, S. E.; Demas, J. N.; Fraser, C. L. Emission Color Tuning with Polymer Molecular Weight for Difluoroboron Dibenzoylmethane-Polylactide. Adv. Mater. 2008, 20, 2099−2104. (107) Yoshihara, T.; Yamaguchi, Y.; Hosaka, M.; Takeuchi, T.; Tobita, S. Ratiometric Molecular Sensor for Monitoring Oxygen Levels in Living Cells. Angew. Chem., Int. Ed. 2012, 51, 4148−4151. (108) Xiang, H. F.; Zhou, L.; Feng, Y.; Cheng, J. H.; Wu, D.; Zhou, X. G. Tunable Fluorescent/Phosphorescent Platinum(II) PorphyrinFluorene Copolymers for Ratiometric Dual Emissive Oxygen Sensing. Inorg. Chem. 2012, 51, 5208−5212. (109) Zhu, C.; Liu, L.; Yang, Q.; Lv, F.; Wang, S. Water-Soluble Conjugated Polymers for Imaging, Diagnosis, and Therapy. Chem. Rev. 2012, 112, 4687−4735. (110) Kim, H. N.; Guo, Z.; Zhu, W.; Yoon, J.; Tian, H. Recent Progress on Polymer-Based Fluorescent and Colorimetric Chemosensors. Chem. Soc. Rev. 2011, 40, 79−93. (111) Wu, C.; Hansen, S. J.; Hou, Q.; Yu, J.; Zeigler, M.; Jin, Y.; Burnham, D. R.; McNeill, J. D.; Olson, J. M.; Chiu, D. T. Design of Highly Emissive Polymer Dot Bioconjugates for In Vivo Tumor Targeting. Angew. Chem., Int. Ed. 2011, 50, 3430−3434. (112) Chan, Y.-H.; Ye, F.; Gallina, M. E.; Zhang, X.; Jin, Y.; Wu, I. C.; Chiu, D. T. Hybrid Semiconducting Polymer Dot−Quantum Dot with Narrow-Band Emission, Near-Infrared Fluorescence, and High Brightness. J. Am. Chem. Soc. 2012, 134, 7309−7312. (113) Xiong, L.; Shuhendler, A. J.; Rao, J. Self-Luminescing BRETFRET Near-Infrared Dots for In Vivo Lymph-Node Mapping and Tumour Imaging. Nat. Commun. 2012, 3, 1193. (114) Zhou, Y.; Huang, W.; Liu, J.; Zhu, X.; Yan, D. Self-Assembly of Hyperbranched Polymers and Its Biomedical Applications. Adv. Mater. 2010, 22, 4567−4590. (115) Zhao, Q.; Zhou, X.; Cao, T.; Zhang, K. Y.; Yang, L.; Liu, S.; Liang, H.; Yang, H.; Li, F.; Huang, W. Fluorescent/Phosphorescent Dual-Emissive Conjugated Polymer Dots for Hypoxia Bioimaging. Chem. Sci. 2015, 6, 1825−1831. (116) Wu, C.; Bull, B.; Christensen, K.; McNeill, J. Ratiometric Single-Nanoparticle Oxygen Sensors for Biological Imaging. Angew. Chem., Int. Ed. 2009, 48, 2741−2745. (117) Picchio, M.; Beck, R.; Haubner, R.; Seidl, S.; Machulla, H.-J.; Johnson, T. D.; Wester, H.-J.; Reischl, G.; Schwaiger, M.; Piert, M. Intratumoral Spatial Distribution of Hypoxia and Angiogenesis Assessed by 18F-FAZA and 125I-Gluco-RGD Autoradiography. J. Nucl. Med. 2008, 49, 597−605.

(80) Ai, H. W.; Hazelwood, K. L.; Davidson, M. W.; Campbell, R. E. Fluorescent Protein FRET Pairs for Ratiometric Imaging of Dual Biosensors. Nat. Methods 2008, 5, 401−403. (81) Zhang, X. L.; Xiao, Y.; Qian, X. H. A Ratiometric Fluorescent Probe Based on FRET for Imaging Hg2+ Ions in Living Cells. Angew. Chem., Int. Ed. 2008, 47, 8025−8029. (82) Kurishita, Y.; Kohira, T.; Ojida, A.; Hamachi, I. Rational Design of FRET-Based Ratiometric Chemosensors for in Vitro and in Cell Fluorescence Analyses of Nucleoside Polyphosphates. J. Am. Chem. Soc. 2010, 132, 13290−13299. (83) Lu, Y.; Zhao, J.; Zhang, R.; Liu, Y.; Liu, D.; Goldys, E. M.; Yang, X.; Xi, P.; Sunna, A.; Lu, J.; et al. Tunable Lifetime Multiplexing Using Luminescent Nanocrystals. Nat. Photonics 2013, 8, 32−36. (84) Tu, D.; Liu, L.; Ju, Q.; Liu, Y.; Zhu, H.; Li, R.; Chen, X. TimeResolved FRET Biosensor Based on Amine-Functionalized Lanthanide-Doped NaYF4 Nanocrystals. Angew. Chem., Int. Ed. 2011, 50, 6306−6310. (85) Zheng, W.; Zhou, S.; Chen, Z.; Hu, P.; Liu, Y.; Tu, D.; Zhu, H.; Li, R.; Huang, M.; Chen, X. Sub-10 nm Lanthanide-Doped CaF2 Nanoprobes for Time-Resolved Luminescent Biodetection. Angew. Chem., Int. Ed. 2013, 52, 6671−6676. (86) Liu, Y.; Zhou, S.; Tu, D.; Chen, Z.; Huang, M.; Zhu, H.; Ma, E.; Chen, X. Amine-Functionalized Lanthanide-Doped Zirconia Nanoparticles: Optical Spectroscopy, Time-Resolved Fluorescence Resonance Energy Transfer Biodetection, and Targeted Imaging. J. Am. Chem. Soc. 2012, 134, 15083−15090. (87) Xiong, X.; Song, F.; Wang, J.; Zhang, Y.; Xue, Y.; Sun, L.; Jiang, N.; Gao, P.; Tian, L.; Peng, X. Thermally Activated Delayed Fluorescence of Fluorescein Derivative for Time-Resolved and Confocal Fluorescence Imaging. J. Am. Chem. Soc. 2014, 136, 9590− 9597. (88) Hanaoka, K.; Kikuchi, K.; Kobayashi, S.; Nagano, T. TimeResolved Long-Lived Luminescence Imaging Method Employing Luminescent Lanthanide Probes with a New Microscopy System. J. Am. Chem. Soc. 2007, 129, 13502−13509. (89) Hirakawa, Y.; Yoshihara, T.; Kamiya, M.; Mimura, I.; Fujikura, D.; Masuda, T.; Kikuchi, R.; Takahashi, I.; Urano, Y.; Tobita, S.; et al. Quantitating Intracellular Oxygen Tension In Vivo by Phosphorescence Lifetime Measurement. Sci. Rep. 2015, 5, 17838. (90) Wang, X.-d.; Chen, X.; Xie, Z.-x.; Wang, X.-r. Reversible Optical Sensor Strip for Oxygen. Angew. Chem., Int. Ed. 2008, 47, 7450−7453. (91) Wang, X.-d.; Meier, R. J.; Link, M.; Wolfbeis, O. S. Photographing Oxygen Distribution. Angew. Chem., Int. Ed. 2010, 49, 4907−4909. (92) Wang, X.-D.; Zhou, T.-Y.; Chen, X.; Wong, K.-Y.; Wang, X.-R. An Optical Biosensor for The Rapid Determination of Glucose in Human Serum. Sens. Actuators, B 2008, 129, 866−873. (93) Lin, L.; Xiao, L.-L.; Huang, S.; Zhao, L.; Cui, J.-S.; Wang, X.-H.; Chen, X. Novel BOD Optical Fiber Biosensor Based on CoImmobilized Microorganisms in Ormosils Matrix. Biosens. Bioelectron. 2006, 21, 1703−1709. (94) Hu, Z.; Deibert, B. J.; Li, J. Luminescent Metal-Organic Frameworks for Chemical Sensing and Explosive Detection. Chem. Soc. Rev. 2014, 43, 5815−5840. (95) Kreno, L. E.; Leong, K.; Farha, O. K.; Allendorf, M.; Van Duyne, R. P.; Hupp, J. T. Metal−Organic Framework Materials as Chemical Sensors. Chem. Rev. 2012, 112, 1105−1125. (96) McKinlay, A. C.; Morris, R. E.; Horcajada, P.; Férey, G.; Gref, R.; Couvreur, P.; Serre, C. BioMOFs: Metal−Organic Frameworks for Biological and Medical Applications. Angew. Chem., Int. Ed. 2010, 49, 6260−6266. (97) Wu, P.; Wang, J.; He, C.; Zhang, X.; Wang, Y.; Liu, T.; Duan, C. Luminescent Metal-Organic Frameworks for Selectively Sensing Nitric Oxide in an Aqueous Solution and in Living Cells. Adv. Funct. Mater. 2012, 22, 1698−1703. (98) Suresh, V. M.; Chatterjee, S.; Modak, R.; Tiwari, V.; Patel, A. B.; Kundu, T. K.; Maji, T. K. Oligo(p-phenyleneethynylene)-Derived Porous Luminescent Nanoscale Coordination Polymer of GdIII: 6210


Chemical Reviews

Review

(118) Nichols, A. J.; Roussakis, E.; Klein, O. J.; Evans, C. L. ClickAssembled, Oxygen-Sensing Nanoconjugates for Depth-Resolved, Near-Infrared Imaging in a 3 D Cancer Model. Angew. Chem., Int. Ed. 2014, 53, 3671−3674. (119) Poon, Z.; Chang, D.; Zhao, X.; Hammond, P. T. Layer-byLayer Nanoparticles with a pH-Sheddable Layer for in Vivo Targeting of Tumor Hypoxia. ACS Nano 2011, 5, 4284−4292. (120) He, C.; Hu, Y.; Yin, L.; Tang, C.; Yin, C. Effects of Particle Size and Surface Charge on Cellular Uptake and Biodistribution of Polymeric Nanoparticles. Biomaterials 2010, 31, 3657−3666. (121) Yuan, Y.-Y.; Mao, C.-Q.; Du, X.-J.; Du, J.-Z.; Wang, F.; Wang, J. Surface Charge Switchable Nanoparticles Based on Zwitterionic Polymer for Enhanced Drug Delivery to Tumor. Adv. Mater. 2012, 24, 5476−5480. (122) Dmitriev, R. I.; Borisov, S. M.; Dussmann, H.; Sun, S. W.; Muller, B. J.; Prehn, J.; Baklaushev, V. P.; Klimant, I.; Papkovsky, D. B. Versatile Conjugated Polymer Nanoparticles for High-Resolution O2 Imaging in Cells and 3D Tissue Models. ACS Nano 2015, 9, 5275− 5288. (123) Pampaloni, F.; Reynaud, E. G.; Stelzer, E. H. K. The Third Dimension Bridges The Gap Between Cell Culture and Live Tissue. Nat. Rev. Mol. Cell Biol. 2007, 8, 839−845. (124) Michalet, X.; Pinaud, F. F.; Bentolila, L. A.; Tsay, J. M.; Doose, S.; Li, J. J.; Sundaresan, G.; Wu, A. M.; Gambhir, S. S.; Weiss, S. Quantum Dots for Live Cells, in Vivo Imaging, and Diagnostics. Science 2005, 307, 538−544. (125) Resch-Genger, U.; Grabolle, M.; Cavaliere-Jaricot, S.; Nitschke, R.; Nann, T. Quantum Dots Versus Organic Dyes as Fluorescent Labels. Nat. Methods 2008, 5, 763−775. (126) Medintz, I. L.; Clapp, A. R.; Mattoussi, H.; Goldman, E. R.; Fisher, B.; Mauro, J. M. Self-Assembled Nanoscale Biosensors Based on Quantum Dot FRET Donors. Nat. Mater. 2003, 2, 630−638. (127) Algar, W. R.; Wegner, D.; Huston, A. L.; Blanco-Canosa, J. B.; Stewart, M. H.; Armstrong, A.; Dawson, P. E.; Hildebrandt, N.; Medintz, I. L. Quantum Dots as Simultaneous Acceptors and Donors in Time-Gated Förster Resonance Energy Transfer Relays: Characterization and Biosensing. J. Am. Chem. Soc. 2012, 134, 1876−1891. (128) Suzuki, M.; Husimi, Y.; Komatsu, H.; Suzuki, K.; Douglas, K. T. Quantum Dot FRET Biosensors that Respond to pH, to Proteolytic or Nucleolytic Cleavage, to DNA Synthesis, or to a Multiplexing Combination. J. Am. Chem. Soc. 2008, 130, 5720−5725. (129) Clapp, A. R.; Medintz, I. L.; Mauro, J. M.; Fisher, B. R.; Bawendi, M. G.; Mattoussi, H. Fluorescence Resonance Energy Transfer Between Quantum Dot Donors and Dye-Labeled Protein Acceptors. J. Am. Chem. Soc. 2004, 126, 301−310. (130) Boeneman, K.; Mei, B. C.; Dennis, A. M.; Bao, G.; Deschamps, J. R.; Mattoussi, H.; Medintz, I. L. Sensing Caspase 3 Activity with Quantum Dot−Fluorescent Protein Assemblies. J. Am. Chem. Soc. 2009, 131, 3828−3829. (131) Dennis, A. M.; Rhee, W. J.; Sotto, D.; Dublin, S. N.; Bao, G. Quantum Dot−Fluorescent Protein FRET Probes for Sensing Intracellular pH. ACS Nano 2012, 6, 2917−2924. (132) Amelia, M.; Lavie-Cambot, A.; McClenaghan, N. D.; Credi, A. A Ratiometric Luminescent Oxygen Sensor Based on a Chemically Functionalized Quantum Dot. Chem. Commun. 2011, 47, 325−327. (133) Park, J.; Lee, J.; Kwag, J.; Baek, Y.; Kim, B.; Yoon, C. J.; Bok, S.; Cho, S. H.; Kim, K. H.; Ahn, G. O.; et al. Quantum Dots in an Amphiphilic Polyethyleneimine Derivative Platform for Cellular Labeling, Targeting, Gene Delivery, and Ratiometric Oxygen Sensing. ACS Nano 2015, 9, 6511−6521. (134) Boussif, O.; Lezoualc'h, F.; Zanta, M. A.; Mergny, M. D.; Scherman, D.; Demeneix, B.; Behr, J. P. A Versatile Vector for Gene and Oligonucleotide Transfer into Cells in Culture and In Vivo: Polyethylenimine. Proc. Natl. Acad. Sci. U. S. A. 1995, 92, 7297−7301. (135) Ataka, K.; Kottke, T.; Heberle, J. Thinner, Smaller, Faster: IR Techniques To Probe the Functionality of Biological and Biomimetic Systems. Angew. Chem., Int. Ed. 2010, 49, 5416−5424.

(136) Zipfel, W. R.; Williams, R. M.; Webb, W. W. Nonlinear Magic: Multiphoton Microscopy in The Biosciences. Nat. Biotechnol. 2003, 21, 1369−1377. (137) Helmchen, F.; Denk, W. Deep Tissue Two-Photon Microscopy. Nat. Methods 2005, 2, 932−940. (138) Zhang, P.; Huang, H.; Chen, Y.; Wang, J.; Ji, L.; Chao, H. Ruthenium(II) Anthraquinone Complexes as Two-Photon Luminescent Probes for Cycling Hypoxia Imaging In Vivo. Biomaterials 2015, 53, 522−531. (139) Kruk, M.; Karotki, A.; Drobizhev, M.; Kuzmitsky, V.; Gael, V.; Rebane, A. Two-Photon Absorption of Tetraphenylporphin Free Base. J. Lumin. 2003, 105, 45−55. (140) Larson, D. R.; Zipfel, W. R.; Williams, R. M.; Clark, S. W.; Bruchez, M. P.; Wise, F. W.; Webb, W. W. Water-Soluble Quantum Dots for Multiphoton Fluorescence Imaging in Vivo. Science 2003, 300, 1434−1436. (141) Pu, S.-C.; Yang, M.-J.; Hsu, C.-C.; Lai, C.-W.; Hsieh, C.-C.; Lin, S. H.; Cheng, Y.-M.; Chou, P.-T. The Empirical Correlation Between Size and Two-Photon Absorption Cross Section of CdSe and CdTe Quantum Dots. Small 2006, 2, 1308−1313. (142) Fowley, C.; Nomikou, N.; McHale, A. P.; McCarron, P. A.; McCaughan, B.; Callan, J. F. Water Soluble Quantum Dots as Hydrophilic Carriers and Two-Photon Excited Energy Donors in Photodynamic Therapy. J. Mater. Chem. 2012, 22, 6456−6462. (143) Liu, L.; Li, H.; Qiu, T.; Zhou, G.; Wong, K.-Y.; He, Z.; Liu, Z. Construction of A Molecular Beacon Based on Two-Photon Excited Fluorescence Resonance Energy Transfer with Quantum Dot as Donor. Chem. Commun. 2011, 47, 2622−2624. (144) Lemon, C. M.; Karnas, E.; Bawendi, M. G.; Nocera, D. G. Two-Photon Oxygen Sensing with Quantum Dot-Porphyrin Conjugates. Inorg. Chem. 2013, 52, 10394−10406. (145) Lemon, C. M.; Karnas, E.; Han, X.; Bruns, O. T.; Kempa, T. J.; Fukumura, D.; Bawendi, M. G.; Jain, R. K.; Duda, D. G.; Nocera, D. G. Micelle-Encapsulated Quantum Dot-Porphyrin Assemblies as In Vivo Two-Photon Oxygen Sensors. J. Am. Chem. Soc. 2015, 137, 9832− 9842. (146) McLaurin, E. J.; Greytak, A. B.; Bawendi, M. G.; Nocera, D. G. Two-Photon Absorbing Nanocrystal Sensors for Ratiometric Detection of Oxygen. J. Am. Chem. Soc. 2009, 131, 12994−13001. (147) Tsai, A. G.; Johnson, P. C.; Intaglietta, M. Oxygen Gradients in the Microcirculation. Physiol. Rev. 2003, 83, 933−963. (148) Haase, M.; Schäfer, H. Upconverting Nanoparticles. Angew. Chem., Int. Ed. 2011, 50, 5808−5829. (149) Chen, G.; Qiu, H.; Prasad, P. N.; Chen, X. Upconversion Nanoparticles: Design, Nanochemistry, and Applications in Theranostics. Chem. Rev. 2014, 114, 5161−5214. (150) Wang, F.; Liu, X. Multicolor Tuning of Lanthanide-Doped Nanoparticles by Single Wavelength Excitation. Acc. Chem. Res. 2014, 47, 1378−1385. (151) Zhang, Y.; Zhang, L.; Deng, R.; Tian, J.; Zong, Y.; Jin, D.; Liu, X. Multicolor Barcoding in a Single Upconversion Crystal. J. Am. Chem. Soc. 2014, 136, 4893−4896. (152) Wang, F.; Liu, X. G. Upconversion Multicolor Fine-Tuning: Visible to Near-Infrared Emission from Lanthanide-Doped NaYF4 Nanoparticles. J. Am. Chem. Soc. 2008, 130, 5642−5643. (153) Nam, S. H.; Bae, Y. M.; Park, Y. I.; Kim, J. H.; Kim, H. M.; Choi, J. S.; Lee, K. T.; Hyeon, T.; Suh, Y. D. Long-Term Real-Time Tracking of Lanthanide Ion Doped Upconverting Nanoparticles in Living Cells. Angew. Chem., Int. Ed. 2011, 50, 6093−6097. (154) Zhou, J.; Liu, Z.; Li, F. Upconversion Nanophosphors for Small-Animal Imaging. Chem. Soc. Rev. 2012, 41, 1323−1349. (155) Park, Y. I.; Lee, K. T.; Suh, Y. D.; Hyeon, T. Upconverting Nanoparticles: A Versatile Platform for Wide-Field Two-Photon Microscopy and Multi-Modal In Vivo Imaging. Chem. Soc. Rev. 2015, 44, 1302−1317. (156) Zhang, P.; Rogelj, S.; Nguyen, K.; Wheeler, D. Design of a Highly Sensitive and Specific Nucleotide Sensor Based on Photon Upconverting Particles. J. Am. Chem. Soc. 2006, 128, 12410−12411. 6211


Chemical Reviews

Review

(157) Chen, Z.; Chen, H.; Hu, H.; Yu, M.; Li, F.; Zhang, Q.; Zhou, Z.; Yi, T.; Huang, C. Versatile Synthesis Strategy for Carboxylic AcidFunctionalized Upconverting Nanophosphors as Biological Labels. J. Am. Chem. Soc. 2008, 130, 3023−3029. (158) Wang, L.; Li, Y. Green Upconversion Nanocrystals for DNA Detection. Chem. Commun. 2006, 28, 2557−2559. (159) Deng, R.; Xie, X.; Vendrell, M.; Chang, Y.-T.; Liu, X. Intracellular Glutathione Detection Using MnO2-Nanosheet-Modified Upconversion Nanoparticles. J. Am. Chem. Soc. 2011, 133, 20168− 20171. (160) Liu, J.; Liu, Y.; Liu, Q.; Li, C.; Sun, L.; Li, F. Iridium(III) Complex-Coated Nanosystem for Ratiometric Upconversion Luminescence Bioimaging of Cyanide Anions. J. Am. Chem. Soc. 2011, 133, 15276−15279. (161) Yao, L.; Zhou, J.; Liu, J.; Feng, W.; Li, F. Iridium-ComplexModified Upconversion Nanophosphors for Effective LRET Detection of Cyanide Anions in Pure Water. Adv. Funct. Mater. 2012, 22, 2667− 2672. (162) Li, Z.; Liang, T.; Lv, S.; Zhuang, Q.; Liu, Z. A Rationally Designed Upconversion Nanoprobe for In Vivo Detection of Hydroxyl Radical. J. Am. Chem. Soc. 2015, 137, 11179−11185. (163) Li, Z.; Lv, S.; Wang, Y.; Chen, S.; Liu, Z. Construction of LRET-Based Nanoprobe Using Upconversion Nanoparticles with Confined Emitters and Bared Surface as Luminophore. J. Am. Chem. Soc. 2015, 137, 3421−3427. (164) Peng, J.; Xu, W.; Teoh, C. L.; Han, S.; Kim, B.; Samanta, A.; Er, J. C.; Wang, L.; Yuan, L.; Liu, X.; et al. High-Efficiency In Vitro and In Vivo Detection of Zn2+ by Dye-Assembled Upconversion Nanoparticles. J. Am. Chem. Soc. 2015, 137, 2336−2342. (165) Liu, Q.; Peng, J.; Sun, L.; Li, F. High-Efficiency Upconversion Luminescent Sensing and Bioimaging of Hg(II) by Chromophoric Ruthenium Complex-Assembled Nanophosphors. ACS Nano 2011, 5, 8040−8048. (166) Liu, Y.; Chen, M.; Cao, T.; Sun, Y.; Li, C.; Liu, Q.; Yang, T.; Yao, L.; Feng, W.; Li, F. A Cyanine-Modified Nanosystem for In Vivo Upconversion Luminescence Bioimaging of Methylmercury. J. Am. Chem. Soc. 2013, 135, 9869−9876. (167) Huang, P.; Zheng, W.; Zhou, S.; Tu, D.; Chen, Z.; Zhu, H.; Li, R.; Ma, E.; Huang, M.; Chen, X. Lanthanide-Doped LiLuF 4 Upconversion Nanoprobes for the Detection of Disease Biomarkers. Angew. Chem., Int. Ed. 2014, 53, 1252−1257. (168) Wang, Y.; Shen, P.; Li, C.; Wang, Y.; Liu, Z. Upconversion Fluorescence Resonance Energy Transfer Based Biosensor for Ultrasensitive Detection of Matrix Metalloproteinase-2 in Blood. Anal. Chem. 2012, 84, 1466−1473. (169) Cen, Y.; Wu, Y.-M.; Kong, X.-J.; Wu, S.; Yu, R.-Q.; Chu, X. Phospholipid-Modified Upconversion Nanoprobe for Ratiometric Fluorescence Detection and Imaging of Phospholipase D in Cell Lysate and in Living Cells. Anal. Chem. 2014, 86, 7119−7127. (170) Zhou, L.; Wang, R.; Yao, C.; Li, X.; Wang, C.; Zhang, X.; Xu, C.; Zeng, A.; Zhao, D.; Zhang, F. Single-Band Upconversion Nanoprobes for Multiplexed Simultaneous in situ Molecular Mapping of Cancer Biomarkers. Nat. Commun. 2015, 6, 6938. (171) Achatz, D. E.; Meier, R. J.; Fischer, L. H.; Wolfbeis, O. S. Luminescent Sensing of Oxygen Using a Quenchable Probe and Upconverting Nanoparticles. Angew. Chem., Int. Ed. 2011, 50, 260− 263. (172) Liu, L.; Li, B.; Qin, R.; Zhao, H.; Ren, X.; Su, Z. Synthesis and Characterization of New Bifunctional Nanocomposites Possessing Upconversion and Oxygen-Sensing Properties. Nanotechnology 2010, 21, 285701. (173) Liu, J.; Liu, Y.; Bu, W.; Bu, J.; Sun, Y.; Du, J.; Shi, J. Ultrasensitive Nanosensors Based on Upconversion Nanoparticles for Selective Hypoxia Imaging In Vivo upon Near-Infrared Excitation. J. Am. Chem. Soc. 2014, 136, 9701−9709. (174) Castellano, F. N.; Lakowicz, J. R. A Water-Soluble Luminescence Oxygen Sensor. Photochem. Photobiol. 1998, 67, 179− 183.

(175) Zhang, Q.; Zhang, T.; Ge, J.; Yin, Y. Permeable Silica Shell through Surface-Protected Etching. Nano Lett. 2008, 8, 2867−2871. (176) Zhang, Q.; Lee, I.; Ge, J.; Zaera, F.; Yin, Y. Surface-Protected Etching of Mesoporous Oxide Shells for the Stabilization of Metal Nanocatalysts. Adv. Funct. Mater. 2010, 20, 2201−2214. (177) Wagner, T.; Haffer, S.; Weinberger, C.; Klaus, D.; Tiemann, M. Mesoporous Materials as Gas Sensors. Chem. Soc. Rev. 2013, 42, 4036−4053. (178) Basu, S.; Sachidanandan, C. Zebrafish: A Multifaceted Tool for Chemical Biologists. Chem. Rev. 2013, 113, 7952−7980. (179) Ko, S.-K.; Chen, X.; Yoon, J.; Shin, I. Zebrafish As A Good Vertebrate Model for Molecular Imaging Using Fluorescent Probes. Chem. Soc. Rev. 2011, 40, 2120−2130. (180) Berezin, M. Y.; Achilefu, S. Fluorescence Lifetime Measurements and Biological Imaging. Chem. Rev. 2010, 110, 2641−2684. (181) Stern, O.; Volmer, M. The Fading Time of Fluorescence. Physikalische Zeitschrift 1919, 20, 183−188. (182) Kurokawa, H.; Ito, H.; Inoue, M.; Tabata, K.; Sato, Y.; Yamagata, K.; Kizaka-Kondoh, S.; Kadonosono, T.; Yano, S.; Inoue, M.; et al. High Resolution Imaging of Intracellular Oxygen Concentration by Phosphorescence Lifetime. Sci. Rep. 2015, 5, 10657. (183) Rogers, G. W.; Brand, M. D.; Petrosyan, S.; Ashok, D.; Elorza, A. A.; Ferrick, D. A.; Murphy, A. N. High Throughput Microplate Respiratory Measurements Using Minimal Quantities of Isolated Mitochondria. PLoS One 2011, 6, e21746. (184) Parpaleix, A.; Houssen, Y. G.; Charpak, S. Imaging Local Neuronal Activity by Monitoring PO2 Transients in Capillaries. Nat. Med. 2013, 19, 241−246. (185) Brinas, R. P.; Troxler, T.; Hochstrasser, R. M.; Vinogradov, S. A. Phosphorescent Oxygen Sensor with Dendritic Protection and Two-Photon Absorbing Antenna. J. Am. Chem. Soc. 2005, 127, 11851− 11862. (186) Finikova, O. S.; Lebedev, A. Y.; Aprelev, A.; Troxler, T.; Gao, F.; Garnacho, C.; Muro, S.; Hochstrasser, R. M.; Vinogradov, S. A. Oxygen Microscopy by Two-Photon-Excited Phosphorescence. ChemPhysChem 2008, 9, 1673−1679. (187) Finikova, O. S.; Troxler, T.; Senes, A.; DeGrado, W. F.; Hochstrasser, R. M.; Vinogradov, S. A. Energy and Electron Transfer in Enhanced Two-Photon-Absorbing Systems with Triplet Cores. J. Phys. Chem. A 2007, 111, 6977−6990. (188) Sakadzic, S.; Roussakis, E.; Yaseen, M. A.; Mandeville, E. T.; Srinivasan, V. J.; Arai, K.; Ruvinskaya, S.; Devor, A.; Lo, E. H.; Vinogradov, S. A.; et al. Two-Photon High-Resolution Measurement of Partial Pressure of Oxygen in Cerebral Vasculature and Tissue. Nat. Methods 2010, 7, 755−759. (189) Sharan, M.; Vovenko, E. P.; Vadapalli, A.; Popel, A. S.; Pittman, R. N. Experimental and Theoretical Studies of Oxygen Gradients in Rat Pial Microvessels. J. Cereb. Blood Flow Metab. 2008, 28, 1597− 1604. (190) Lecoq, J.; Parpaleix, A.; Roussakis, E.; Ducros, M.; Houssen, Y. G.; Vinogradov, S. A.; Charpak, S. Simultaneous Two-Photon Imaging of Oxygen and Blood Flow in Deep Cerebral Vessels. Nat. Med. 2011, 17, 893−898. (191) Wolfbeis, O. S. Materials for Fluorescence-Based Optical Chemical Sensors. J. Mater. Chem. 2005, 15, 2657−2669. (192) Jiang, X.; Peng, J.; Wang, J.; Guo, X.; Zhao, D.; Ma, Y. IridiumBased High-Sensitivity Oxygen Sensors and Photosensitizers with Ultralong Triplet Lifetimes. ACS Appl. Mater. Interfaces 2016, 8, 3591−3600. (193) Nagl, S.; Baleizão, C.; Borisov, S. M.; Schäferling, M.; Berberan-Santos, M. N.; Wolfbeis, O. S. Optical Sensing and Imaging of Trace Oxygen with Record Response. Angew. Chem., Int. Ed. 2007, 46, 2317−2319. (194) Zhang, G.; Chen, J.; Payne, S. J.; Kooi, S. E.; Demas, J. N.; Fraser, C. L. Multi-Emissive Difluoroboron Dibenzoylmethane Polylactide Exhibiting Intense Fluorescence and Oxygen-Sensitive Room-Temperature Phosphorescence. J. Am. Chem. Soc. 2007, 129, 8942−8943. 6212


Chemical Reviews

Review

Imaging Tumour Hypoxia with Positron Emission Tomography. Br. J. Cancer 2015, 112, 238−250. (214) Wuest, M.; Wuest, F. Positron Emission Tomography Radiotracers for Imaging Hypoxia. J. Labelled Compd. Radiopharm. 2013, 56, 244−250. (215) Rajendran, J. G.; Mankoff, D. A.; O’Sullivan, F.; Peterson, L. M.; Schwartz, D. L.; Conrad, E. U.; Spence, A. M.; Muzi, M.; Farwell, D. G.; Krohn, K. A. Hypoxia and Glucose Metabolism in Malignant Tumors: Evaluation by [ 18 F]Fluoromisonidazole and [ 18 F]Fluorodeoxyglucose Positron Emission Tomography Imaging. Clin. Cancer Res. 2004, 10, 2245−2252. (216) McQuade, P.; Rowland, D. J.; Lewis, J. S.; Welch, M. J. Positron-Emitting Isotopes Produced on Biomedical Cyclotrons. Curr. Med. Chem. 2005, 12, 807−818. (217) Li, Z.; Conti, P. S. Radiopharmaceutical chemistry for positron emission tomography. Adv. Drug Delivery Rev. 2010, 62, 1031−1051. (218) Nunn, A.; Linder, K.; Strauss, H. W. Nitroimidazoles and Imaging Hypoxia. Eur. J. Nucl. Med. 1995, 22, 265−280. (219) Handley, M. G.; Medina, R. A.; Nagel, E.; Blower, P. J.; Southworth, R. PET Imaging of Cardiac Hypoxia: Opportunities and Challenges. J. Mol. Cell. Cardiol. 2011, 51, 640−650. (220) Whitmore, G.; Varghese, A. The Biological Properties of Reduced Nitroheterocyclics and Possible Underlying Biochemical Mechanisms. Biochem. Pharmacol. 1986, 35, 97−103. (221) Strauss, H. W.; Nunn, A.; Linder, K. Nitroimidazoles for Imaging Hypoxic Myocardium. J. Nucl. Cardiol. 1995, 2, 437−445. (222) Piert, M.; Machulla, H.-J.; Picchio, M.; Reischl, G.; Ziegler, S.; Kumar, P.; Wester, H.-J.; Beck, R.; McEwan, A. J. B.; Wiebe, L. I.; et al. Hypoxia-Specific Tumor Imaging with 18F-Fluoroazomycin Arabinoside. J. Nucl. Med. 2005, 46, 106−113. (223) Rajendran, J. G.; Wilson, D. C.; Conrad, E. U.; Peterson, L. M.; Bruckner, J. D.; Rasey, J. S.; Chin, L. K.; Hofstrand, P. D.; Grierson, J. R.; Eary, J. F.; et al. [18F]FMISO and [18F]FDG PET Imaging in Soft Tissue Sarcomas: Correlation of Hypoxia, Metabolism and VEGF Expression. Eur. J. Nucl. Med. Mol. Imaging 2003, 30, 695−704. (224) Carlin, S.; Humm, J. L. PET of Hypoxia: Current and Future Perspectives. J. Nucl. Med. 2012, 53, 1171−1174. (225) Swanson, K. R.; Chakraborty, G.; Wang, C. H.; Rockne, R.; Harpold, H. L. P.; Muzi, M.; Adamsen, T. C. H.; Krohn, K. A.; Spence, A. M. Complementary but Distinct Roles for MRI and 18FFluoromisonidazole PET in the Assessment of Human Glioblastomas. J. Nucl. Med. 2008, 50, 36−44. (226) Sato, J.; Kitagawa, Y.; Yamazaki, Y.; Hata, H.; Okamoto, S.; Shiga, T.; Shindoh, M.; Kuge, Y.; Tamaki, N. 18F-Fluoromisonidazole PET Uptake Is Correlated with Hypoxia-Inducible Factor-1α Expression in Oral Squamous Cell Carcinoma. J. Nucl. Med. 2013, 54, 1060−1065. (227) Cheng, J.; Lei, L.; Xu, J.; Sun, Y.; Zhang, Y.; Wang, X.; Pan, L.; Shao, Z.; Zhang, Y.; Liu, G. 18F-Fluoromisonidazole PET/CT: A Potential Tool for Predicting Primary Endocrine Therapy Resistance in Breast Cancer. J. Nucl. Med. 2013, 54, 333−340. (228) Vera, P.; Bohn, P.; Edet-Sanson, A.; Salles, A.; Hapdey, S.; Gardin, I.; Ménard, J.-F.; Modzelewski, R.; Thiberville, L.; Dubray, B. Simultaneous Positron Emission Tomography (PET) Assessment of Metabolism with 18F-fluoro-2-deoxy-d-glucose (FDG), Proliferation with 18F-fluoro-thymidine (FLT), and Hypoxia with 18fluoromisonidazole (F-miso) Before and During Radiotherapy in Patients with Non-Small-Cell Lung Cancer (NSCLC): A Pilot Study. Radiother. Oncol. 2011, 98, 109−116. (229) Hugonnet, F.; Fournier, L.; Medioni, J.; Smadja, C.; Hindié, E.; Huchet, V.; Itti, E.; Cuenod, C.-A.; Chatellier, G.; Oudard, S.; et al. Metastatic Renal Cell Carcinoma: Relationship Between Initial Metastasis Hypoxia, Change After 1 Month’s Sunitinib, and Therapeutic Response: An 18F-Fluoromisonidazole PET/CT Study. J. Nucl. Med. 2011, 52, 1048−1055. (230) Busk, M.; Horsman, M. R.; Overgaard, J. Resolution in PET hypoxia imaging: Voxel size matters. Acta Oncol. 2008, 47, 1201−1210. (231) Dubois, L. J.; Lieuwes, N. G.; Janssen, M. H. M.; Peeters, W. J. M.; Windhorst, A. D.; Walsh, J. C.; Kolb, H. C.; Ollers, M. C.; Bussink,

(195) Xu, S.; Evans, R. E.; Liu, T.; Zhang, G.; Demas, J. N.; Trindle, C. O.; Fraser, C. L. Aromatic Difluoroboron β-Diketonate Complexes: Effects of π-Conjugation and Media on Optical Properties. Inorg. Chem. 2013, 52, 3597−3610. (196) Kochmann, S.; Baleizão, C.; Berberan-Santos, M. N.; Wolfbeis, O. S. Sensing and Imaging of Oxygen with Parts per Billion Limits of Detection and Based on the Quenching of the Delayed Fluorescence of 13C70 Fullerene in Polymer Hosts. Anal. Chem. 2013, 85, 1300− 1304. (197) Borisov, S. M.; Vasylevska, A. S.; Krause, C.; Wolfbeis, O. S. Composite Luminescent Material for Dual Sensing of Oxygen and Temperature. Adv. Funct. Mater. 2006, 16, 1536−1542. (198) Lehner, P.; Staudinger, C.; Borisov, S. M.; Klimant, I. UltraSensitive Optical Oxygen Sensors for Characterization of Nearly Anoxic Systems. Nat. Commun. 2014, 5, 4460. (199) Bodmeier, R.; Chen, H.; Tyle, P.; Jarosz, P. Spontaneous Formation of Drug-Containing Acrylic Nanoparticles. J. Microencapsulation 1991, 8, 161−170. (200) Fercher, A.; Borisov, S. M.; Zhdanov, A. V.; Klimant, I.; Papkovsky, D. B. Intracellular O2 Sensing Probe Based on CellPenetrating Phosphorescent Nanoparticles. ACS Nano 2011, 5, 5499− 5508. (201) van der Aa, M. A. E. M.; Huth, U. S.; Häfele, S. Y.; Schubert, R.; Oosting, R. S.; Mastrobattista, E.; Hennink, W. E.; Peschka-Süss, R.; Koning, G. A.; Crommelin, D. J. A. Cellular Uptake of Cationic Polymer-DNA Complexes Via Caveolae Plays a Pivotal Role in Gene Transfection in COS-7 Cells. Pharm. Res. 2007, 24, 1590−1598. (202) Kondrashina, A. V.; Dmitriev, R. I.; Borisov, S. M.; Klimant, I.; O’Brien, I.; Nolan, Y. M.; Zhdanov, A. V.; Papkovsky, D. B. A Phosphorescent Nanoparticle-Based Probe for Sensing and Imaging of (Intra)Cellular Oxygen in Multiple Detection Modalities. Adv. Funct. Mater. 2012, 22, 4931−4939. (203) Lv, W.; Yang, T.; Yu, Q.; Zhao, Q.; Zhang, K. Y.; Liang, H.; Liu, S.; Li, F.; Huang, W. A Phosphorescent Iridium(III) ComplexModified Nanoprobe for Hypoxia Bioimaging via Time-Resolved Luminescence Microscopy. Adv. Sci. 2015, 2, 1500107. (204) Sørensen, B. S.; Hao, J.; Overgaard, J.; Vorum, H.; Honoré, B.; Alsner, J.; Horsman, M. R. Influence of Oxygen Concentration and pH on Expression of Hypoxia Induced Genes. Radiother. Oncol. 2005, 76, 187−193. (205) Helmlinger, G.; Yuan, F.; Dellian, M.; Jain, R. K. Interstitial pH and pO2 Gradients in Solid Tumors In Vivo: High-Resolution Measurements Reveal A Lack of Correlation. Nat. Med. 1997, 3, 177− 182. (206) Schäferling, M. The Art of Fluorescence Imaging with Chemical Sensors. Angew. Chem., Int. Ed. 2012, 51, 3532−3554. (207) Han, M.; Gao, X.; Su, J. Z.; Nie, S. Quantum-dot-tagged microbeads for multiplexed optical coding of biomolecules. Nat. Biotechnol. 2001, 19, 631−635. (208) Vasylevska, G. S.; Borisov, S. M.; Krause, C.; Wolfbeis, O. S. Indicator-Loaded Permeation-Selective Microbeads for Use in Fiber Optic Simultaneous Sensing of pH and Dissolved Oxygen. Chem. Mater. 2006, 18, 4609−4616. (209) Wang, X.-d.; Stolwijk, J. A.; Lang, T.; Sperber, M.; Meier, R. J.; Wegener, J.; Wolfbeis, O. S. Ultra-Small, Highly Stable, and Sensitive Dual Nanosensors for Imaging Intracellular Oxygen and pH in Cytosol. J. Am. Chem. Soc. 2012, 134, 17011−17014. (210) Meier, R. J.; Schreml, S.; Wang, X. D.; Landthaler, M.; Babilas, P.; Wolfbeis, O. S. Simultaneous Photographing of Oxygen and pH In Vivo Using Sensor Films. Angew. Chem., Int. Ed. 2011, 50, 10893− 10896. (211) Antaris, A. L.; Chen, H.; Cheng, K.; Sun, Y.; Hong, G.; Qu, C.; Diao, S.; Deng, Z.; Hu, X.; Zhang, B.; et al. A small-molecule dye for NIR-II imaging. Nat. Mater. 2016, 15, 235−242. (212) Gambhir, S. S. Molecular Imaging of Cancer with Positron Emission Tomography. Nat. Rev. Cancer 2002, 2, 683−693. (213) Fleming, I. N.; Manavaki, R.; Blower, P. J.; West, C.; Williams, K. J.; Harris, A. L.; Domarkas, J.; Lord, S.; Baldry, C.; Gilbert, F. J. 6213


Chemical Reviews

Review

J.; van Dongen, G. A. M. S.; et al. Preclinical Evaluation and Validation of [18F]HX4, A Promising Hypoxia Marker for PET Imaging. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 14620−14625. (232) Chen, L.; Zhang, Z.; Kolb, H. C.; Walsh, J. C.; Zhang, J.; Guan, Y. 18F-HX4 Hypoxia Imaging with PET/CT in Head and Neck Cancer: a Comparison with 18F-FMISO. Nucl. Med. Commun. 2012, 33, 1096−1102. (233) Airley, R. E.; Mobasheri, A. Hypoxic Regulation of Glucose Transport, Anaerobic Metabolism and Angiogenesis in Cancer: Novel Pathways and Targets for Anticancer Therapeutics. Chemotherapy 2007, 53, 233−256. (234) Busk, M.; Horsman, M. R.; Kristjansen, P. E. G.; van der Kogel, A. J.; Bussink, J.; Overgaard, J. Aerobic glycolysis in cancers: Implications for the usability of oxygen-responsive genes and fluorodeoxyglucose-PET as markers of tissue hypoxia. Int. J. Cancer 2008, 122, 2726−2734. (235) Christian, N.; Deheneffe, S.; Bol, A.; De Bast, M.; Labar, D.; Lee, J. A.; Grégoire, V. Is 18F-FDG a surrogate tracer to measure tumor hypoxia? Comparison with the hypoxic tracer 14C-EF3 in animal tumor models. Radiother. Oncol. 2010, 97, 183−188. (236) Dierckx, R.; Van de Wiele, C. FDG Uptake, a Surrogate of Tumour Hypoxia? Eur. J. Nucl. Med. Mol. Imaging 2008, 35, 1544− 1549. (237) Dehdashti, F.; Mintun, M. A.; Lewis, J. S.; Bradley, J.; Govindan, R.; Laforest, R.; Welch, M. J.; Siegel, B. A. In Vivo Assessment of Tumor Hypoxia in Lung Cancer with 60Cu-ATSM. Eur. J. Nucl. Med. Mol. Imaging 2003, 30, 844−850. (238) Fujibayashi, Y.; Taniuchi, H.; Yonekura, Y.; Ohtani, H. Copper-62-ATSM: A New Hypoxia Imaging Agent with High Membrane Permeability and Low Redox Potential. J. Nucl. Med. 1997, 38, 1155−1160. (239) Colombié, M.; Gouard, S.; Frindel, M.; Vidal, A.; Chérel, M.; Kraeber-Bodéré, F.; Rousseau, C.; Bourgeois, M. Focus on the Controversial Aspects of 64Cu-ATSM in Tumoral Hypoxia Mapping by PET Imaging. Front. Med. 2015, 2, 58. (240) Dearling, J. L. J.; Packard, A. B. Some Thoughts on The Mechanism of Cellular Trapping of Cu(II)-ATSM. Nucl. Med. Biol. 2010, 37, 237−243. (241) Lewis, J. S.; Laforest, R.; Dehdashti, F.; Grigsby, P. W.; Welch, M. J.; Siegel, B. A. An Imaging Comparison of 64Cu-ATSM and 60CuATSM in Cancer of the Uterine Cervix. J. Nucl. Med. 2008, 49, 1177− 1182. (242) Lee, N.; Nehmeh, S.; Schöder, H.; Fury, M.; Chan, K.; Ling, C. C.; Humm, J. Prospective Trial Incorporating Pre-/Mid-Treatment [18F]-Misonidazole Positron Emission Tomography for Head-andNeck Cancer Patients Undergoing Concurrent Chemoradiotherapy. Int. J. Radiat. Oncol., Biol., Phys. 2009, 75, 101−108. (243) Bortfeld, T. IMRT: a review and preview. Phys. Med. Biol. 2006, 51, R363−R379. (244) Horsman, M. R.; Mortensen, L. S.; Petersen, J. B.; Busk, M.; Overgaard, J. Imaging hypoxia to improve radiotherapy outcome. Nat. Rev. Clin. Oncol. 2012, 9, 674−687. (245) Rischin, D.; Hicks, R. J.; Fisher, R.; Binns, D.; Corry, J.; Porceddu, S.; Peters, L. J. Prognostic significance of F-18 -misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: A substudy of TransTasman Radiation Oncology Group study 98.02. J. Clin. Oncol. 2006, 24, 2098−2104. (246) Schenkman, L. Second Thoughts About CT Imaging. Science 2011, 331, 1002−1004. (247) Willmann, J. K.; van Bruggen, N.; Dinkelborg, L. M.; Gambhir, S. S. Molecular Imaging in Drug Development. Nat. Rev. Drug Discovery 2008, 7, 591−607. (248) De Leon-Rodriguez, L. M.; Lubag, A. J. M.; Malloy, C. R.; Martinez, G. V.; Gillies, R. J.; Sherry, A. D. Responsive MRI Agents for Sensing Metabolism In Vivo. Acc. Chem. Res. 2009, 42, 948−957.

(249) Do, Q. N.; Ratnakar, J. S.; Kovacs, Z.; Sherry, A. D. Redox- and Hypoxia-Responsive MRI Contrast Agents. ChemMedChem 2014, 9, 1116−1129. (250) Lee, N.; Hyeon, T. Designed Synthesis of Uniformly Sized Iron Oxide Nanoparticles for Efficient Magnetic Resonance Imaging Contrast Agents. Chem. Soc. Rev. 2012, 41, 2575−2589. (251) Prasad, P. V.; Edelman, R. R.; Epstein, F. H. Noninvasive Evaluation of Intrarenal Oxygenation with BOLD MRI. Circulation 1996, 94, 3271−3275. (252) Baudelet, C.; Gallez, B. How Does Blood Oxygen LevelDependent (BOLD) Contrast Correlate with Oxygen Partial Pressure (pO2) Inside Tumors? Magn. Reson. Med. 2002, 48, 980−986. (253) Zhao, D.; Jiang, L.; Hahn, E. W.; Mason, R. P. Comparison of 1 H Blood Oxygen Level−Dependent (BOLD) and 19F MRI to Investigate Tumor Oxygenation. Magn. Reson. Med. 2009, 62, 357− 364. (254) Dunn, J. F.; O’Hara, J. A.; Zaim-Wadghiri, Y.; Lei, H.; Meyerand, M. E.; Grinberg, O. Y.; Hou, H.; Hoopes, P. J.; Demidenko, E.; Swartz, H. M. Changes in Oxygenation of Intracranial Tumors with Carbogen: A BOLD MRI and EPR Oximetry Study. J. Magn. Reson. Imaging 2002, 16, 511−521. (255) Al-Hallaq, H.; River, J.; Zamora, M.; Oikawa, H.; Karczmar, G Correlation of Magnetic Resonance and Oxygen Microelectrode Measurements of Carbogen-Induced Changes in Tumor Oxygenation 1. Int. J. Radiat. Oncol., Biol., Phys. 1998, 41, 151−159. (256) Chopra, S.; Foltz, W. D.; Milosevic, M. F.; Toi, A.; Bristow, R. G.; Ménard, C.; Haider, M. A. Comparing Oxygen-Sensitive MRI (BOLD R2*) with Oxygen Electrode Measurements: A Pilot Study in Men with Prostate Cancer. Int. J. Radiat. Biol. 2009, 85, 805−813. (257) Jiang, L.; Weatherall, P. T.; McColl, R. W.; Tripathy, D.; Mason, R. P. Blood Oxygenation Level-Dependent (BOLD) Contrast Magnetic Resonance Imaging (MRI) for Prediction of Breast Cancer Chemotherapy Response: A Pilot Study. J. Magn. Reson. Imaging 2013, 37, 1083−1092. (258) Hallac, R. R.; Ding, Y.; Yuan, Q.; McColl, R. W.; Lea, J.; Sims, R. D.; Weatherall, P. T.; Mason, R. P. Oxygenation in Cervical Cancer and Normal Uterine Cervix Assessed Using Blood Oxygenation LevelDependent (BOLD) MRI at 3T. NMR Biomed. 2012, 25, 1321−1330. (259) Alonzi, R.; Padhani, A. R.; Maxwell, R. J.; Taylor, N. J.; Stirling, J. J.; Wilson, J. I.; d’Arcy, J. A.; Collins, D. J.; Saunders, M. I.; Hoskin, P. J. Carbogen Breathing Increases Prostate Cancer Oxygenation: a Translational MRI Study in Murine Xenografts and Humans. Br. J. Cancer 2009, 100, 644−648. (260) Zhao, Z.; Zhou, Z.; Bao, J.; Wang, Z.; Hu, J.; Chi, X.; Ni, K.; Wang, R.; Chen, X.; Chen, Z.; et al. Octapod Iron Oxide Nanoparticles as High-Performance T2 Contrast Agents for Magnetic Resonance Imaging. Nat. Commun. 2013, 4, 2266. (261) Na, H. B.; Song, I. C.; Hyeon, T. Inorganic Nanoparticles for MRI Contrast Agents. Adv. Mater. 2009, 21, 2133−2148. (262) Na, H. B.; Hyeon, T. Nanostructured T1 MRI Contrast Agents. J. Mater. Chem. 2009, 19, 6267−6273. (263) Werner, E. J.; Datta, A.; Jocher, C. J.; Raymond, K. N. HighRelaxivity MRI Contrast Agents: Where Coordination Chemistry Meets Medical Imaging. Angew. Chem., Int. Ed. 2008, 47, 8568−8580. (264) Iwaki, S.; Hanaoka, K.; Piao, W.; Komatsu, T.; Ueno, T.; Terai, T.; Nagano, T. Development of Hypoxia-Sensitive Gd3+-Based MRI Contrast Agents. Bioorg. Med. Chem. Lett. 2012, 22, 2798−2802. (265) Garcia, J.; Neelavalli, J.; Haacke, E. M.; Allen, M. J. EuIIContaining Cryptates as Contrast Agents for Ultra-High Field Strength Magnetic Resonance Imaging. Chem. Commun. 2011, 47, 12858−12860. (266) Burai, L.; Scopelliti, R.; Toth, E. EuII-Cryptate With Optimal Water Exchange and Electronic Relaxation: a Synthon for Potential pO2 Responsive Macromolecular MRI Contrast Agents. Chem. Commun. 2002, 2366−2367. (267) Burai, L.; Tóth, É.; Moreau, G.; Sour, A.; Scopelliti, R.; Merbach, A. E. Novel Macrocyclic EuII Complexes: Fast Water Exchange Related to an Extreme M-Owater Distance. Chem. - Eur. J. 2003, 9, 1394−1404. 6214


Chemical Reviews

Review

(268) Burai, L.; Tóth, É.; Seibig, S.; Scopelliti, R.; Merbach, A. E. Solution and Solid-State Characterization of EuII Chelates: A Possible Route Towards Redox Responsive MRI Contrast Agents. Chem. - Eur. J. 2000, 6, 3761−3770. (269) Gamage, N.-D. H.; Mei, Y.; Garcia, J.; Allen, M. J. Oxidatively Stable, Aqueous Europium(II) Complexes through Steric and Electronic Manipulation of Cryptand Coordination Chemistry. Angew. Chem., Int. Ed. 2010, 49, 8923−8925. (270) Chen, Y.; Chen, H.; Sun, Y.; Zheng, Y.; Zeng, D.; Li, F.; Zhang, S.; Wang, X.; Zhang, K.; Ma, M.; et al. Multifunctional Mesoporous Composite Nanocapsules for Highly Efficient MRI-Guided HighIntensity Focused Ultrasound Cancer Surgery. Angew. Chem., Int. Ed. 2011, 50, 12505−12509. (271) Kim, T.; Cho, E.-J.; Chae, Y.; Kim, M.; Oh, A.; Jin, J.; Lee, E.S.; Baik, H.; Haam, S.; Suh, J.-S.; et al. Urchin-Shaped Manganese Oxide Nanoparticles as pH-Responsive Activatable T1 Contrast Agents for Magnetic Resonance Imaging. Angew. Chem., Int. Ed. 2011, 50, 10589−10593. (272) Kim, T.; Momin, E.; Choi, J.; Yuan, K.; Zaidi, H.; Kim, J.; Park, M.; Lee, N.; McMahon, M. T.; Quinones-Hinojosa, A.; et al. Mesoporous Silica-Coated Hollow Manganese Oxide Nanoparticles as Positive T1 Contrast Agents for Labeling and MRI Tracking of Adipose-Derived Mesenchyrnal Stem Cells. J. Am. Chem. Soc. 2011, 133, 2955−2961. (273) Na, H. B.; Lee, J. H.; An, K.; Park, Y. I.; Park, M.; Lee, I. S.; Nam, D. H.; Kim, S. T.; Kim, S. H.; Kim, S. W.; et al. Development of A T1 Contrast Agent for Magnetic Resonance Imaging Using MnO Nanoparticles. Angew. Chem. 2007, 119, 5493−5497. (274) Cai, X.; Gao, W.; Ma, M.; Wu, M.; Zhang, L.; Zheng, Y.; Chen, H.; Shi, J. A Prussian Blue-Based Core−Shell Hollow-Structured Mesoporous Nanoparticle as a Smart Theranostic Agent with Ultrahigh pH-Responsive Longitudinal Relaxivity. Adv. Mater. 2015, 27, 6382−6389. (275) Gale, E. M.; Mukherjee, S.; Liu, C.; Loving, G. S.; Caravan, P. Structure-Redox-Relaxivity Relationships for Redox Responsive Manganese-Based Magnetic Resonance Imaging Probes. Inorg. Chem. 2014, 53, 10748−10761. (276) Aime, S.; Botta, M.; Gianolio, E.; Terreno, E. A p(O2)Responsive MRI Contrast Agent Based on the Redox Switch of Manganese(II/III) − Porphyrin Complexes. Angew. Chem., Int. Ed. 2000, 39, 747−750. (277) Loving, G. S.; Mukherjee, S.; Caravan, P. Redox-Activated Manganese-Based MR Contrast Agent. J. Am. Chem. Soc. 2013, 135, 4620−4623. (278) Aime, S.; Fedeli, F.; Sanino, A.; Terreno, E. A R2/R1 Ratiometric Procedure for a Concentration-Independent, pHResponsive, Gd(III)-Based MRI Agent. J. Am. Chem. Soc. 2006, 128, 11326−11327. (279) Okada, S.; Mizukami, S.; Sakata, T.; Matsumura, Y.; Yoshioka, Y.; Kikuchi, K. Ratiometric MRI Sensors Based on Core−Shell Nanoparticles for Quantitative pH Imaging. Adv. Mater. 2014, 26, 2989−2992. (280) Catanzaro, V.; Gringeri, C. V.; Menchise, V.; Padovan, S.; Boffa, C.; Dastrù, W.; Chaabane, L.; Digilio, G.; Aime, S. A R2p/R1p Ratiometric Procedure to Assess Matrix Metalloproteinase-2 Activity by Magnetic Resonance Imaging. Angew. Chem., Int. Ed. 2013, 52, 3926−3930. (281) Di Gregorio, E.; Ferrauto, G.; Gianolio, E.; Lanzardo, S.; Carrera, C.; Fedeli, F.; Aime, S. An MRI Method To Map Tumor Hypoxia Using Red Blood Cells Loaded with a pO2-Responsive GdAgent. ACS Nano 2015, 9, 8239−8248. (282) Aime, S.; Ascenzi, P.; Comoglio, E.; Fasano, M.; Paoletti, S. Molecular Recognition of R- and T-States of Human Adult Hemoglobin by a Paramagnetic Gd(III) Complex by Means of the Measurement of Solvent Water Proton Relaxation Rate. J. Am. Chem. Soc. 1995, 117, 9365−9366. (283) Terreno, E.; Castelli, D. D.; Viale, A.; Aime, S. Challenges for Molecular Magnetic Resonance Imaging. Chem. Rev. 2010, 110, 3019− 3042.

(284) Lippert, A. R.; Keshari, K. R.; Kurhanewicz, J.; Chang, C. J. A Hydrogen Peroxide-Responsive Hyperpolarized 13C MRI Contrast Agent. J. Am. Chem. Soc. 2011, 133, 3776−3779. (285) Reineri, F.; Viale, A.; Giovenzana, G.; Santelia, D.; Dastrù, W.; Gobetto, R.; Aime, S. New Hyperpolarized Contrast Agents for 13CMRI from Para-Hydrogenation of Oligooxyethylenic Alkynes. J. Am. Chem. Soc. 2008, 130, 15047−15053. (286) Mizukami, S.; Takikawa, R.; Sugihara, F.; Hori, Y.; Tochio, H.; Wälchli, M.; Shirakawa, M.; Kikuchi, K. Paramagnetic RelaxationBased 19F MRI Probe To Detect Protease Activity. J. Am. Chem. Soc. 2008, 130, 794−795. (287) Yuan, Y.; Sun, H.; Ge, S.; Wang, M.; Zhao, H.; Wang, L.; An, L.; Zhang, J.; Zhang, H.; Hu, B.; et al. Controlled Intracellular SelfAssembly and Disassembly of 19F Nanoparticles for MR Imaging of Caspase 3/7 in Zebrafish. ACS Nano 2015, 9, 761−768. (288) Shapiro, E. M.; Borthakur, A.; Gougoutas, A.; Reddy, R. 23Na MRI Accurately Measures Fixed Charge Density in Articular Cartilage. Magn. Reson. Med. 2002, 47, 284−291. (289) Kotera, N.; Tassali, N.; Léonce, E.; Boutin, C.; Berthault, P.; Brotin, T.; Dutasta, J.-P.; Delacour, L.; Traoré, T.; Buisson, D.-A.; et al. A Sensitive Zinc-Activated 129Xe MRI Probe. Angew. Chem. 2012, 124, 4176−4179. (290) Driehuys, B.; Cofer, G. P.; Pollaro, J.; Mackel, J. B.; Hedlund, L. W.; Johnson, G. A. Imaging Alveolar−Capillary Gas Transfer Using Hyperpolarized 129Xe MRI. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 18278−18283. (291) Tirotta, I.; Dichiarante, V.; Pigliacelli, C.; Cavallo, G.; Terraneo, G.; Bombelli, F. B.; Metrangolo, P.; Resnati, G. 19F Magnetic Resonance Imaging (MRI): From Design of Materials to Clinical Applications. Chem. Rev. 2015, 115, 1106−1129. (292) Srinivas, M.; Heerschap, A.; Ahrens, E. T.; Figdor, C. G.; Vries, I. J. M. d. 19F MRI for Quantitative In Vivo Cell Tracking. Trends Biotechnol. 2010, 28, 363−370. (293) Tanabe, K.; Harada, H.; Narazaki, M.; Tanaka, K.; Inafuku, K.; Komatsu, H.; Ito, T.; Yamada, H.; Chujo, Y.; Matsuda, T.; et al. Monitoring of Biological One-Electron Reduction by 19F NMR Using Hypoxia Selective Activation of an 19F-Labeled Indolequinone Derivative. J. Am. Chem. Soc. 2009, 131, 15982−15983. (294) Xie, D.; King, T. L.; Banerjee, A.; Kohli, V.; Que, E. L. Exploiting Copper Redox for 19F Magnetic Resonance-Based Detection of Cellular Hypoxia. J. Am. Chem. Soc. 2016, 138, 2937− 2940. (295) Clore, G. M.; Iwahara, J. Theory, Practice, and Applications of Paramagnetic Relaxation Enhancement for the Characterization of Transient Low-Population States of Biological Macromolecules and Their Complexes. Chem. Rev. 2009, 109, 4108−4139. (296) Ward, K.; Aletras, A.; Balaban, R. A New Class of Contrast Agents for MRI Based on Proton Chemical Exchange Dependent Saturation Transfer (CEST). J. Magn. Reson. 2000, 143, 79−87. (297) Zhang, S.; Merritt, M.; Woessner, D. E.; Lenkinski, R. E.; Sherry, A. D. PARACEST Agents: Modulating MRI Contrast via Water Proton Exchange. Acc. Chem. Res. 2003, 36, 783−790. (298) Viswanathan, S.; Kovacs, Z.; Green, K. N.; Ratnakar, S. J.; Sherry, A. D. Alternatives to Gadolinium-Based Metal Chelates for Magnetic Resonance Imaging. Chem. Rev. 2010, 110, 2960−3018. (299) Woods, M.; Woessner, D. E.; Sherry, A. D. Paramagnetic Lanthanide Complexes as PARACEST Agents for Medical Imaging. Chem. Soc. Rev. 2006, 35, 500−511. (300) Viswanathan, S.; Ratnakar, S. J.; Green, K. N.; Kovacs, Z.; De León-Rodríguez, L. M.; Sherry, A. D. Multi-Frequency PARACEST Agents Based on Europium(III)-DOTA-Tetraamide Ligands. Angew. Chem. 2009, 121, 9494−9497. (301) Ratnakar, S. J.; Woods, M.; Lubag, A. J. M.; Kovács, Z.; Sherry, A. D. Modulation of Water Exchange in Europium(III) DOTATetraamide Complexes via Electronic Substituent Effects. J. Am. Chem. Soc. 2008, 130, 6−7. (302) Ratnakar, S. J.; Viswanathan, S.; Kovacs, Z.; Jindal, A. K.; Green, K. N.; Sherry, A. D. Europium(III) DOTA-tetraamide 6215


Chemical Reviews

Review

Complexes as Redox-Active MRI Sensors. J. Am. Chem. Soc. 2012, 134, 5798−5800. (303) Ratnakar, S. J.; Soesbe, T. C.; Lumata, L. L.; Do, Q. N.; Viswanathan, S.; Lin, C.-Y.; Sherry, A. D.; Kovacs, Z. Modulation of CEST Images In Vivo by T1 Relaxation: A New Approach in the Design of Responsive PARACEST Agents. J. Am. Chem. Soc. 2013, 135, 14904−14907. (304) Vallet, P.; van Haverbeke, Y.; Bonnet, P. A.; Subra, G.; Chapat, J.-P.; Muller, R. N. Relaxivity Enhancement of Low Molecular Weight Nitroxide Stable Free Radicals: Importance of Structure and Medium. Magn. Reson. Med. 1994, 32, 11−15. (305) Tsitovich, P. B.; Spernyak, J. A.; Morrow, J. R. A RedoxActivated MRI Contrast Agent that Switches Between Paramagnetic and Diamagnetic States. Angew. Chem., Int. Ed. 2013, 52, 13997− 14000. (306) Lawrance, G. A.; Lay, P. A.; Sargeson, A. M. Organic Substituent Effects in Macrobicyclic (Hexaamine)cobalt(III/II) Complexes: A New Method of Obtaining Polar Substituent Constants. Inorg. Chem. 1990, 29, 4808−4816. (307) Bertini, I.; Luchinat, C.; Parigi, G.; Pierattelli, R. NMR Spectroscopy of Paramagnetic Metalloproteins. ChemBioChem 2005, 6, 1536−1549. (308) Dorazio, S. J.; Olatunde, A. O.; Spernyak, J. A.; Morrow, J. R. CoCEST: Cobalt(II) Amide-Appended ParaCEST MRI Contrast Agents. Chem. Commun. 2013, 49, 10025−10027. (309) Dorazio, S. J.; Tsitovich, P. B.; Siters, K. E.; Spernyak, J. A.; Morrow, J. R. Iron(II) PARACEST MRI Contrast Agents. J. Am. Chem. Soc. 2011, 133, 14154−14156. (310) Townsend, D.; Cherry, S. Combining Anatomy and Function: The Path to True Image Fusion. Eur. Radiol. 2001, 11, 1968−1974. (311) Townsend, D. W. Dual-Modality Imaging: Combining Anatomy and Function. J. Nucl. Med. 2008, 49, 938−955. (312) Louie, A. Y. Multimodality Imaging Probes: Design and Challenges. Chem. Rev. 2010, 110, 3146−3195. (313) Zhao, Z.; Fan, H.; Zhou, G.; Bai, H.; Liang, H.; Wang, R.; Zhang, X.; Tan, W. Activatable Fluorescence/MRI Bimodal Platform for Tumor Cell Imaging via MnO2 Nanosheet-Aptamer Nanoprobe. J. Am. Chem. Soc. 2014, 136, 11220−11223. (314) Tu, C.; Nagao, R.; Louie, A. Y. Multimodal MagneticResonance/Optical-Imaging Contrast Agent Sensitive to NADH. Angew. Chem., Int. Ed. 2009, 48, 6547−6551. (315) Tu, C.; Louie, A. Y. Photochromically-Controlled, ReversiblyActivated MRI and Optical Contrast Agent. Chem. Commun. 2007, 1331−1333. (316) Namgung, R.; Kim, W. J. A Highly Entangled Polymeric Nanoconstruct Assembled by siRNA and its Reduction-Triggered siRNA Release for Gene Silencing. Small 2012, 8, 3209−3219. (317) Mok, H.; Veiseh, O.; Fang, C.; Kievit, F. M.; Wang, F. Y.; Park, J. O.; Zhang, M. pH-Sensitive siRNA Nanovector for Targeted Gene Silencing and Cytotoxic Effect in Cancer Cells. Mol. Pharmaceutics 2010, 7, 1930−1939. (318) Auguste, D. T.; Furman, K.; Wong, A.; Fuller, J.; Armes, S. P.; Deming, T. J.; Langer, R. Triggered Release of siRNA from Poly(ethylene glycol)-Protected, pH-dependent Liposomes. J. Controlled Release 2008, 130, 266−274. (319) Sowers, M. A.; McCombs, J. R.; Wang, Y.; Paletta, J. T.; Morton, S. W.; Dreaden, E. C.; Boska, M. D.; Ottaviani, M. F.; Hammond, P. T.; Rajca, A.; et al. Redox-Responsive BranchedBottlebrush Polymers for In Vivo MRI and Fluorescence Imaging. Nat. Commun. 2014, 5, 5460. (320) Leitgeb, A.; Wappel, J.; Slugovc, C. The ROMP Toolbox Upgraded. Polymer 2010, 51, 2927−2946. (321) Blinco, J. P.; Fairfull-Smith, K. E.; Morrow, B. J.; Bottle, S. E. Profluorescent Nitroxides as Sensitive Probes of Oxidative Change and Free Radical Reactions. Aust. J. Chem. 2011, 64, 373−389. (322) Rajca, A.; Wang, Y.; Boska, M.; Paletta, J. T.; Olankitwanit, A.; Swanson, M. A.; Mitchell, D. G.; Eaton, S. S.; Eaton, G. R.; Rajca, S. Organic Radical Contrast Agents for Magnetic Resonance Imaging. J. Am. Chem. Soc. 2012, 134, 15724−15727.

(323) Bobko, A. A.; Kirilyuk, I. A.; Grigor’ev, I. A.; Zweier, J. L.; Khramtsov, V. V. Reversible Reduction of Nitroxides to Hydroxylamines: Roles for Ascorbate and Glutathione. Free Radical Biol. Med. 2007, 42, 404−412. (324) Geraldes, C. F. G. C.; Laurent, S. Classification and Basic Properties of Contrast Agents for Magnetic Resonance Imaging. Contrast Media Mol. Imaging 2009, 4, 1−23. (325) Longo, D. L.; Sun, P. Z.; Consolino, L.; Michelotti, F. C.; Uggeri, F.; Aime, S. A General MRI-CEST Ratiometric Approach for pH Imaging: Demonstration of In Vivo pH Mapping with Iobitridol. J. Am. Chem. Soc. 2014, 136, 14333−14336. (326) Terreno, E.; Boffa, C.; Menchise, V.; Fedeli, F.; Carrera, C.; Castelli, D. D.; Digilio, G.; Aime, S. Gadolinium-Doped LipoCEST Agents: A Potential Novel Class of Dual 1H-MRI Probes. Chem. Commun. 2011, 47, 4667−4669. (327) Rust, M. J.; Bates, M.; Zhuang, X. Sub-Diffraction-Limit Imaging by Stochastic Optical Reconstruction Microscopy (STORM). Nat. Methods 2006, 3, 793−796. (328) Weissleder, R.; Pittet, M. J. Imaging in The Era of Molecular Oncology. Nature 2008, 452, 580−589. (329) Ku, G.; Wang, L. V. Deeply Penetrating Photoacoustic Tomography in Biological Tissues Enhanced with An Optical Contrast Agent. Opt. Lett. 2005, 30, 507−509. (330) Wang, L. V.; Hu, S. Photoacoustic Tomography: In Vivo Imaging from Organelles to Organs. Science 2012, 335, 1458−1462. (331) Ntziachristos, V. Going Deeper Than Microscopy: The Optical Imaging Frontier in Biology. Nat. Methods 2010, 7, 603−614. (332) Zhang, H. F.; Maslov, K.; Stoica, G.; Wang, L. V. Functional Photoacoustic Microscopy for High-Resolution and Noninvasive In Vivo Imaging. Nat. Biotechnol. 2006, 24, 848−851. (333) Ntziachristos, V.; Razansky, D. Molecular Imaging by Means of Multispectral Optoacoustic Tomography (MSOT). Chem. Rev. 2010, 110, 2783−2794. (334) Kim, C.; Favazza, C.; Wang, L. H. V. In Vivo Photoacoustic Tomography of Chemicals: High-Resolution Functional and Molecular Optical Imaging at New Depths. Chem. Rev. 2010, 110, 2756− 2782. (335) Nie, L.; Chen, X. Structural and Functional Photoacoustic Molecular Tomography Aided by Emerging Contrast Agents. Chem. Soc. Rev. 2014, 43, 7132−7170. (336) Zhang, H. F.; Maslov, K.; Sivaramakrishnan, M.; Stoica, G.; Wang, L. V. Imaging of Hemoglobin Oxygen Saturation Variations in Single Vessels In Vivo Using Photoacoustic Microscopy. Appl. Phys. Lett. 2007, 90, 053901. (337) Horecker, B. L. The Absorption Spectra of Hemoglobin and Its Derivatives in The Visible and Near Infra-Red Regions. J. Biol. Chem. 1943, 148, 173−183. (338) Luke, G.; Yeager, D.; Emelianov, S. Biomedical Applications of Photoacoustic Imaging with Exogenous Contrast Agents. Ann. Biomed. Eng. 2012, 40, 422−437. (339) Li, M.-L.; Oh, J.-T.; Xie, X.; Ku, G.; Wang, W.; Li, C.; Lungu, G.; Stoica, G.; Wang, L. V. Simultaneous Molecular and Hypoxia Imaging of Brain Tumors In Vivo Using Spectroscopic Photoacoustic Tomography. Proc. IEEE 2008, 96, 481−489. (340) Wang, Y.; Hu, S.; Maslov, K.; Zhang, Y.; Xia, Y.; Wang, L. V. In Vivo Integrated Photoacoustic and Confocal Microscopy of Hemoglobin Oxygen Saturation and Oxygen Partial Pressure. Opt. Lett. 2011, 36, 1029−1031. (341) Shao, Q.; Morgounova, E.; Jiang, C. L.; Choi, J.; Bischof, J.; Ashkenazi, S. In Vivo Photoacoustic Lifetime Imaging of Tumor Hypoxia in Small Animals. J. Biomed. Opt. 2013, 18, 076019. (342) Ashkenazi, S.; Huang, S.-W.; Horvath, T.; Koo, Y.-E. L.; Kopelman, R. Photoacoustic Probing of Fluorophore Excited State Lifetime with Application to Oxygen Sensing. J. Biomed. Opt. 2008, 13, 034023. (343) Ashkenazi, S. Photoacoustic Lifetime Imaging of Dissolved Oxygen Using Methylene Blue. J. Biomed. Opt. 2010, 15, 040501. 6216


Chemical Reviews

Review

(344) Shao, Q.; Ashkenazi, S. Photoacoustic Lifetime Imaging for Direct In Vivo Tissue Oxygen Monitoring. J. Biomed. Opt. 2015, 20, 036004. (345) Gerling, M.; Zhao, Y.; Nania, S.; Norberg, K. J.; Verbeke, C. S.; Englert, B.; Kuiper, R. V.; Bergstrom, A.; Hassan, M.; Neesse, A.; et al. Real-Time Assessment of Tissue Hypoxia In Vivo with Combined Photoacoustics and High-Frequency Ultrasound. Theranostics 2014, 4, 604−613. (346) Eggeling, C.; Widengren, J.; Rigler, R.; Seidel, C. A. M. Photobleaching of Fluorescent Dyes under Conditions Used for Single-Molecule Detection: Evidence of Two-Step Photolysis. Anal. Chem. 1998, 70, 2651−2659. (347) Altınoğlu, E. I.; Russin, T. J.; Kaiser, J. M.; Barth, B. M.; Eklund, P. C.; Kester, M.; Adair, J. H. Near-Infrared Emitting Fluorophore-Doped Calcium Phosphate Nanoparticles for In Vivo Imaging of Human Breast Cancer. ACS Nano 2008, 2, 2075−2084. (348) Pu, K.; Shuhendler, A. J.; Jokerst, J. V.; Mei, J.; Gambhir, S. S.; Bao, Z.; Rao, J. Semiconducting polymer nanoparticles as photoacoustic molecular imaging probes in living mice. Nat. Nanotechnol. 2014, 9, 233−239. (349) Shannon, A. M.; Bouchier-Hayes, D. J.; Condron, C. M.; Toomey, D. Tumour Hypoxia, Chemotherapeutic Resistance and Hypoxia-Related Therapies. Cancer Treat. Rev. 2003, 29, 297−307. (350) Moeller, B.; Richardson, R.; Dewhirst, M. Hypoxia and Radiotherapy: Opportunities for Improved Outcomes in Cancer Treatment. Cancer Metastasis Rev. 2007, 26, 241−248. (351) Bertout, J. A.; Patel, S. A.; Simon, M. C. The Impact of O2 Availability on Human Cancer. Nat. Rev. Cancer 2008, 8, 967−975. (352) Zheng, D.-W.; Li, B.; Li, C.-X.; Fan, J.-X.; Lei, Q.; Li, C.; Xu, Z.; Zhang, X.-Z. Carbon-Dot-Decorated Carbon Nitride Nanoparticles for Enhanced Photodynamic Therapy against Hypoxic Tumor via Water Splitting. ACS Nano 2016, 10, 8715−8722. (353) Matsumoto, S.; Batra, S.; Saito, K.; Yasui, H.; Choudhuri, R.; Gadisetti, C.; Subramanian, S.; Devasahayam, N.; Munasinghe, J. P.; Mitchell, J. B.; et al. Antiangiogenic Agent Sunitinib Transiently Increases Tumor Oxygenation and Suppresses Cycling Hypoxia. Cancer Res. 2011, 71, 6350−6359. (354) Fogal, V.; Sugahara, K.; Ruoslahti, E.; Christian, S. Cell Surface Nucleolin Antagonist Causes Endothelial Cell Apoptosis and Normalization of Tumor Vasculature. Angiogenesis 2009, 12, 91−100. (355) Myers, A. L.; Williams, R. F.; Ng, C. Y.; Hartwich, J. E.; Davidoff, A. M. Bevacizumab-Induced Tumor Vessel Remodeling in Rhabdomyosarcoma Xenografts Increases The Effectiveness of Adjuvant Ionizing Radiation. J. Pediatr. Surg. 2010, 45, 1080−1085. (356) Carmeliet, P. Angiogenesis in Life, Disease and Medicine. Nature 2005, 438, 932−936. (357) Segers, J.; Fazio, V. D.; Ansiaux, R.; Martinive, P.; Feron, O.; Wallemacq, P.; Gallez, B. Potentiation of Cyclophosphamide Chemotherapy Using the Anti-Angiogenic Drug Thalidomide: Importance of Optimal Scheduling to Exploit The ‘Normalization’ Window of The Tumor Vasculature. Cancer Lett. 2006, 244, 129−135. (358) Jain, R. K. Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy. Science 2005, 307, 58−62. (359) Alayash, A. I. Hemoglobin-Based Blood Substitutes: Oxygen Carriers, Pressor Agents, or Oxidants? Nat. Biotechnol. 1999, 17, 545− 549. (360) Greenburg, A. G.; Kim, H. Hemoglobin-Based Oxygen Carriers. Crit. Care 2004, 8, S61−S64. (361) Wu, W.; Yang, Q.; Li, T.; Zhang, P.; Zhou, R. H.; Yang, C. M.; Wu, W.; Yang, Q. Hemoglobin-based Oxygen Carriers Combined with Anticancer Drugs May Enhance Sensitivity of Radiotherapy and Chemotherapy to Solid Tumors. Artif. Cell. Blood Sub. 2009, 37, 163− 165. (362) Trotta, F.; Cavalli, R. Characterization and Applications of New Hyper-Cross-Linked Cyclodextrins. Compos. Interfaces 2009, 16, 39−48. (363) Cavalli, R.; Akhter, A. K.; Bisazza, A.; Giustetto, P.; Trotta, F.; Vavia, P. Nanosponge Formulations as Oxygen Delivery Systems. Int. J. Pharm. 2010, 402, 254−257.

(364) Trotta, F.; Cavalli, R.; Martina, K.; Biasizzo, M.; Vitillo, J.; Bordiga, S.; Vavia, P.; Ansari, K. Cyclodextrin Nanosponges as Effective Gas Carriers. J. Inclusion Phenom. Mol. Recognit. Chem. 2011, 71, 189−194. (365) Abdi, S.; Choi, J.; Lau, H.; Lim, J. Controlled Release of Oxygen from PLGA-Alginate Layered Matrix and Its In Vitro Characterization on The Viability of Muscle Cells under Hypoxic Environment. Tissue Eng. Regener. Med. 2013, 10, 131−138. (366) Li, Z.; Guo, X.; Guan, J. An Oxygen Release System to Augment Cardiac Progenitor Cell Survival and Differentiation under Hypoxic Condition. Biomaterials 2012, 33, 5914−5923. (367) Pedraza, E.; Coronel, M. M.; Fraker, C. A.; Ricordi, C.; Stabler, C. L. Preventing Hypoxia-Induced Cell Death in Beta Cells and Islets via Hydrolytically Activated, Oxygen-Generating Biomaterials. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 4245−4250. (368) Wang, J.; Zhu, Y.; Bawa, H. K.; Ng, G.; Wu, Y.; Libera, M.; van der Mei, H. C.; Busscher, H. J.; Yu, X. Oxygen-Generating Nanofiber Cell Scaffolds with Antimicrobial Properties. ACS Appl. Mater. Interfaces 2011, 3, 67−73. (369) Oh, S. H.; Ward, C. L.; Atala, A.; Yoo, J. J.; Harrison, B. S. Oxygen Generating Scaffolds for Enhancing Engineered Tissue Survival. Biomaterials 2009, 30, 757−762. (370) Ward, C. L.; Corona, B. T.; Yoo, J. J.; Harrison, B. S.; Christ, G. J. Oxygen Generating Biomaterials Preserve Skeletal Muscle Homeostasis under Hypoxic and Ischemic Conditions. PLoS One 2013, 8, e72485. (371) Harrison, B. S.; Eberli, D.; Lee, S. J.; Atala, A.; Yoo, J. J. Oxygen Producing Biomaterials for Tissue Regeneration. Biomaterials 2007, 28, 4628−4634. (372) Benz, S.; Nötzli, S.; Siegel, J. S.; Eberli, D.; Jessen, H. J. Controlled Oxygen Release from Pyridone Endoperoxides Promotes Cell Survival under Anoxic Conditions. J. Med. Chem. 2013, 56, 10171−10182. (373) Castro, C. I.; Briceno, J. C. Perfluorocarbon-Based Oxygen Carriers: Review of Products and Trials. Artif. Organs 2010, 34, 622− 634. (374) Khattak, S. F.; Chin, K.-s.; Bhatia, S. R.; Roberts, S. C. Enhancing Oxygen Tension and Cellular Function in Alginate Cell Encapsulation Devices through The Use of Perfluorocarbons. Biotechnol. Bioeng. 2007, 96, 156−166. (375) Cheng, Y.; Cheng, H.; Jiang, C.; Qiu, X.; Wang, K.; Huan, W.; Yuan, A.; Wu, J.; Hu, Y. Perfluorocarbon Nanoparticles Enhance Reactive Oxygen Levels and Tumour Growth Inhibition in Photodynamic Therapy. Nat. Commun. 2015, 6, 8785. (376) Fuchs, J.; Thiele, J. The Role of Oxygen in Cutaneous Photodynamic Therapy. Free Radical Biol. Med. 1998, 24, 835−847. (377) Lee, H.-Y.; Kim, H.-W.; Lee, J. H.; Oh, S. H. Controlling Oxygen Release from Hollow Microparticles for Prolonged Cell Survival under Hypoxic Environment. Biomaterials 2015, 53, 583−591. (378) Lovell, J. F.; Liu, T. W. B.; Chen, J.; Zheng, G. Activatable Photosensitizers for Imaging and Therapy. Chem. Rev. 2010, 110, 2839−2857. (379) Wang, C.; Cheng, L.; Liu, Y.; Wang, X.; Ma, X.; Deng, Z.; Li, Y.; Liu, Z. Imaging-Guided pH-Sensitive Photodynamic Therapy Using Charge Reversible Upconversion Nanoparticles under NearInfrared Light. Adv. Funct. Mater. 2013, 23, 3077−3086. (380) Peng, C.-L.; Yang, L.-Y.; Luo, T.-Y.; Lai, P.-S.; Yang, S.-J.; Lin, W.-J.; Shieh, M.-J. Development of pH Sensitive 2(Diisopropylamino)Ethyl Methacrylate Based Nanoparticles for Photodynamic Therapy. Nanotechnology 2010, 21, 155103. (381) Tian, J.; Ding, L.; Xu, H.-J.; Shen, Z.; Ju, H.; Jia, L.; Bao, L.; Yu, J.-S. Cell-Specific and pH-Activatable Rubyrin-Loaded Nanoparticles for Highly Selective Near-Infrared Photodynamic Therapy against Cancer. J. Am. Chem. Soc. 2013, 135, 18850−18858. (382) Lau, J. T.; Lo, P.-C.; Jiang, X.-J.; Wang, Q.; Ng, D. K. A Dual Activatable Photosensitizer toward Targeted Photodynamic Therapy. J. Med. Chem. 2014, 57, 4088−4097. (383) Yogo, T.; Urano, Y.; Mizushima, A.; Sunahara, H.; Inoue, T.; Hirose, K.; Iino, M.; Kikuchi, K.; Nagano, T. Selective Photo6217


Chemical Reviews

Review

inactivation of Protein Function through Environment-Sensitive Switching of Singlet Oxygen Generation by Photosensitizer. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 28−32. (384) Cló, E.; Snyder, J. W.; Voigt, N. V.; Ogilby, P. R.; Gothelf, K. V. DNA-Programmed Control of Photosensitized Singlet Oxygen Production. J. Am. Chem. Soc. 2006, 128, 4200−4201. (385) Lo, P.-C.; Chen, J.; Stefflova, K.; Warren, M. S.; Navab, R.; Bandarchi, B.; Mullins, S.; Tsao, M.; Cheng, J. D.; Zheng, G. Photodynamic Molecular Beacon Triggered by Fibroblast Activation Protein on Cancer-Associated Fibroblasts for Diagnosis and Treatment of Epithelial Cancers. J. Med. Chem. 2009, 52, 358−368. (386) Zheng, G.; Chen, J.; Stefflova, K.; Jarvi, M.; Li, H.; Wilson, B. C. Photodynamic Molecular Beacon as An Activatable Photosensitizer Based on Protease-Controlled Singlet Oxygen Quenching and Activation. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 8989−8994. (387) Chen, J.; Stefflova, K.; Niedre, M. J.; Wilson, B. C.; Chance, B.; Glickson, J. D.; Zheng, G. Protease-Triggered Photosensitizing Beacon Based on Singlet Oxygen Quenching and Activation. J. Am. Chem. Soc. 2004, 126, 11450−11451. (388) Chen, H.; Tian, J.; He, W.; Guo, Z. H2O2-Activatable and O2Evolving Nanoparticles for Highly Efficient and Selective Photodynamic Therapy against Hypoxic Tumor Cells. J. Am. Chem. Soc. 2015, 137, 1539−1547. (389) Danhier, F.; Ansorena, E.; Silva, J. M.; Coco, R.; Le Breton, A.; Préat, V. PLGA-Based Nanoparticles: An Overview of Biomedical Applications. J. Controlled Release 2012, 161, 505−522. (390) Ke, C.-J.; Chiang, W.-L.; Liao, Z.-X.; Chen, H.-L.; Lai, P.-S.; Sun, J.-S.; Sung, H.-W. Real-Time Visualization of pH-Responsive PLGA Hollow Particles Containing A Gas-Generating Agent Targeted for Acidic Organelles for Overcoming Multi-Drug Resistance. Biomaterials 2013, 34, 1−10. (391) Sahu, A.; Choi, W. I.; Lee, J. H.; Tae, G. Graphene Oxide Mediated Delivery of Methylene Blue for Combined Photodynamic and Photothermal Therapy. Biomaterials 2013, 34, 6239−6248. (392) He, X.; Wu, X.; Wang, K.; Shi, B.; Hai, L. Methylene BlueEncapsulated Phosphonate-Terminated Silica Nanoparticles for Simultaneous In Vivo Imaging and Photodynamic Therapy. Biomaterials 2009, 30, 5601−5609. (393) Chen, H.; He, W.; Guo, Z. An H2O2-Responsive Nanocarrier for Dual-Release of Platinum Anticancer Drugs and O2: Controlled Release and Enhanced Cytotoxicity Against Cisplatin Resistant Cancer Cells. Chem. Commun. 2014, 50, 9714−9717. (394) Prasad, P.; Gordijo, C. R.; Abbasi, A. Z.; Maeda, A.; Ip, A.; Rauth, A. M.; DaCosta, R. S.; Wu, X. Y. Multifunctional Albumin− MnO2 Nanoparticles Modulate Solid Tumor Microenvironment by Attenuating Hypoxia, Acidosis, Vascular Endothelial Growth Factor and Enhance Radiation Response. ACS Nano 2014, 8, 3202−3212. (395) Gordijo, C. R.; Abbasi, A. Z.; Amini, M. A.; Lip, H. Y.; Maeda, A.; Cai, P.; O’Brien, P. J.; DaCosta, R. S.; Rauth, A. M.; Wu, X. Y. Design of Hybrid MnO2-Polymer-Lipid Nanoparticles with Tunable Oxygen Generation Rates and Tumor Accumulation for Cancer Treatment. Adv. Funct. Mater. 2015, 25, 1858−1872. (396) Woodhams, J. H.; MacRobert, A. J.; Bown, S. G. The Role of Oxygen Monitoring During Photodynamic Therapy and Its Potential for Treatment Dosimetry. Photoch. Photobio. Sci. 2007, 6, 1246−1256. (397) Wang, H.-W.; Putt, M. E.; Emanuele, M. J.; Shin, D. B.; Glatstein, E.; Yodh, A. G.; Busch, T. M. Treatment-Induced Changes in Tumor Oxygenation Predict Photodynamic Therapy Outcome. Cancer Res. 2004, 64, 7553−7561. (398) Shi, H. F.; Ma, X.; Zhao, Q.; Liu, B.; Qu, Q. Y.; An, Z. F.; Zhao, Y. L.; Huang, W. Ultrasmall Phosphorescent Polymer Dots for Ratiometric Oxygen Sensing and Photodynamic Cancer Therapy. Adv. Funct. Mater. 2014, 24, 4823−4830. (399) Lincoln, R.; Kohler, L.; Monro, S.; Yin, H.; Stephenson, M.; Zong, R.; Chouai, A.; Dorsey, C.; Hennigar, R.; Thummel, R. P.; et al. Exploitation of Long-Lived 3IL Excited States for Metal−Organic Photodynamic Therapy: Verification in a Metastatic Melanoma Model. J. Am. Chem. Soc. 2013, 135, 17161−17175.

(400) Zhou, X.; Liang, H.; Jiang, P.; Zhang, K. Y.; Liu, S.; Yang, T.; Zhao, Q.; Yang, L.; Lv, W.; Yu, Q.; et al. Multifunctional Phosphorescent Conjugated Polymer Dots for Hypoxia Imaging and Photodynamic Therapy of Cancer Cells. Adv. Sci. 2016, 3, 1500155. (401) Fan, W.; Bu, W.; Shen, B.; He, Q.; Cui, Z.; Liu, Y.; Zheng, X.; Zhao, K.; Shi, J. Intelligent MnO2 Nanosheets Anchored with Upconversion Nanoprobes for Concurrent pH-/H2O2-Responsive UCL Imaging and Oxygen-Elevated Synergetic Therapy. Adv. Mater. 2015, 27, 4155−4161. (402) Chen, Q.; Feng, L.; Liu, J.; Zhu, W.; Dong, Z.; Wu, Y.; Liu, Z. Intelligent Albumin−MnO2 Nanoparticles as pH-/H2O2-Responsive Dissociable Nanocarriers to Modulate Tumor Hypoxia for Effective Combination Therapy. Adv. Mater. 2016, 28, 7129−7136. (403) Song, M.; Liu, T.; Shi, C.; Zhang, X.; Chen, X. Bioconjugated Manganese Dioxide Nanoparticles Enhance Chemotherapy Response by Priming Tumor-Associated Macrophages toward M1-like Phenotype and Attenuating Tumor Hypoxia. ACS Nano 2016, 10, 633−647. (404) Chen, Y.; Ye, D.; Wu, M.; Chen, H.; Zhang, L.; Shi, J.; Wang, L. Break-up of Two-Dimensional MnO2 Nanosheets Promotes Ultrasensitive pH-Triggered Theranostics of Cancer. Adv. Mater. 2014, 26, 7019−7026. (405) Liu, J.; Bu, J.; Bu, W.; Zhang, S.; Pan, L.; Fan, W.; Chen, F.; Zhou, L.; Peng, W.; Zhao, K.; et al. Real-Time In Vivo Quantitative Monitoring of Drug Release by Dual-Mode Magnetic Resonance and Upconverted Luminescence Imaging. Angew. Chem., Int. Ed. 2014, 53, 4551−4555. (406) Denko, N. C. Hypoxia, HIF1 and Glucose Metabolism in The Solid Tumour. Nat. Rev. Cancer 2008, 8, 705−713. (407) Carmeliet, P.; Jain, R. K. Angiogenesis in Cancer and Other Diseases. Nature 2000, 407, 249−257. (408) Ferrara, N.; Gerber, H.-P.; LeCouter, J. The Biology of VEGF and Its Receptors. Nat. Med. 2003, 9, 669−676. (409) Tibbitt, M. W.; Dahlman, J. E.; Langer, R. Emerging Frontiers in Drug Delivery. J. Am. Chem. Soc. 2016, 138, 704−717. (410) Yang, P.; Gai, S.; Lin, J. Functionalized Mesoporous Silica Materials for Controlled Drug Delivery. Chem. Soc. Rev. 2012, 41, 3679−3698. (411) Torney, F.; Trewyn, B. G.; Lin, V. S. Y.; Wang, K. Mesoporous Silica Nanoparticles Deliver DNA and Chemicals into Plants. Nat. Nanotechnol. 2007, 2, 295−300. (412) Tang, F.; Li, L.; Chen, D. Mesoporous Silica Nanoparticles: Synthesis, Biocompatibility and Drug Delivery. Adv. Mater. 2012, 24, 1504−1534. (413) He, Q.; Shi, J. MSN Anti-Cancer Nanomedicines: Chemotherapy Enhancement, Overcoming of Drug Resistance, and Metastasis Inhibition. Adv. Mater. 2014, 26, 391−411. (414) He, L.; Lai, H.; Chen, T. Dual-Function Nanosystem for Synergetic Cancer Chemo-/Radiotherapy through ROS-Mediated Signaling Pathways. Biomaterials 2015, 51, 30−42. (415) Liu, J.; Bu, W.; Pan, L.; Shi, J. NIR-Triggered Anticancer Drug Delivery by Upconverting Nanoparticles with Integrated AzobenzeneModified Mesoporous Silica. Angew. Chem., Int. Ed. 2013, 52, 4375− 4379. (416) Li, Y.; Shi, J. Hollow-Structured Mesoporous Materials: Chemical Synthesis, Functionalization and Applications. Adv. Mater. 2014, 26, 3176−3205. (417) Fan, W.; Shen, B.; Bu, W.; Chen, F.; Zhao, K.; Zhang, S.; Zhou, L.; Peng, W.; Xiao, Q.; Xing, H.; et al. Rattle-Structured Multifunctional Nanotheranostics for Synergetic Chemo-/Radiotherapy and Simultaneous Magnetic/Luminescent Dual-Mode Imaging. J. Am. Chem. Soc. 2013, 135, 6494−6503. (418) Chen, F.; Bu, W.; Zhang, S.; Liu, X.; Liu, J.; Xing, H.; Xiao, Q.; Zhou, L.; Peng, W.; Wang, L.; et al. Positive and Negative Lattice Shielding Effects Co-existing in Gd (III) Ion Doped Bifunctional Upconversion Nanoprobes. Adv. Funct. Mater. 2011, 21, 4285−4294. (419) Liu, C.; Gao, Z.; Zeng, J.; Hou, Y.; Fang, F.; Li, Y.; Qiao, R.; Shen, L.; Lei, H.; Yang, W.; et al. Magnetic/Upconversion Fluorescent NaGdF4:Yb,Er Nanoparticle-Based Dual-Modal Molecular Probes for Imaging Tiny Tumors In Vivo. ACS Nano 2013, 7, 7227−7240. 6218


Chemical Reviews

Review

(420) Xia, A.; Chen, M.; Gao, Y.; Wu, D.; Feng, W.; Li, F. Gd3+ Complex-Modified NaLuF4-Based Upconversion Nanophosphors for Trimodality Imaging of NIR-to-NIR Upconversion Luminescence, XRay Computed Tomography and Magnetic Resonance. Biomaterials 2012, 33, 5394−5405. (421) Ni, D.; Zhang, J.; Bu, W.; Xing, H.; Han, F.; Xiao, Q.; Yao, Z.; Chen, F.; He, Q.; Liu, J.; et al. Dual-Targeting Upconversion Nanoprobes across the Blood-Brain Barrier for Magnetic Resonance/Fluorescence Imaging of Intracranial Glioblastoma. ACS Nano 2014, 8, 1231−1242. (422) Xing, H.; Zheng, X.; Ren, Q.; Bu, W.; Ge, W.; Xiao, Q.; Zhang, S.; Wei, C.; Qu, H.; Wang, Z.; et al. Computed Tomography ImagingGuided Radiotherapy by Targeting Upconversion Nanocubes with Significant Imaging and Radiosensitization Enhancements. Sci. Rep. 2013, 3, 1751. (423) Pan, L.; He, Q.; Liu, J.; Chen, Y.; Ma, M.; Zhang, L.; Shi, J. Nuclear-Targeted Drug Delivery of TAT Peptide-Conjugated Monodisperse Mesoporous Silica Nanoparticles. J. Am. Chem. Soc. 2012, 134, 5722−5725. (424) Pan, L.; Liu, J.; He, Q.; Wang, L.; Shi, J. Overcoming Multidrug Resistance of Cancer Cells by Direct Intranuclear Drug Delivery Using TAT-Conjugated Mesoporous Silica Nanoparticles. Biomaterials 2013, 34, 2719−2730. (425) Fan, W.; Shen, B.; Bu, W.; Zheng, X.; He, Q.; Cui, Z.; Zhao, K.; Zhang, S.; Shi, J. Design of An Intelligent Sub-50 nm Nucleartargeting Nanotheranostic System for Imaging Guided Intranuclear Radiosensitization. Chem. Sci. 2015, 6, 1747−1753. (426) Liu, Y.; Liu, Y.; Bu, W.; Xiao, Q.; Sun, Y.; Zhao, K.; Fan, W.; Liu, J.; Shi, J. Radiation-/Hypoxia-Induced Solid Tumor Metastasis and Regrowth Inhibited by Hypoxia-Specific Upconversion Nanoradiosensitizer. Biomaterials 2015, 49, 1−8. (427) De Ridder, M.; Verellen, D.; Verovski, V.; Storme, G. Hypoxic Tumor Cell Radiosensitization through Nitric Oxide. Nitric Oxide 2008, 19, 164−169. (428) Kim, J.; Yung, B. C.; Kim, W. J.; Chen, X. Combination of Nitric Oxide and Drug Delivery Systems: Tools for Overcoming Drug Resistance in Chemotherapy. J. Controlled Release 2016, 10.1016/ j.jconrel.2016.12.026. (429) Huang, L. E.; Willmore, W. G.; Gu, J.; Goldberg, M. A.; Bunn, H. F. Inhibition of Hypoxia-inducible Factor 1 Activation by Carbon Monoxide and Nitric Oxide: Implications for Oxygen Sensing and Signaling. J. Biol. Chem. 1999, 274, 9038−9044. (430) Cook, T.; Wang, Z.; Alber, S.; Liu, K.; Watkins, S. C.; Vodovotz, Y.; Billiar, T. R.; Blumberg, D. Nitric Oxide and Ionizing Radiation Synergistically Promote Apoptosis and Growth Inhibition of Cancer by Activating p53. Cancer Res. 2004, 64, 8015−8021. (431) Hagen, T.; Taylor, C. T.; Lam, F.; Moncada, S. Redistribution of Intracellular Oxygen in Hypoxia by Nitric Oxide: Effect on HIF1α. Science 2003, 302, 1975−1978. (432) Fan, W.; Bu, W.; Zhang, Z.; Shen, B.; Zhang, H.; He, Q.; Ni, D.; Cui, Z.; Zhao, K.; Bu, J.; et al. X-ray Radiation-Controlled NORelease for On-Demand Depth-Independent Hypoxic Radiosensitization. Angew. Chem., Int. Ed. 2015, 54, 14026−14030. (433) Choi, K. Y.; Yoon, H. Y.; Kim, J.-H.; Bae, S. M.; Park, R.-W.; Kang, Y. M.; Kim, I.-S.; Kwon, I. C.; Choi, K.; Jeong, S. Y.; et al. Smart Nanocarrier Based on PEGylated Hyaluronic Acid for Cancer Therapy. ACS Nano 2011, 5, 8591−8599. (434) Ma, N.; Xu, H.; An, L.; Li, J.; Sun, Z.; Zhang, X. RadiationSensitive Diselenide Block Co-polymer Micellar Aggregates: Toward the Combination of Radiotherapy and Chemotherapy. Langmuir 2011, 27, 5874−5878. (435) Carter, J. D.; Cheng, N. N.; Qu, Y.; Suarez, G. D.; Guo, T. Nanoscale Energy Deposition by X-Ray Absorbing Nanostructures. J. Phys. Chem. B 2007, 111, 11622−11625. (436) Henderson, B. W.; Fingar, V. H. Relationship of Tumor Hypoxia and Response to Photodynamic Treatment in an Experimental Mouse Tumor. Cancer Res. 1987, 47, 3110−3114. (437) Maas, A. L.; Carter, S. L.; Wileyto, E. P.; Miller, J.; Yuan, M.; Yu, G.; Durham, A. C.; Busch, T. M. Tumor Vascular Microenviron-

ment Determines Responsiveness to Photodynamic Therapy. Cancer Res. 2012, 72, 2079−2088. (438) Camerin, M.; Rodgers, M. A. J.; Kenney, M. E.; Jori, G. Photothermal Sensitisation: Evidence for the Lack of Oxygen Effect on the Photosensitising Activity. Photoch. Photobio. Sci. 2005, 4, 251−253. (439) Choi, M.-R.; Stanton-Maxey, K. J.; Stanley, J. K.; Levin, C. S.; Bardhan, R.; Akin, D.; Badve, S.; Sturgis, J.; Robinson, J. P.; Bashir, R.; et al. A Cellular Trojan Horse for Delivery of Therapeutic Nanoparticles into Tumors. Nano Lett. 2007, 7, 3759−3765. (440) Cheng, L.; Wang, C.; Feng, L.; Yang, K.; Liu, Z. Functional Nanomaterials for Phototherapies of Cancer. Chem. Rev. 2014, 114, 10869−10939. (441) Jin, C. S.; Lovell, J. F.; Chen, J.; Zheng, G. Ablation of Hypoxic Tumors with Dose-Equivalent Photothermal, but Not Photodynamic, Therapy Using a Nanostructured Porphyrin Assembly. ACS Nano 2013, 7, 2541−2550. (442) O’Connor, A. E.; Gallagher, W. M.; Byrne, A. T. Porphyrin and Nonporphyrin Photosensitizers in Oncology: Preclinical and Clinical Advances in Photodynamic Therapy. Photochem. Photobiol. 2009, 85, 1053−1074. (443) Lovell, J. F.; Jin, C. S.; Huynh, E.; Jin, H.; Kim, C.; Rubinstein, J. L.; Chan, W. C. W.; Cao, W.; Wang, L. V.; Zheng, G. Porphysome Nanovesicles Generated by Porphyrin Bilayers for Use as Multimodal Biophotonic Contrast Agents. Nat. Mater. 2011, 10, 324−332. (444) Huang, X.; El-Sayed, I. H.; Qian, W.; El-Sayed, M. A. Cancer Cell Imaging and Photothermal Therapy in The Near-Infrared Region by Using Gold Nanorods. J. Am. Chem. Soc. 2006, 128, 2115−2120. (445) Yavuz, M. S.; Cheng, Y. Y.; Chen, J. Y.; Cobley, C. M.; Zhang, Q.; Rycenga, M.; Xie, J. W.; Kim, C.; Song, K. H.; Schwartz, A. G.; et al. Gold Nanocages Covered by Smart Polymers for Controlled Release with Near-Infrared Light. Nat. Mater. 2009, 8, 935−939. (446) Qin, Z.; Bischof, J. C. Thermophysical and Biological Responses of Gold Nanoparticle Laser Heating. Chem. Soc. Rev. 2012, 41, 1191−1217. (447) Dykman, L.; Khlebtsov, N. Gold Nanoparticles in Biomedical Applications: Recent Advances and Perspectives. Chem. Soc. Rev. 2012, 41, 2256−2282. (448) Shi Kam, N. W.; O’Connell, M.; Wisdom, J. A.; Dai, H. Carbon Nanotubes as Multifunctional Biological Transporters and NearInfrared Agents for Selective Cancer Cell Destruction. Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 11600−11605. (449) Robinson, J. T.; Tabakman, S. M.; Liang, Y.; Wang, H.; Sanchez Casalongue, H.; Vinh, D.; Dai, H. Ultrasmall Reduced Graphene Oxide with High Near-Infrared Absorbance for Photothermal Therapy. J. Am. Chem. Soc. 2011, 133, 6825−6831. (450) Chen, Y.; Tan, C.; Zhang, H.; Wang, L. Two-Dimensional Graphene Analogues for Biomedical Applications. Chem. Soc. Rev. 2015, 44, 2681−2701. (451) Yang, K.; Zhang, S.; Zhang, G.; Sun, X.; Lee, S.-T.; Liu, Z. Graphene in Mice: Ultrahigh In Vivo Tumor Uptake and Efficient Photothermal Therapy. Nano Lett. 2010, 10, 3318−3323. (452) Yin, W. Y.; Yan, L.; Yu, J.; Tian, G.; Zhou, L. J.; Zheng, X. P.; Zhang, X.; Yong, Y.; Li, J.; Gu, Z. J.; et al. High-Throughput Synthesis of Single-Layer MoS2 Nanosheets as a Near-Infrared PhotothermalTriggered Drug Delivery for Effective Cancer Therapy. ACS Nano 2014, 8, 6922−6933. (453) Zhang, H. Ultrathin Two-Dimensional Nanomaterials. ACS Nano 2015, 9, 9451−9469. (454) Chou, S. S.; Kaehr, B.; Kim, J.; Foley, B. M.; De, M.; Hopkins, P. E.; Huang, J.; Brinker, C. J.; Dravid, V. P. Chemically Exfoliated MoS2 as Near-Infrared Photothermal Agents. Angew. Chem. 2013, 125, 4254−4258. (455) Cheng, L.; He, W.; Gong, H.; Wang, C.; Chen, Q.; Cheng, Z.; Liu, Z. PEGylated Micelle Nanoparticles Encapsulating a NonFluorescent Near-Infrared Organic Dye as a Safe and Highly-Effective Photothermal Agent for In Vivo Cancer Therapy. Adv. Funct. Mater. 2013, 23, 5893−5902. 6219


Chemical Reviews

Review

magnetic nanoparticles for efficient heat induction. Nat. Nanotechnol. 2011, 6, 418−422. (473) Lee, N.; Yoo, D.; Ling, D.; Cho, M. H.; Hyeon, T.; Cheon, J. Iron Oxide Based Nanoparticles for Multimodal Imaging and Magnetoresponsive Therapy. Chem. Rev. 2015, 115, 10637−10689. (474) Chen, Y.; Jiang, L.; Wang, R.; Lu, M.; Zhang, Q.; Zhou, Y.; Wang, Z.; Lu, G.; Liang, P.; Ran, H.; et al. Injectable Smart PhaseTransformation Implants for Highly Efficient In Vivo MagneticHyperthermia Regression of Tumors. Adv. Mater. 2014, 26, 7468− 7473. (475) Liu, F.; Hou, Y.; Gao, S. Exchange-Coupled Nanocomposites: Chemical Synthesis, Characterization and Applications. Chem. Soc. Rev. 2014, 43, 8098−8113. (476) Yoo, D.; Jeong, H.; Noh, S.-H.; Lee, J.-H.; Cheon, J. Magnetically Triggered Dual Functional Nanoparticles for Resistance-Free Apoptotic Hyperthermia. Angew. Chem., Int. Ed. 2013, 52, 13047−13051. (477) Li, T.-J.; Huang, C.-C.; Ruan, P.-W.; Chuang, K.-Y.; Huang, K.J.; Shieh, D.-B.; Yeh, C.-S. In Vivo Anti-Cancer Efficacy of Magnetite Nanocrystal - Based System Using Locoregional Hyperthermia Combined with 5-Fluorouracil Chemotherapy. Biomaterials 2013, 34, 7873−7883. (478) Liu, X.; Chen, H.-j.; Chen, X.; Parini, C.; Wen, D. Low Frequency Heating of Gold Nanoparticle Dispersions for NonInvasive Thermal Therapies. Nanoscale 2012, 4, 3945−3953. (479) Collins, C. B.; McCoy, R. S.; Ackerson, B. J.; Collins, G. J.; Ackerson, C. J. Radiofrequency Heating Pathways for Gold Nanoparticles. Nanoscale 2014, 6, 8459−8472. (480) Shi, H.; Niu, M.; Tan, L.; Liu, T.; Shao, H.; Fu, C.; Ren, X.; Ma, T.; Ren, J.; Li, L.; et al. A Smart All-In-One Theranostic Platform for CT Imaging Guided Tumor Microwave Thermotherapy Based on IL@ZrO2 Nanoparticles. Chem. Sci. 2015, 6, 5016−5026. (481) Shi, H.; Liu, T.; Fu, C.; Li, L.; Tan, L.; Wang, J.; Ren, X.; Ren, J.; Wang, J.; Meng, X. Insights into A Microwave Susceptible Agent for Minimally Invasive Microwave Tumor Thermal Therapy. Biomaterials 2015, 44, 91−102. (482) Du, Q.; Fu, C.; Tie, J.; Liu, T.; Li, L.; Ren, X.; Huang, Z.; Liu, H.; Tang, F.; Li, L.; et al. Gelatin Microcapsules for Enhanced Microwave Tumor Hyperthermia. Nanoscale 2015, 7, 3147−3154. (483) Huang, J.; Xu, J. S.; Xu, R. X. Heat-Sensitive Microbubbles for Intraoperative Assessment of Cancer Ablation Margins. Biomaterials 2010, 31, 1278−1286. (484) Moon, G. D.; Choi, S.-W.; Cai, X.; Li, W.; Cho, E. C.; Jeong, U.; Wang, L. V.; Xia, Y. A New Theranostic System Based on Gold Nanocages and Phase-Change Materials with Unique Features for Photoacoustic Imaging and Controlled Release. J. Am. Chem. Soc. 2011, 133, 4762−4765. (485) Horsman, M. R.; Overgaard, J. Hyperthermia: a Potent Enhancer of Radiotherapy. Clin. Oncol. 2007, 19, 418−426. (486) Lal, S.; Clare, S. E.; Halas, N. J. Nanoshell-Enabled Photothermal Cancer Therapy: Impending Clinical Impact. Acc. Chem. Res. 2008, 41, 1842−1851. (487) Zhou, M.; Zhang, R.; Huang, M.; Lu, W.; Song, S.; Melancon, M. P.; Tian, M.; Liang, D.; Li, C. A Chelator-Free Multifunctional [64Cu]CuS Nanoparticle Platform for Simultaneous Micro-PET/CT Imaging and Photothermal Ablation Therapy. J. Am. Chem. Soc. 2010, 132, 15351−15358. (488) Tian, Q.; Tang, M.; Sun, Y.; Zou, R.; Chen, Z.; Zhu, M.; Yang, S.; Wang, J.; Wang, J.; Hu, J. Hydrophilic Flower-Like CuS Superstructures as an Efficient 980 nm Laser-Driven Photothermal Agent for Ablation of Cancer Cells. Adv. Mater. 2011, 23, 3542−3547. (489) Zhou, M.; Chen, Y.; Adachi, M.; Wen, X.; Erwin, B.; Mawlawi, O.; Lai, S. Y.; Li, C. Single Agent Nanoparticle for Radiotherapy and Radio-Photothermal Therapy in Anaplastic Thyroid Cancer. Biomaterials 2015, 57, 41−49. (490) Yi, X.; Yang, K.; Liang, C.; Zhong, X.; Ning, P.; Song, G.; Wang, D.; Ge, C.; Chen, C.; Chai, Z.; et al. Imaging-Guided Combined Photothermal and Radiotherapy to Treat Subcutaneous

(456) Cheng, L.; Yang, K.; Chen, Q.; Liu, Z. Organic Stealth Nanoparticles for Highly Effective In Vivo Near-Infrared Photothermal Therapy of Cancer. ACS Nano 2012, 6, 5605−5613. (457) Yang, K.; Xu, H.; Cheng, L.; Sun, C.; Wang, J.; Liu, Z. In Vitro and In Vivo Near-Infrared Photothermal Therapy of Cancer Using Polypyrrole Organic Nanoparticles. Adv. Mater. 2012, 24, 5586−5592. (458) Kuo, W.-S.; Chang, C.-N.; Chang, Y.-T.; Yang, M.-H.; Chien, Y.-H.; Chen, S.-J.; Yeh, C.-S. Gold Nanorods in Photodynamic Therapy, as Hyperthermia Agents, and in Near-Infrared Optical Imaging. Angew. Chem., Int. Ed. 2010, 49, 2711−2715. (459) Jang, B.; Park, J.-Y.; Tung, C.-H.; Kim, I.-H.; Choi, Y. Gold Nanorod−Photosensitizer Complex for Near-Infrared Fluorescence Imaging and Photodynamic/Photothermal Therapy In Vivo. ACS Nano 2011, 5, 1086−1094. (460) Wang, J.; Zhu, G.; You, M.; Song, E.; Shukoor, M. I.; Zhang, K.; Altman, M. B.; Chen, Y.; Zhu, Z.; Huang, C. Z.; et al. Assembly of Aptamer Switch Probes and Photosensitizer on Gold Nanorods for Targeted Photothermal and Photodynamic Cancer Therapy. ACS Nano 2012, 6, 5070−5077. (461) Tian, B.; Wang, C.; Zhang, S.; Feng, L.; Liu, Z. Photothermally Enhanced Photodynamic Therapy Delivered by Nano-Graphene Oxide. ACS Nano 2011, 5, 7000−7009. (462) Wang, S.; Huang, P.; Nie, L.; Xing, R.; Liu, D.; Wang, Z.; Lin, J.; Chen, S.; Niu, G.; Lu, G.; et al. Single Continuous Wave Laser Induced Photodynamic/Plasmonic Photothermal Therapy Using Photosensitizer-Functionalized Gold Nanostars. Adv. Mater. 2013, 25, 3055−3061. (463) Zhang, M.; Murakami, T.; Ajima, K.; Tsuchida, K.; Sandanayaka, A. S. D.; Ito, O.; Iijima, S.; Yudasaka, M. Fabrication of ZnPc/protein Nanohorns for Double Photodynamic and Hyperthermic Cancer Phototherapy. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 14773−14778. (464) Lin, J.; Wang, S.; Huang, P.; Wang, Z.; Chen, S.; Niu, G.; Li, W.; He, J.; Cui, D.; Lu, G.; et al. Photosensitizer-Loaded Gold Vesicles with Strong Plasmonic Coupling Effect for Imaging-Guided Photothermal/Photodynamic Therapy. ACS Nano 2013, 7, 5320−5329. (465) Li, Y.; Lin, T.-y.; Luo, Y.; Liu, Q.; Xiao, W.; Guo, W.; Lac, D.; Zhang, H.; Feng, C.; Wachsmann-Hogiu, S.; et al. A Smart and Versatile Theranostic Nanomedicine Platform Based on Nanoporphyrin. Nat. Commun. 2014, 5, 4712. (466) Gao, L.; Fei, J.; Zhao, J.; Li, H.; Cui, Y.; Li, J. HypocrellinLoaded Gold Nanocages with High Two-Photon Efficiency for Photothermal/Photodynamic Cancer Therapy in Vitro. ACS Nano 2012, 6, 8030−8040. (467) Sheng, Z. H.; Hu, D. H.; Zheng, M. B.; Zhao, P. F.; Liu, H. L.; Gao, D. Y.; Gong, P.; Gao, G. H.; Zhang, P. F.; Ma, Y. F.; et al. Smart Human Serum Albumin-Indocyanine Green Nanoparticles Generated by Programmed Assembly for Dual-Modal Imaging-Guided Cancer Synergistic Phototherapy. ACS Nano 2014, 8, 12310−12322. (468) Kolemen, S.; Ozdemir, T.; Lee, D.; Kim, G. M.; Karatas, T.; Yoon, J.; Akkaya, E. U. Remote-Controlled Release of Singlet Oxygen by the Plasmonic Heating of Endoperoxide-Modified Gold Nanorods: Towards a Paradigm Change in Photodynamic Therapy. Angew. Chem., Int. Ed. 2016, 55, 3606−3610. (469) Aubry, J.-M.; Pierlot, C.; Rigaudy, J.; Schmidt, R. Reversible Binding of Oxygen to Aromatic Compounds. Acc. Chem. Res. 2003, 36, 668−675. (470) Martins, S.; Farinha, J. P. S.; Baleizao, C.; Berberan-Santos, M. N. Controlled Release of Singlet Oxygen Using Diphenylanthracene Functionalized Polymer Nanoparticles. Chem. Commun. 2014, 50, 3317−3320. (471) Huang, W.-C.; Shen, M.-Y.; Chen, H.-H.; Lin, S.-C.; Chiang, W.-H.; Wu, P.-H.; Chang, C.-W.; Chiang, C.-S.; Chiu, H.-C. Monocytic Delivery of Therapeutic Oxygen Bubbles for Dual-Modality Treatment of Tumor Hypoxia. J. Controlled Release 2015, 220, 738− 750. (472) Lee, J.-H.; Jang, J.-t.; Choi, J.-s.; Moon, S. H.; Noh, S.-h.; Kim, J.-w.; Kim, J.-G.; Kim, I.-S.; Park, K. I.; Cheon, J. Exchange-coupled 6220


Chemical Reviews

Review

and Metastatic Tumors Using Iodine-131-Doped Copper Sulfide Nanoparticles. Adv. Funct. Mater. 2015, 25, 4689−4699. (491) Chen, L.; Zhong, X.; Yi, X.; Huang, M.; Ning, P.; Liu, T.; Ge, C.; Chai, Z.; Liu, Z.; Yang, K. Radionuclide 131I Labeled Reduced Graphene Oxide for Nuclear Imaging Guided Combined Radio- and Photothermal Therapy of Cancer. Biomaterials 2015, 66, 21−28. (492) Lewis, J. S.; Laforest, R.; Buettner, T. L.; Song, S.-K.; Fujibayashi, Y.; Connett, J. M.; Welch, M. J. Copper-64-diacetylbis(N4-methylthiosemicarbazone): An Agent for Radiotherapy. Proc. Natl. Acad. Sci. U. S. A. 2001, 98, 1206−1211. (493) Xiao, Q.; Zheng, X.; Bu, W.; Ge, W.; Zhang, S.; Chen, F.; Xing, H.; Ren, Q.; Fan, W.; Zhao, K.; et al. A Core/Satellite Multifunctional Nanotheranostic for In Vivo Imaging and Tumor Eradication by Radiation/Photothermal Synergistic Therapy. J. Am. Chem. Soc. 2013, 135, 13041−13048. (494) Li, B.; Ye, K.; Zhang, Y.; Qin, J.; Zou, R.; Xu, K.; Huang, X.; Xiao, Z.; Zhang, W.; Lu, X.; et al. Photothermal Theragnosis Synergistic Therapy Based on Bimetal Sulphide Nanocrystals Rather Than Nanocomposites. Adv. Mater. 2015, 27, 1339−1345. (495) Ai, K.; Liu, Y.; Liu, J.; Yuan, Q.; He, Y.; Lu, L. Large-Scale Synthesis of Bi2S3 Nanodots as a Contrast Agent for In Vivo X-ray Computed Tomography Imaging. Adv. Mater. 2011, 23, 4886−4891. (496) Wang, S.; Li, K.; Chen, Y.; Chen, H.; Ma, M.; Feng, J.; Zhao, Q.; Shi, J. Biocompatible PEGylated MoS2 Nanosheets: Controllable Bottom-Up Synthesis and Highly Efficient Photothermal Regression of Tumor. Biomaterials 2015, 39, 206−217. (497) Yong, Y.; Cheng, X.; Bao, T.; Zu, M.; Yan, L.; Yin, W.; Ge, C.; Wang, D.; Gu, Z.; Zhao, Y. Tungsten Sulfide Quantum Dots as Multifunctional Nanotheranostics for In Vivo Dual-Modal ImageGuided Photothermal/Radiotherapy Synergistic Therapy. ACS Nano 2015, 9, 12451−12463. (498) Cheng, L.; Liu, J.; Gu, X.; Gong, H.; Shi, X.; Liu, T.; Wang, C.; Wang, X.; Liu, G.; Xing, H.; et al. PEGylated WS2 Nanosheets as a Multifunctional Theranostic Agent for In Vivo Dual-Modal CT/ Photoacoustic Imaging Guided Photothermal Therapy. Adv. Mater. 2014, 26, 1886−1893. (499) Wang, S.; Li, X.; Chen, Y.; Cai, X.; Yao, H.; Gao, W.; Zheng, Y.; An, X.; Shi, J.; Chen, H. A Facile One-Pot Synthesis of a TwoDimensional MoS2/Bi2S3 Composite Theranostic Nanosystem for Multi-Modality Tumor Imaging and Therapy. Adv. Mater. 2015, 27, 2775−2782. (500) Chou, S. S.; Kaehr, B.; Kim, J.; Foley, B. M.; De, M.; Hopkins, P. E.; Huang, J.; Brinker, C. J.; Dravid, V. P. Chemically Exfoliated MoS2 as Near-Infrared Photothermal Agents. Angew. Chem. 2013, 125, 4254−4258. (501) Yin, W.; Yan, L.; Yu, J.; Tian, G.; Zhou, L.; Zheng, X.; Zhang, X.; Yong, Y.; Li, J.; Gu, Z.; et al. High-Throughput Synthesis of SingleLayer MoS2 Nanosheets as a Near-Infrared Photothermal-Triggered Drug Delivery for Effective Cancer Therapy. ACS Nano 2014, 8, 6922−6933. (502) Liu, T.; Wang, C.; Gu, X.; Gong, H.; Cheng, L.; Shi, X.; Feng, L.; Sun, B.; Liu, Z. Drug Delivery with PEGylated MoS2 Nano-sheets for Combined Photothermal and Chemotherapy of Cancer. Adv. Mater. 2014, 26, 3433−3440. (503) Rabin, O.; Manuel Perez, J.; Grimm, J.; Wojtkiewicz, G.; Weissleder, R. An X-Ray Computed Tomography Imaging Agent Based on Long-Circulating Bismuth Sulphide Nanoparticles. Nat. Mater. 2006, 5, 118−122. (504) Ma, M.; Huang, Y.; Chen, H.; Jia, X.; Wang, S.; Wang, Z.; Shi, J. Bi2S3-Embedded Mesoporous Silica Nanoparticles for Efficient Drug Delivery and Interstitial Radiotherapy Sensitization. Biomaterials 2015, 37, 447−455. (505) Nicolosi, V.; Chhowalla, M.; Kanatzidis, M. G.; Strano, M. S.; Coleman, J. N. Liquid Exfoliation of Layered Materials. Science 2013, 340, 1226419. (506) Chhowalla, M.; Shin, H. S.; Eda, G.; Li, L.-J.; Loh, K. P.; Zhang, H. The Chemistry of Two-Dimensional Layered Transition Metal Dichalcogenide Nanosheets. Nat. Chem. 2013, 5, 263−275.

(507) Chou, S. S.; De, M.; Kim, J.; Byun, S.; Dykstra, C.; Yu, J.; Huang, J.; Dravid, V. P. Ligand Conjugation of Chemically Exfoliated MoS2. J. Am. Chem. Soc. 2013, 135, 4584−4587. (508) Eda, G.; Yamaguchi, H.; Voiry, D.; Fujita, T.; Chen, M.; Chhowalla, M. Photoluminescence from Chemically Exfoliated MoS2. Nano Lett. 2011, 11, 5111−5116. (509) Cheng, L.; Yuan, C.; Shen, S.; Yi, X.; Gong, H.; Yang, K.; Liu, Z. Bottom-Up Synthesis of Metal-Ion-Doped WS2 Nanoflakes for Cancer Theranostics. ACS Nano 2015, 9, 11090−11101. (510) Song, G.; Liang, C.; Gong, H.; Li, M.; Zheng, X.; Cheng, L.; Yang, K.; Jiang, X.; Liu, Z. Core−Shell MnSe@Bi2Se3 Fabricated via a Cation Exchange Method as Novel Nanotheranostics for Multimodal Imaging and Synergistic Thermoradiotherapy. Adv. Mater. 2015, 27, 6110−6117. (511) Beberwyck, B. J.; Surendranath, Y.; Alivisatos, A. P. Cation Exchange: A Versatile Tool for Nanomaterials Synthesis. J. Phys. Chem. C 2013, 117, 19759−19770. (512) Song, G.; Liang, C.; Yi, X.; Zhao, Q.; Cheng, L.; Yang, K.; Liu, Z. Perfluorocarbon-Loaded Hollow Bi2Se3 Nanoparticles for Timely Supply of Oxygen under Near-Infrared Light to Enhance the Radiotherapy of Cancer. Adv. Mater. 2016, 28, 2716−2723. (513) Dolmans, D. E. J. G. J.; Fukumura, D.; Jain, R. K. Photodynamic Therapy for Cancer. Nat. Rev. Cancer 2003, 3, 380− 387. (514) Celli, J. P.; Spring, B. Q.; Rizvi, I.; Evans, C. L.; Samkoe, K. S.; Verma, S.; Pogue, B. W.; Hasan, T. Imaging and Photodynamic Therapy: Mechanisms, Monitoring, and Optimization. Chem. Rev. 2010, 110, 2795−2838. (515) Lucky, S. S.; Soo, K. C.; Zhang, Y. Nanoparticles in Photodynamic Therapy. Chem. Rev. 2015, 115, 1990−2042. (516) Allison, R. R.; Downie, G. H.; Cuenca, R.; Hu, X.-H.; Childs, C. J. H.; Sibata, C. H. Photosensitizers in Clinical PDT. Photodiagn. Photodyn. Ther. 2004, 1, 27−42. (517) Ethirajan, M.; Chen, Y.; Joshi, P.; Pandey, R. K. The Role of Porphyrin Chemistry in Tumor Imaging and Photodynamic Therapy. Chem. Soc. Rev. 2011, 40, 340−362. (518) Kantonis, G.; Trikeriotis, M.; Ghanotakis, D. F. Biocompatible Protoporphyrin IX-Containing Nanohybrids with Potential Applications in Photodynamic Therapy. J. Photochem. Photobiol., A 2007, 185, 62−66. (519) Berkovitch, G.; Doron, D.; Nudelman, A.; Malik, Z.; Rephaeli, A. Novel Multifunctional Acyloxyalkyl Ester Prodrugs of 5-Aminolevulinic Acid Display Improved Anticancer Activity Independent and Dependent on Photoactivation. J. Med. Chem. 2008, 51, 7356−7369. (520) Giuntini, F.; Bourré, L.; MacRobert, A. J.; Wilson, M.; Eggleston, I. M. Improved Peptide Prodrugs of 5-ALA for PDT: Rationalization of Cellular Accumulation and Protoporphyrin IX Production by Direct Determination of Cellular Prodrug Uptake and Prodrug Metabolization. J. Med. Chem. 2009, 52, 4026−4037. (521) Chan, A. L.; Juarez, M.; Allen, R.; Volz, W.; Albertson, T. Pharmacokinetics and Clinical Effects of Mono-l-Aspartyl Chlorin e6 (NPe6) Photodynamic Therapy in Adult Patients with Primary or Secondary Cancer of the Skin and Mucosal Surfaces. Photodermatol., Photoimmunol. Photomed. 2005, 21, 72−78. (522) Agostinis, P.; Berg, K.; Cengel, K. A.; Foster, T. H.; Girotti, A. W.; Gollnick, S. O.; Hahn, S. M.; Hamblin, M. R.; Juzeniene, A.; Kessel, D.; et al. Photodynamic Therapy of Cancer: an Update. CaCancer J. Clin. 2011, 61, 250−281. (523) Vakrat-Haglili, Y.; Weiner, L.; Brumfeld, V.; Brandis, A.; Salomon, Y.; McLlroy, B.; Wilson, B. C.; Pawlak, A.; Rozanowska, M.; Sarna, T.; et al. The Microenvironment Effect on the Generation of Reactive Oxygen Species by Pd−Bacteriopheophorbide. J. Am. Chem. Soc. 2005, 127, 6487−6497. (524) Lai, Y.-C.; Chang, C.-C. Photostable BODIPY-Based Molecule with Simultaneous Type I and Type II Photosensitization for Selective Photodynamic Cancer Therapy. J. Mater. Chem. B 2014, 2, 1576− 1583. (525) Ding, H.; Yu, H.; Dong, Y.; Tian, R.; Huang, G.; Boothman, D. A.; Sumer, B. D.; Gao, J. Photoactivation Switch from Type II to Type 6221


Chemical Reviews

Review

I Reactions by Electron-Rich Micelles for Improved Photodynamic Therapy of Cancer Cells under Hypoxia. J. Controlled Release 2011, 156, 276−280. (526) Ding, H.; Sumer, B. D.; Kessinger, C. W.; Dong, Y.; Huang, G.; Boothman, D. A.; Gao, J. Nanoscopic Micelle Delivery Improves The Photophysical Properties and Efficacy of Photodynamic Therapy of Protoporphyrin IX. J. Controlled Release 2011, 151, 271−277. (527) Park, W.; Bae, B.-c.; Na, K. A Highly Tumor-Specific LightTriggerable Drug Carrier Responds to Hypoxic Tumor Conditions for Effective Tumor Treatment. Biomaterials 2016, 77, 227−234. (528) Zhao, L.; Liu, M.; Wang, J.; Zhai, G. Chondroitin Sulfate-Based Nanocarriers for Drug/Gene Delivery. Carbohydr. Polym. 2015, 133, 391−399. (529) Hawkins, C. L.; Davies, M. J. Direct Detection and Identification of Radicals Generated During The Tydroxyl RadicalInduced Degradation of Hyaluronic Acid and Related Materials. Free Radical Biol. Med. 1996, 21, 275−290. (530) Schweikert, C.; Liszkay, A.; Schopfer, P. Polysaccharide Degradation by Fenton Reaction- or Peroxidase-Generated Hydroxyl Radicals in Isolated Plant Cell Walls. Phytochemistry 2002, 61, 31−35. (531) Zhang, C.; Zhao, K.; Bu, W.; Ni, D.; Liu, Y.; Feng, J.; Shi, J. Marriage of Scintillator and Semiconductor for Synchronous Radiotherapy and Deep Photodynamic Therapy with Diminished Oxygen Dependence. Angew. Chem., Int. Ed. 2015, 54, 1770−1774. (532) Chen, W.; Zhang, J. Using Nanoparticles to Enable Simultaneous Radiation and Photodynamic Therapies for Cancer Treatment. J. Nanosci. Nanotechnol. 2006, 6, 1159−1166. (533) Chen, H.; Wang, G. D.; Chuang, Y.-J.; Zhen, Z.; Chen, X.; Biddinger, P.; Hao, Z.; Liu, F.; Shen, B.; Pan, Z.; et al. NanoscintillatorMediated X-ray Inducible Photodynamic Therapy for In Vivo Cancer Treatment. Nano Lett. 2015, 15, 2249−2256. (534) Elmenoufy, A. H.; Tang, Y. a.; Hu, J.; Xu, H.; Yang, X. A Novel Deep Photodynamic Therapy Modality Combined with CT Imaging Established via X-ray Stimulated Silica-Modified Lanthanide Scintillating Nanoparticles. Chem. Commun. 2015, 51, 12247−12250. (535) Chen, Z.; Li, Z.; Wang, J.; Ju, E.; Zhou, L.; Ren, J.; Qu, X. A Multi-synergistic Platform for Sequential Irradiation-Activated HighPerformance Apoptotic Cancer Therapy. Adv. Funct. Mater. 2014, 24, 522−529. (536) Kašcǎ ḱ ová, S.; Giuliani, A.; Lacerda, S.; Pallier, A.; Mercere, P.; Tóth, É.; Réfrégiers, M. X-Ray-Induced Radiophotodynamic Therapy (RPDT) Using Lanthanide Micelles: Beyond Depth Limitations. Nano Res. 2015, 8, 2373−2379. (537) Hu, J.; Tang, Y. a.; Elmenoufy, A. H.; Xu, H.; Cheng, Z.; Yang, X. Nanocomposite-Based Photodynamic Therapy Strategies for Deep Tumor Treatment. Small 2015, 11, 5860−5887. (538) Alvarez, M. G.; Prucca, C.; Milanesio, M. E.; Durantini, E. N.; Rivarola, V. Photodynamic Activity of a New Sensitizer Derived from Porphyrin-C60 Dyad and Its Biological Consequences in a Human Carcinoma Cell Line. Int. J. Biochem. Cell Biol. 2006, 38, 2092−2101. (539) Guan, M.; Qin, T.; Ge, J.; Zhen, M.; Xu, W.; Chen, D.; Li, S.; Wang, C.; Su, H.; Shu, C. Amphiphilic TrismethylpyridylporphyrinFullerene (C70) Dyad: An Efficient Photosensitizer under Hypoxia Conditions. J. Mater. Chem. B 2015, 3, 776−783. (540) Xu, W.; Feng, L.; Wu, Y.; Wang, T.; Wu, J.; Xiang, J.; Li, B.; Jiang, L.; Shu, C.; Wang, C. Construction and Photophysics Study of Supramolecular Complexes Composed of Three-Point Binding Fullerene-Trispyridylporphyrin Dyads and Zinc Porphyrin. Phys. Chem. Chem. Phys. 2011, 13, 428−433. (541) Zhang, C.; Zhao, J.; Wu, S.; Wang, Z.; Wu, W.; Ma, J.; Guo, S.; Huang, L. Intramolecular RET Enhanced Visible Light-Absorbing Bodipy Organic Triplet Photosensitizers and Application in Photooxidation and Triplet−Triplet Annihilation Upconversion. J. Am. Chem. Soc. 2013, 135, 10566−10578. (542) Brown, J. M.; Wilson, W. R. Exploiting tumour hypoxia in cancer treatment. Nat. Rev. Cancer 2004, 4, 437−447. (543) Kling, J. Hypoxia-Activated Prodrugs Forge Ahead in Cancer. Nat. Biotechnol. 2012, 30, 381−381.

(544) Graf, N.; Lippard, S. J. Redox Activation of Metal-Based Prodrugs as A Strategy for Drug Delivery. Adv. Drug Delivery Rev. 2012, 64, 993−1004. (545) Chen, Y.; Hu, L. Q. Design of Anticancer Prodrugs for Reductive Activation. Med. Res. Rev. 2009, 29, 29−64. (546) Denny, W. A. The Role of Hypoxia-Activated Prodrugs in Cancer Therapy. Lancet Oncol. 2000, 1, 25−29. (547) Denny, W. A. Hypoxia-Activated Prodrugs in Cancer Therapy: Progress to The Clinic. Future Oncol. 2010, 6, 419−428. (548) Trédan, O.; Galmarini, C. M.; Patel, K.; Tannock, I. F. Drug Resistance and The Solid Tumor Microenvironment. J. Natl. Cancer I. 2007, 99, 1441−1454. (549) Minchinton, A. I.; Tannock, I. F. Drug Penetration in Solid Tumours. Nat. Rev. Cancer 2006, 6, 583−592. (550) Ma, J.; Chen, C.-S.; Blute, T.; Waxman, D. J. Antiangiogenesis Enhances Intratumoral Drug Retention. Cancer Res. 2011, 71, 2675− 2685. (551) Ma, J.; Waxman, D. J. Combination of Antiangiogenesis with Chemotherapy for More Effective Cancer Treatment. Mol. Cancer Ther. 2008, 7, 3670−3684. (552) Ferrari, M. Cancer Nanotechnology: Opportunities and Challenges. Nat. Rev. Cancer 2005, 5, 161−171. (553) Edwards, D. I. Nitroimidazole Drugs-Action and Resistance Mechanisms I. Mechanism of Action. J. Antimicrob. Chemother. 1993, 31, 9−20. (554) Hodgkiss, R. J.; Middleton, R. W.; Parrick, J.; Rami, H. K.; Wardman, P.; Wilson, G. D. Bioreductive Fluorescent Markers for Hypoxic Cells: A Study of 2-Nitroimidazoles with 1-Substituents Containing Fluorescent, Bridgehead-Nitrogen, Bicyclic Systems. J. Med. Chem. 1992, 35, 1920−1926. (555) Thambi, T.; Deepagan, V. G.; Yoon, H. Y.; Han, H. S.; Kim, S.H.; Son, S.; Jo, D.-G.; Ahn, C.-H.; Suh, Y. D.; Kim, K.; et al. HypoxiaResponsive Polymeric Nanoparticles for Tumor-Targeted Drug Delivery. Biomaterials 2014, 35, 1735−1743. (556) Fleige, E.; Quadir, M. A.; Haag, R. Stimuli-Responsive Polymeric Nanocarriers for The Controlled Transport of Active Compounds: Concepts and Applications. Adv. Drug Delivery Rev. 2012, 64, 866−884. (557) Thambi, T.; Son, S.; Lee, D. S.; Park, J. H. Poly(ethylene glycol)-b-poly(lysine) Copolymer Bearing Nitroaromatics for Hypoxia-Sensitive Drug Delivery. Acta Biomater. 2016, 29, 261−270. (558) Spencer, J. A.; Ferraro, F.; Roussakis, E.; Klein, A.; Wu, J.; Runnels, J. M.; Zaher, W.; Mortensen, L. J.; Alt, C.; Turcotte, R.; et al. Direct Measurement of Local Oxygen Concentration in The Bone Marrow of Live Animals. Nature 2014, 508, 269−273. (559) Takasawa, M.; Moustafa, R. R.; Baron, J.-C. Applications of Nitroimidazole In Vivo Hypoxia Imaging in Ischemic Stroke. Stroke 2008, 39, 1629−1637. (560) Lin, Q.; Bao, C.; Yang, Y.; Liang, Q.; Zhang, D.; Cheng, S.; Zhu, L. Highly Discriminating Photorelease of Anticancer Drugs Based on Hypoxia Activatable Phototrigger Conjugated Chitosan Nanoparticles. Adv. Mater. 2013, 25, 1981−1986. (561) Schade, B.; Hagen, V.; Schmidt, R.; Herbrich, R.; Krause, E.; Eckardt, T.; Bendig, J. Deactivation Behavior and Excited-State Properties of (Coumarin-4-yl)methyl Derivatives. 1. Photocleavage of (7-Methoxycoumarin-4-yl)methyl-Caged Acids with Fluorescence Enhancement. J. Org. Chem. 1999, 64, 9109−9117. (562) Babin, J.; Pelletier, M.; Lepage, M.; Allard, J.-F.; Morris, D.; Zhao, Y. A New Two-Photon-Sensitive Block Copolymer Nanocarrier. Angew. Chem., Int. Ed. 2009, 48, 3329−3332. (563) Lin, Q.; Huang, Q.; Li, C.; Bao, C.; Liu, Z.; Li, F.; Zhu, L. Anticancer Drug Release from a Mesoporous Silica Based Nanophotocage Regulated by Either a One- or Two-Photon Process. J. Am. Chem. Soc. 2010, 132, 10645−10647. (564) Wagner, V.; Dullaart, A.; Bock, A.-K.; Zweck, A. The Emerging Nanomedicine Landscape. Nat. Biotechnol. 2006, 24, 1211−1217. (565) Torchilin, V. P. Recent Advances with Liposomes as Pharmaceutical Carriers. Nat. Rev. Drug Discovery 2005, 4, 145−160. 6222


Chemical Reviews

Review

(566) Wang, Y.; Yan, Y.; Cui, J.; Hosta-Rigau, L.; Heath, J. K.; Nice, E. C.; Caruso, F. Encapsulation of Water-Insoluble Drugs in Polymer Capsules Prepared Using Mesoporous Silica Templates for Intracellular Drug Delivery. Adv. Mater. 2010, 22, 4293−4297. (567) Chen, Y.; Chen, H.; Ma, M.; Chen, F.; Guo, L.; Zhang, L.; Shi, J. Double Mesoporous Silica Shelled Spherical/Ellipsoidal Nanostructures: Synthesis and Hydrophilic/Hydrophobic Anticancer Drug Delivery. J. Mater. Chem. 2011, 21, 5290−5298. (568) Chen, Y.; Meng, Q.; Wu, M.; Wang, S.; Xu, P.; Chen, H.; Li, Y.; Zhang, L.; Wang, L.; Shi, J. Hollow Mesoporous Organosilica Nanoparticles: A Generic Intelligent Framework-Hybridization Approach for Biomedicine. J. Am. Chem. Soc. 2014, 136, 16326−16334. (569) Dong, K.; Liu, Z.; Li, Z.; Ren, J.; Qu, X. Hydrophobic Anticancer Drug Delivery by a 980 nm Laser-Driven Photothermal Vehicle for Efficient Synergistic Therapy of Cancer Cells In Vivo. Adv. Mater. 2013, 25, 4452−4458. (570) Liu, H. M.; Zhang, R. L.; Niu, Y. W.; Li, Y.; Qiao, C. M.; Weng, J.; Li, J.; Zhang, X. N.; Xiao, Z. B.; Zhang, X. Development of HypoxiaTriggered Prodrug Micelles as Doxorubicin Carriers for Tumor Therapy. RSC Adv. 2015, 5, 20848−20857. (571) Niidome, T.; Huang, L. Gene Therapy Progress and Prospects: Nonviral Vectors. Gene Ther. 2002, 9, 1647−1652. (572) McManus, M. T.; Sharp, P. A. Gene Silencing in Mammals by Small Interfering RNAs. Nat. Rev. Genet. 2002, 3, 737−747. (573) Dykxhoorn, D. M.; Novina, C. D.; Sharp, P. A. Killing the Messenger: Short RNAs that Silence Gene Expression. Nat. Rev. Mol. Cell Biol. 2003, 4, 457−467. (574) Rosi, N. L.; Giljohann, D. A.; Thaxton, C. S.; Lytton-Jean, A. K.; Han, M. S.; Mirkin, C. A. Oligonucleotide-Modified Gold Nanoparticles for Intracellular Gene Regulation. Science 2006, 312, 1027−1030. (575) Mintzer, M. A.; Simanek, E. E. Nonviral Vectors for Gene Delivery. Chem. Rev. 2009, 109, 259−302. (576) Miller, A. D. Cationic Liposomes for Gene Therapy. Angew. Chem., Int. Ed. 1998, 37, 1768−1785. (577) Schaffert, D.; Wagner, E. Gene Therapy Progress and Prospects: Synthetic Polymer-Based Systems. Gene Ther. 2008, 15, 1131−1138. (578) Anderson, D. G.; Peng, W.; Akinc, A.; Hossain, N.; Kohn, A.; Padera, R.; Langer, R.; Sawicki, J. A. A Polymer Library Approach to Suicide Gene Therapy for Cancer. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 16028−16033. (579) Roy, I.; Ohulchanskyy, T. Y.; Bharali, D. J.; Pudavar, H. E.; Mistretta, R. A.; Kaur, N.; Prasad, P. N. Optical Tracking of Organically Modified Silica Nanoparticles as DNA Carriers: A Nonviral, Nanomedicine Approach for Gene Delivery. Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 279−284. (580) Wu, M.; Meng, Q.; Chen, Y.; Du, Y.; Zhang, L.; Li, Y.; Zhang, L.; Shi, J. Large-Pore Ultrasmall Mesoporous Organosilica Nanoparticles: Micelle/Precursor Co-templating Assembly and NuclearTargeted Gene Delivery. Adv. Mater. 2015, 27, 215−222. (581) Bonoiu, A. C.; Mahajan, S. D.; Ding, H.; Roy, I.; Yong, K.-T.; Kumar, R.; Hu, R.; Bergey, E. J.; Schwartz, S. A.; Prasad, P. N. Nanotechnology Approach for Drug Addiction Therapy: Gene Silencing Using Delivery of Gold Nanorod-siRNA Nanoplex in Dopaminergic Neurons. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 5546−5550. (582) Arsianti, M.; Lim, M.; Marquis, C. P.; Amal, R. Assembly of Polyethylenimine-Based Magnetic Iron Oxide Vectors: Insights into Gene Delivery. Langmuir 2010, 26, 7314−7326. (583) Yezhelyev, M. V.; Qi, L.; O’Regan, R. M.; Nie, S.; Gao, X. Proton-Sponge Coated Quantum Dots for siRNA Delivery and Intracellular Imaging. J. Am. Chem. Soc. 2008, 130, 9006−9012. (584) You, J.-O.; Auguste, D. T. Nanocarrier Cross-Linking Density and pH Sensitivity Regulate Intracellular Gene Transfer. Nano Lett. 2009, 9, 4467−4473. (585) Wu, M.; Meng, Q.; Chen, Y.; Zhang, L.; Li, M.; Cai, X.; Li, Y.; Yu, P.; Zhang, L.; Shi, J. Large Pore-Sized Hollow Mesoporous

Organosilica for Redox-Responsive Gene Delivery and Synergistic Cancer Chemotherapy. Adv. Mater. 2016, 28, 1963−1969. (586) Kizaka-Kondoh, S.; Tanaka, S.; Harada, H.; Hiraoka, M. The HIF-1-Active Microenvironment: An Environmental Target for Cancer Therapy. Adv. Drug Delivery Rev. 2009, 61, 623−632. (587) Wilson, W. R.; Hay, M. P. Targeting Hypoxia in Cancer Therapy. Nat. Rev. Cancer 2011, 11, 393−410. (588) Perche, F.; Biswas, S.; Wang, T.; Zhu, L.; Torchilin, V. P. Hypoxia- Targeted siRNA Delivery. Angew. Chem., Int. Ed. 2014, 53, 3362−3366. (589) Lee, S. H.; Kim, S. H.; Park, T. G. Intracellular siRNA Delivery System Using Polyelectrolyte Complex Micelles Prepared from VEGF siRNA-PEG Conjugate and Cationic Fusogenic Peptide. Biochem. Biophys. Res. Commun. 2007, 357, 511−516. (590) Moyer, M. W. Targeting Hypoxia Brings Breath of Fresh Air to Cancer Therapy. Nat. Med. 2012, 18, 636−637. (591) Liu, Y.; Liu, Y.; Bu, W.; Cheng, C.; Zuo, C.; Xiao, Q.; Sun, Y.; Ni, D.; Zhang, C.; Liu, J.; et al. Hypoxia Induced by UpconversionBased Photodynamic Therapy: Towards Highly Effective Synergistic Bioreductive Therapy in Tumors. Angew. Chem., Int. Ed. 2015, 54, 8105−8109. (592) Qiao, X.-F.; Zhou, J.-C.; Xiao, J.-W.; Wang, Y.-F.; Sun, L.-D.; Yan, C.-H. Triple-Functional Core-Shell Structured Upconversion Luminescent Nanoparticles Covalently Grafted with Photosensitizer for Luminescent, Magnetic Resonance Imaging and Photodynamic Therapy In Vitro. Nanoscale 2012, 4, 4611−4623. (593) Qian, C.; Yu, J.; Chen, Y.; Hu, Q.; Xiao, X.; Sun, W.; Wang, C.; Feng, P.; Shen, Q.-D.; Gu, Z. Light-Activated Hypoxia-Responsive Nanocarriers for Enhanced Anticancer Therapy. Adv. Mater. 2016, 28, 3313−3320. (594) Patel, D. G.; Feng, F.; Ohnishi, Y.-y.; Abboud, K. A.; Hirata, S.; Schanze, K. S.; Reynolds, J. R. It Takes More Than an Imine: The Role of the Central Atom on the Electron-Accepting Ability of Benzotriazole and Benzothiadiazole Oligomers. J. Am. Chem. Soc. 2012, 134, 2599−2612. (595) Yu, J.; Zhang, Y.; Ye, Y.; DiSanto, R.; Sun, W.; Ranson, D.; Ligler, F. S.; Buse, J. B.; Gu, Z. Microneedle-Array Patches Loaded with Hypoxia-Sensitive Vesicles Provide Fast Glucose-Responsive Insulin Delivery. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 8260−8265. (596) Baker, M. Whole-Animal Imaging: The Whole Picture. Nature 2010, 463, 977−980. (597) Wouters, B. G.; Brown, J. M. Cells at Intermediate Oxygen Levels Can Be More Important Than the ″Hypoxic Fraction″ in Determining Tumor Response to Fractionated Radiotherapy. Radiat. Res. 1997, 147, 541−550. (598) Beyer, T.; Townsend, D. W.; Brun, T.; Kinahan, P. E.; Charron, M.; Roddy, R.; Jerin, J.; Young, J.; Byars, L.; Nutt, R. A Combined PET/CT Scanner for Clinical Oncology. J. Nucl. Med. 2000, 41, 1369−1379. (599) Townsend, D. W.; Carney, J. P. J.; Yap, J. T.; Hall, N. C. PET/ CT Today and Tomorrow. J. Nucl. Med. 2004, 45, 4S−14S. (600) Schillaci, O. Hybrid SPECT/CT: A New Era for SPECT Imaging? Eur. J. Nucl. Med. Mol. Imaging 2005, 32, 521−524. (601) Mariani, G.; Bruselli, L.; Kuwert, T.; Kim, E.; Flotats, A.; Israel, O.; Dondi, M.; Watanabe, N. A Review on The Clinical Uses of SPECT/CT. Eur. J. Nucl. Med. Mol. Imaging 2010, 37, 1959−1985. (602) Judenhofer, M. S.; Wehrl, H. F.; Newport, D. F.; Catana, C.; Siegel, S. B.; Becker, M.; Thielscher, A.; Kneilling, M.; Lichy, M. P.; Eichner, M.; et al. Simultaneous PET-MRI: A New Approach for Functional and Morphological Imaging. Nat. Med. 2008, 14, 459−465. (603) Pichler, B. J.; Kolb, A.; Nägele, T.; Schlemmer, H.-P. PET/ MRI: Paving The Way for The Next Generation of Clinical Multimodality Imaging Applications. J. Nucl. Med. 2010, 51, 333−336. (604) Frullano, L.; Catana, C.; Benner, T.; Sherry, A. D.; Caravan, P. Bimodal MR−PET Agent for Quantitative pH Imaging. Angew. Chem. 2010, 122, 2432−2434. (605) Catana, C.; Procissi, D.; Wu, Y.; Judenhofer, M. S.; Qi, J.; Pichler, B. J.; Jacobs, R. E.; Cherry, S. R. Simultaneous In Vivo 6223


Chemical Reviews

Review

Positron Emission Tomography and Magnetic Resonance Imaging. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 3705−3710. (606) Kizaka-Kondoh, S.; Inoue, M.; Harada, H.; Hiraoka, M. Tumor Hypoxia: A Target for Selective Cancer Therapy. Cancer Sci. 2003, 94, 1021−1028. (607) Felfoul, O.; Mohammadi, M.; Taherkhani, S.; de Lanauze, D.; Xu, Y. Z.; Loghin, D.; Essa, S.; Jancik, S.; Houle, D.; Lafleur, M.; et al. Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions. Nat. Nanotechnol. 2016, 11, 941−947. (608) Peer, D.; Karp, J. M.; Hong, S.; FaroKhzad, O. C.; Margalit, R.; Langer, R. Nanocarriers as an Emerging Platform for Cancer Therapy. Nat. Nanotechnol. 2007, 2, 751−760. (609) Rivera-Gil, P.; Jimenez De Aberasturi, D.; Wulf, V.; Pelaz, B.; Del Pino, P.; Zhao, Y.; De La Fuente, J. M.; Ruiz De Larramendi, I.; Rojo, T.; Liang, X.-J.; et al. The Challenge To Relate the Physicochemical Properties of Colloidal Nanoparticles to Their Cytotoxicity. Acc. Chem. Res. 2013, 46, 743−749.

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