Modulating Hypoxia via Nanomaterials Chemistry for Efficient

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Modulating Hypoxia via Nanomaterials Chemistry for Efficient Treatment of Solid Tumors Yanyan Liu,† Yaqin Jiang,† Meng Zhang,‡ Zhongmin Tang,‡ Mingyuan He,† and Wenbo Bu*,†,‡ †

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Shanghai Key Laboratory of Green Chemistry and Chemical Processes, College of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhong-shan Road, Shanghai 200062, P. R. China ‡ State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Ding-xi Road, Shanghai 200050, P. R. China CONSPECTUS: The common existence of hypoxia in solid tumors has been heavily researched because it renders tumors more resistant to most standard therapeutic methods, such as radiotherapy (RT), chemotherapy, and photodynamic therapy (PDT), and is associated with a more malignant phenotype and poor survival in patients with tumors. The development of hypoxia modulation methods for advanced therapeutic activity is therefore of great interest but remains a considerable challenge. Since the significant development of nanotechnology and nanomedicine, functionalized nanomaterials can be exploited as adjuvant “drugs” for these oxygen-dependent standard therapies or as hypoxia initiators for advanced new therapies to solid tumors. In this Account, we summarize our recent studies on the design and synthesis of nanomaterials with a set of desired chemistry benefits achievable by modulating hypoxia, suggesting a valid therapeutic option for tumors. The investigated strategies can be categorized into three groups: The first strategy is based on countering hypoxia. Considering that O2 deficiency is the major obstacle for the oxygen-dependent therapies, we initially developed methods to supply O2 by taking advantage of the hypoxia-responsive properties of nano-MnO2 or nanomaterials’ photothermal effects for increased intratumoral blood flow. The second approach is to disregard hypoxia. Possible benefits of nanoagents include reducing/eliminating reliance on O2 or making O2 replacements as adjuvants to standard therapies. To this end, we investigated a nano-upconversion/scintillator with the capacity toup-/down-convert nearinfrared light (NIR)/X-ray to luminescence in the ultraviolet/visible region fortype-I PDT with minimized oxygen-tension dependency or developed Fe-based nanomaterials for chemodynamic therapy (CDT) without external energy and oxygen participation for efficient free radical killing of deep tumors. The third strategy involves exploiting hypoxia. The unique biological characteristics of hypoxia are exploited to activate nanoagents for new therapies. To address the discrepancy between the nanoagents’ demand and supply within the hypoxia region, a smart “molecule−nano” medicine that stays small-molecule-like in the bloodstream and turns into self-assembled nanovesicles after entry into the hypoxia region was constructed for hypoxiaadaptive photothermal therapy (PTT). In addition to traditional anti-angiogenesis therapy, we prepared Mg2Si nanoparticles by a special self-propagating high-temperature synthesis approach. These nanoparticles can directly remove the intratumoral oxygen via the oxidation reactions of Mg2Si and later efficiently block the rapid reoxygenation via tumor blood vessels by the resultant SiO2 microsheets for cancer starvation therapy. Taken together, these findings indicate that nanomaterials will assume a valuable role for anticancer exploration based on either their properties to make up oxygen deficiency or the use of hypoxia for therapeutic applications.

1. INTRODUCTION

metabolism, which decreases the cytotoxicity of drugs; (3) enhanced genetic instability, which confers the rapid evolution of drug resistance and tumor progression.1−4 Thus, a number of trials have been designed to overcome hypoxia, such as inspiratory hyperoxia, but unfortunately, this technique is difficult to apply in a clinical setting and the effect is marginal because of the dynamic fluctuating hypoxia and severe structural abnormalities of microvessels in tumors.5 Thus, efforts to exploit reliable methods for advanced therapeutic activity are significant for the development of oncology.

Hypoxia is a common feature of many malignant solid tumors. To survive in hypoxia, cells often use glycolysis to obtain energy, which is an efficient pathway against oxygen deficiency but leads to marked changes in metabolic and bioenergetic status, increases in lactate level and reductive enzymes, and overexpression of hypoxia-inducible genes. As the underlying mechanisms of hypoxia have been dissected at the molecular level, its existence has been seen as a flaw in current tumor therapies as follows: (1) direct effects due to the lack of O2, which oxygen-dependent X-ray radiation therapy (RT), chemotherapy, and photodynamic therapy (PDT) require to be maximally cytotoxic; (2) indirect effects via changed cellular © XXXX American Chemical Society

Received: May 17, 2018

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DOI: 10.1021/acs.accounts.8b00214 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Figure 1. (a) Schematic illustration of the redox reaction between UCSMs and acidic H2O2, leading to the decomposition of MnO2 nanosheets for enhanced UCL imaging as well as the massive generation of O2 for improved PDT/RT effects. (b) TEM images of UCSMs. (c) Representative 2D photoacoustic images of solid tumors obtained by measuring deoxygenated hemoglobin (λ = 750 nm) and oxygenated hemoglobin (λ = 850 nm) before and after injection of saline or UCSMs. Reproduced with permission from ref 11. Copyright 2015 John Wiley and Sons.

The emergence of nanotechnology opens up the new field of nanomedicine, which has attracted considerable attention. Substantial research efforts have been undertaken in this field in the past decade.6,7 Designing and synthesizing intelligent nanomaterials to enable the modulation of hypoxia for highly efficient tumor therapy exploitations has been an ongoing target of our research. Considering that O2 deficiency is the major obstacle for efficient tumor treatment, the initially developed method was to supply O2 in tumors during the establishment of standard therapeutic means. In fact, functional nanoagents may represent an alternative to O2, in which nanoagents act as promising promoters for significant anticancer activity. Moreover, since hypoxic conditions constitute a major difference from normoxic tissues and cells, it can be exploited as a therapeutic target for selective cancer therapy or as an endogenous stimulation to activate cytotoxicity to overcome the resistance of hypoxia as a whole.8 In this Account, we describe our efforts to design and synthesize versatile nanoagents for novel and efficient tumor therapeutic methods through modulation of hypoxia. Strategies that have been investigated can be categorized into three groups: (1) countering hypoxia, (2) disregarding hypoxia, and (3) exploiting hypoxia. We aim to elucidate the general features of hypoxia and later provide the strategies for acquiring nanomaterials with a set of desired properties to demonstrate new antitumor concepts. We seek to stimulate new ideas and inspire continued research into practical antitumor applications in the future.

induces DNA damage and thereby kills the cancerous cells. If possible, O2 further reacts with the DNA’s broken ends to form stable organic peroxides, ensuring that the damaged DNA is not easily repaired, thereby greatly enhancing the degree of RT-induced cellular damage.9 Studies have demonstrated that the sensitivity of tumor cells to X-rays is 3 times as great for irradiation in normoxic media compared with anoxic conditions. Regarding PDT, this method should consume large amounts of tissue oxygen for generation of reactive oxygen species (ROS), which attack cancer cells as well as endothelial cells within vessel walls, causing severe hypoxia, which conversely leads to greatly reduced effectiveness of this protocol.10 In clinical settings, carbon or oxygen breathing and perfluorochemical emulsions have been explored in conjunction with RT in solid tumor models, leading to a number of positive results accompanied by notable side effects, such as hyperoxic seizures and barotrauma. Thus, our efforts were focused on the development of functional nanomaterials to counter hypoxia by promoting the oxygenation status, especially in tumors. 2.1. Oxygen-Elevated Therapy

Our group first developed an intelligent theranostic nanomaterial with 2D exfoliated MnO2 nanosheets anchored on a theranostic upconversion nanoprobe (UCSM) for tumorresponsive imaging/oxygen-elevated therapy (Figure 1a,b).11 In a malignant tumor, cells produce excessive amounts of H2O2; meanwhile, the upregulated glycolytic metabolism in hypoxia leads to massive lactic acid generation. As a result of the acid-/redox-responsive properties, the amorphous MnO2 of UCSM can be reduced into Mn2+ by the acidic H2O2 in tumors, along with the release of O2 (MnO2 + H+ + H2O2 → Mn2+ + H2O + O2), which significantly enhances the vascular saturated O2 (Figure 1c), so as to increase the performance of the oxygen-dependent RT/PDT effects in solid tumors. Moreover, as the MnO2−H2O2 redox reaction continues, the

2. COUNTERING HYPOXIA Increasing oxygenation is a useful way of improving the antitumor outcomes for oxygen-dependent standard therapies, such as RT and PDT, because O2 exerts a strong influence on biological response by participating in the chemical reactions in tissues and cells. Like RT, ionization of surrounding water brings the formation of toxic O2-centered radicals, which B

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Figure 2. (a) Schematic diagram of a CSNT for synergistic RT/PTA therapy. The upconversion nanoparticle (UCNP) core is used to enlarge the local radiation dose for enhanced RT, and CuS satellites are responsible for converting NIR emission into heat for PTA. (b) TEM images of (b1) UCNP, (b2) UCNP@SiO2-NH2, and (b3, b4) CSNTs at different magnifications. Reproduced from ref 15. Copyright 2013 American Chemical Society. (c) Schematic of PEG-Bi2Se3@PFC@O2 for enhanced RT by locally concentrated radiation energy and NIR-triggered burst release of oxygen. (d) The changed O2 concentration in various solutions under 808 nm laser irradiation. (e) Dramatically enhanced O2 level in tumors preinjected with PEG-Bi2Se3@PFC@O2 and irradiated with NIR light. Reproduced with permission from ref 18. Copyright 2016 John Wiley and Sons.

upconversion luminescence (UCL) absorbed/quenched by MnO2 gradually recovers, enabling the simultaneous UCL imaging and positioned RT/PDT treatment of solid tumors. Afterward, many smart MnO2-based nanosystems were developed for enhanced treatment effects of RT,12 PDT,13 and immunotherapy14 partially by the in situ generation of O2 within the tumor. This oxygen-elevated therapy is likely to inspire further exploitation of nanochemical reactions that can be effectively applied in countering hypoxia for efficient treatment of tumors.

relatively radiosensitive so that they can be totally eradicated by the high-Z rare earth element-enhanced radiation dose. Soon after this, Liu’s group tactically developed MnSe@Bi2Se3 core−shell nanocrystals, in which the Bi2Se3 shell endowed this nanosystem with strong absorbance of both NIR light and Xrays for synergetic RT and photothermal therapy (PTT).16 To further greatly enhance the oxygen delivery into tumors, Hu’s group first created an oxygen self-enriching photodynamic therapy by loading photosensitizer molecules into oxygen-rich dissolved perfluorocarbon (PFC) nanodroplets, leading to significantly enhanced photodynamic effects due to the selfenriching oxygen.17 However, the release of oxygen was uncontrolled. Afterward, Liu’s group ingeniously loaded these PFCs saturated with oxygen into hollow PEG-Bi2Se3 nanoparticles (PEG-Bi2Se3@PFC@O2). By taking advantage of Bi2Se3, its strong NIR thermal effect can trigger a burst release of oxygen, ensuring the timely supply of O2 for enhanced RT (Figure 2c−e).18

2.2. Timely Oxygen Supply Controlled by Light

For clinical applications, the real-time supply of oxygen is highly significant, especially when used in combination with RT/PDT. On the basis of the theory of molecules’ thermal motion, our group first utilized photothermal ablation (PTA) to increase intratumoral blood flow for subsequently enhanced oxygenation status in the tumor microenvironment, which can effectively improve the radiation damage.15 We decorated nearinfrared (NIR) photothermal CuS nanoparticles onto the surface of silica-coated rare-earth upconversion nanoparticles (CSNTs) (Figure 2a,b), and upon sequential irradiation with NIR light and X-rays, hyperpyrexia can kill a fraction of superficial cancer cells and partially radioresistant hypoxic cells as well as benefit the oxygenation of residual cells, leaving them

3. DISREGARDING HYPOXIA Newly developed tumors have to form their own blood supply. However, the vasculatures induced by hypoxia angiogenesis are abnormal.5 These vasculatures are highly irregular and tortuous, with increased vascular permeability and high fractions of arteriovenous shunt perfusion, leading to low C

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Figure 3. (a) Schematic of SnWO4−UCNP-mediated enhanced PDT/RT therapy. Reproduced with permission from ref 21. Copyright 2018 Elsevier Ltd. (b) Therapeutic mechanism of azo initiators in AuNCs under different oxygen tensions. Reproduced with permission from ref 22. Copyright 2017 John Wiley and Sons. (c) Mechanism of ionizing-radiation-induced PDT by SCNP@SiO2@ZnO. (d) STEM images of SZNPs in (d1) SEM, (d2) dark-field, and (d3) bright-field modes and (d4) corresponding element mappings for Y, Ce, Si, and Zn of SCNP@SiO2@ZnO. Reproduced with permission from ref 23. Copyright 2015 John Wiley and Sons.

3.1. PDT with Minimized Oxygen Dependency

overall levels of oxygenation within most tumors. In addition, within these newly formed vessels, blood flows have temporal fluctuations with intermittent flow stops in individual vessels, causing the tumor microenvironment to be unpredictable and often unable to be rectified. The dynamic architecture means that no forms of anticancer modalities can give a uniform effect against a significant proportion of solid tumor cells.19 New therapeutic methods that can disregard hypoxia, possibly by reducing/eliminating the dependence on oxygen or making oxygen replacements as adjuvants to standard therapies are promising for improved antitumor efficacy as a whole.

PDT has been seen as a noninvasive approach for precise ablation of local tumors with many unique merits, such as insignificant side effects, precise target treatment, and specific immunoactivity, but the strong oxygen dependence and limited penetration depth of the excitation light make it unavailable for the treatment of deep tumors.20 Upconversion nanoparticles (UCNPs), with the ability to upconvert NIR light (700−1300 nm, the optical window of biological tissue) to visible/ ultraviolet light, can serve as an inner light source to activate most organic photosensitizers (PSs) for cytotoxic 1O2. In fact, photoexcitation of inorganic semiconductors results in electrons and holes for continued generation of advanced D

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Figure 4. (a) Preparation of AFeNPs by the hubble-bubble process. (b1) Low- and (b2) high-resolution TEM images of AFeNPs and (b3) the corresponding selected-area electron diffraction (SAED) pattern. (c) Time-dependent ionization of AFeNPs at various pH values. (d) Electron spin resonance spectra for the detection of formed ·OH under various conditions. Reproduced with permission from ref 31. Copyright 2016 John Wiley and Sons. (e) Schematic illustration of the surface oxidation of FeS2−PEG in response to H2O2 with the generation of ·OH. (f) TEM image of FeS2. (g) Intensity changes of T1-weighted and T2-weighted MRI signals at different time points in tumor. Reproduced with permission from ref 32. Copyright 2017 John Wiley and Sons.

oxidizing ·OH and long-lived O2•−, a type-I PDT with minimized oxygen-tension dependence, by changing the raw material for ROS from O2 to H2O. On the basis of this approach, a SnWO4−UCNP nanohybrid was constructed in which all of the UCNP-emitted light was effectively absorbed by the SnWO4 semiconductor for the production of multiple ROS (·OH and O2•−) (Figure 3a).21 Recently, Zhang’s group presented a very meaningful work on a novel PDT with total independence of O2. These researchers loaded azo initiators into the hollow interior of Au nanocages (AuNCs), in which the plasmonic heating of AuNCs under NIR irradiation results in thermal decomposition of the azo initiators to produce R· free radicals, causing elevated oxidative stress and DNA damage for apoptotic cell death under various oxygen tensions (Figure 3b).22 However, for PDT solely, the limited penetration of NIR (approximately 5−10 mm) cannot meet the actual requirement in a clinical setting. We applied X-ray with limitless penetration in the biosome to activate PSs for efficient treatment of deep-seated tumors. A Ce III-doped LiYF 4 nanoscintillator (SCNP) was first prepared as a nanoconverter and later coated with a SiO2 layer for further decoration of ultrafine ZnO semiconductor nanoparticles outside (SCNP@ SiO2@ZnO).23 In this system, SCNP has the distinctive property of downconverting high-energy electromagnetic radiation to luminescence in the ultraviolet/visible region,

which can activate ZnO to form highly biotoxic ROS (Figure 3c,d). This system is the first example of the use of a nanoscintillator with a semiconductor for efficient radiationinduced type-I PDT, offering solutions for both strong oxygen dependence and limited light penetration depth with important guidance and reference significance. 3.2. RT with Oxygen-Mimicking Radiosensitizers

It has been well-recognized that hypoxia is the major factor contributing to radioresistance.24 With the discovery of hypoxia-induced transcription factors (HIFs), increasing numbers of studies have shown that HIFs directly regulate the signaling pathways involved in decreased cell death, enhanced gene instability, increased invasiveness and metastasis, and acquisition and maintenance of cancer stem cells.25 Thus, hypoxia tends to do worse in terms of both locoregional recurrence and distant metastases. Radiosensitizers that could substitute oxygen or target HIF-related pathways to knock them out will provide systematic effects for efficient resistance to solid tumors.26,27 Thus, a rattle-structured nanocarrier with a high-Z UCNP and a sufficient amount of radiosensitizers (cisplatin, CDDP) coloaded in the cavity encircled by a porous SiO2 shell was constructed, which can produce unambiguous synergetic therapeutic effects of high-Z metal element/chemodrug-sensitized radiotherapy.28 However, CDDP lacks specificity to hypoxia and cannot address the chemoresistance of hypoxic cells. Hence, the bioreductive prodrug tirapazamine E

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Figure 5. (a) Representative TEM images of (a1) UCNP, (a2) UCNP@dense-SiO2 with PS molecules, and (a3) further coated with a mesoporous silica outer shell (UC/PS). (b) CT, early and late PET, and CT/PET imaging of HeLa cell xenograft tumors pretreated with UC/PS after intravenous injection of 18F-labeled MISO: (i) tumor irradiated with a 980 nm laser between the two PET scans; (ii) tumor without any further treatment. (c) Synergetic therapy: UC-PDT-induced acute hypoxia activates the codelivered TPZ for cytotoxic species formation, thereby potentiating their synergetic antitumor efficacy. (d) Time-dependent tumor growth curves obtained after the indicated in vivo treatments. Reproduced with permission from ref 33. Copyright 2015 John Wiley and Sons.

(TPZ) with high selective cytotoxicity and radiosensitivity to hypoxia was chosen to replace CDDP for the hypoxia-specific upconversion nanoradiosensitizer (TPZ@UCHM).29 Because of the fluctuating hypoxia in tumors, hypoxic cells exposed to TPZ@UCHM can be either be killed or be sensitized to subsequent irradiation under well-oxygenated conditions.30 The results showed that combining TPZ@UCHM with RT could produce a large increase in cell death compared with that using low-dose radiation alone and also could counteract the radiation-/hypoxia-stimulated cancer cell invasion and metastasis with the hypoxia-regulating transcription factors being significantly silenced.

nature of the ferrous ion release so as to directly reflect the running process of CDT. Notably, H2O2 was essential and has substantial effects on the process of CDT. Thus, we were inspired to develop a pyrite−poly(ethylene glycol) (FeS2− PEG) nanocube that can catalyze H2O2 disproportionation for efficient generation of ·OH (Figure 4e,f), and the simultaneous transition from antiferromagnetic FeS2−PEG to ferromagnetic FeS2@FexO−PEG can be further used for MRI monitoring of H2O2 content in tumors indirectly (Figure 4g).32 Recent results have suggested the importance of CDT, which by now has emerged as particularly promising for tumor therapy.

3.3. CDT without Energy and Oxygen Participation

4. EXPLOITING HYPOXIA Even though the existence of hypoxia is a negative prognostic indicator for treatment efficacy, its unique biology characteristics provide several important targets for selective antitumor therapy. Thus, it is favorable to select or design agents for the material chemistry involved, from the sensitive response to the differences between tumoral and normal tissues to manage the change of chemical compositions in tumor for hastened cell death. Taken together, these properties present a significant challenge. With the significant improvements of nanotechnology, various functional nanomaterials, including drug delivery nanocarriers, acidity/reducibility-response nanoagents, and photothermal/dynamic nanoplatforms, have emerged to deploy unique delivery nanosystems, hypoxia-responsive nanopromoters, and even novel hypoxia-specific strategies.

For both RT and PDT, external energy supply is the prerequisite, defining their strong dependence on costly and sizable equipment. The development of direct energy conversion strategies that do not require external energy input is highly desired because of the economic and practical benefits. Therefore, a chemodynamic therapy (CDT) that enables a highly specific cancer therapy without the need for external energy input and special instruments has been proposed by our group.31 With a novel hubble-bubble approach, amorphous iron nanoparticles (AFeNPs) were prepared (Figure 4a) and showed clear pH-dependent release of ferrous ions owing to the metastable random structure of AFeNPs (Figure 4b,c). Under tumoral acidic conditions, these rapidly released ferrous ions could induce a localized/ intratumoral Fenton reaction via promotion of the disproportionation of H2O2 for the production of reactive ·OH species to kill tumors (Fe2+ + H2O2 → Fe3+ + ·OH + OH−) (Figure 4d). Moreover, the intrinsic spin-canting effect induced by the chaotic arrangement of iron atoms provided AFeNPs a relatively high r1 as contrast agents for magnetic resonance imaging (MRI), which could confirm the on/off

4.1. Hypoxia-Enhanced Bioreductive Therapy

Bioreductive TPZ is a compound that can be reduced by biological reductase enzymes only or preferentially in the absence of oxygen to generate toxic active metabolites. Since TPZ is selectively toxic to hypoxic cells, it alone could not kill all cells in the tumor, as many well-oxygenated cells exist. An idea was to combine TPZ with oxygen-dependent PDT for F

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Figure 6. (a) Schematic diagram of the self-assembly of the acid-induced POM cluster into a large hollow aggregate via oxygen-protonationinduced hydrogen bonding. (b) Fourier transform spectra of the k2-weighted Mo K-edge EXAFS oscillations for the POM clusters dispersed in aqueous solutions with varied pH. The inset shows the corresponding k2-weighted oscillator functions. (c) TEM images of the POM clusters at pH 7.4, the nanovesicles at pH 6.5, and the much larger assemblies at pH 4.5. The insets show the corresponding zoom-in images. (d) Digital photographs of POM clusters under varied reductions. (e) Schematic diagram of photothermal conversion in the POM cluster. (f) Representative photographs of a tumor-bearing Balb/c mouse with large-area 808 nm laser irradiation. All three tumors are covered by the laser beam (f1). Representative thermal images were acquired in 5 min with 808 nm laser irradiation at 1 h after intravenous injection of (f2) saline and (f3) POM. (f4) Line distributions of temperatures in f2 (line 1) and f3 (line 2). Reproduced from ref 35. Copyright 2016 American Chemical Society.

synergetic tumor therapeutic effects of the combined TPZ and UC-PDT, achieved first by UC-PDT in the normal oxygen environment and immediately followed by the induced cytotoxicity of activated TPZ when oxygen was depleted by UC-PDT (Figure 5c,d). Afterward, a similar method was developed by Liu’s group, with the combined application of glucose oxidase (GOx) to exhaust intratumoral oxygen and then to activate the bioreductive prodrug banoxantrone dihydrochloride for effective cancer treatment.34

enhanced bioreductive therapy as a whole: (1) ROS in PDT can directly work on cancer cells as well as the tumor blood vessels, resulting in a range of vascular destruction effects with increased hypoxic fractions, and (2) nanocarriers enable the delivery of hydrophobic TPZ into the tumor, which can be effectively activated in this potentiated hypoxia for substantial antitumor activity. Thus, a double-silica-shelled UCNP nanostructure capable of codelivering PS molecules and TPZ bioreductive prodrugs was designed (TPZ-UC/PS), in which PS molecules were grafted into the inner SiO2 to ensure high payload and negligible leakage and TPZ was loaded in the outer mesoporous SiO2 for on-demand drug release in tumors (Figure 5a).33 18F-labeled MISO positron emission tomography showed that the hypoxic subvolumes in tumors were significantly enlarged in 30 min, starting from UCNP-based PDT (UC-PDT) treatment with NIR laser irradiation, indicating the induced strong local hypoxia by UC-PDT (Figure 5b). In vitro and in vivo experiments all confirmed the

4.2. Hypoxia-Adaptive Photothermal Therapy

The mentioned method may appear to be perfect, but it actually is not, as there is a discrepancy between nanoagents’ demand and supply to the hypoxia region in tumors. This discrepancy occurs because hypoxia is located far from functioning blood vessels with strong internal pressure, and nanoagents with large sizes hardly reach them; moreover, nanoagents target into the tumor primarily by the enhanced G

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Figure 7. (a) Schematic of MS NPs used as specific intratumoral DOA for tumor-starving therapy. (b1, b2) TEM images of (b1) highly dispersed MS NPs and (b2) a representative MS NP (the inset is the corresponding SAED pattern). (b3) HRTEM image showing the serrated edge of the nanoparticle (highlighted by black arrows). (c) 29Si MAS NMR spectra of 4T1 tumors collected at 0.5, 12, and 60 h after MS NP administration, confirming the incomplete condensation of the SiO2 microsheets formed in situ in the tumors. (d) Representative time-course TEM images revealing the evolution of MS NPs in the morphology and crystallization during the deoxygenation in vivo. Reproduced with permission from ref 36. Copyright 2017 Springer Nature.

4.3. Hypoxia-Activated Tumor Starvation Therapy

permeability and retention (EPR) effect, and nanoparticles with large sizes (>10 nm) present an excellent EPR effect for effective delivery into tumor tissues. Thus, the design of nanomaterials for hypoxic tumors falls into a dilemma. Given the chemical and structural conversion of polyoxometalate (POM) clusters in acidic/reductive environments, we developed a Mo-based POM composed of Na+ and NH4+ cations and Keggin-type macroanionic units for hypoxiaadaptive PTT (Figure 6a).35 In the bloodstream, this POM could remain small-molecule-like for extended circulation and successful entry into the hypoxia region; at low pH, the POM became self-assembled nanovesicles as a result of protonation of edge-sharing oxygen atoms and subsequent formation of hydrogen bonding caused by the increased attractive forces (Figure 6b,c); more prominently, under reducing conditions, the blue color of the POM cluster deepened proportionally, corresponding to increased NIR absorbance, providing a more efficient temperature increase under 808 nm laser irradiation (Figure 6d). The mechanism lies entirely in the acid-sensitive naked electronic structure of the POM cluster for typical NIR absorption and the charge transfer between Mo(V) and Mo(VI) via the bridging oxygen bonds in the POM for photothermal conversion (Figure 6e,f). This finding stands to establish a new physicochemical paradigm for “molecule− nano” medicine, which can break through the natural limitations of conventional nanomedicines for solid tumor treatment. Thus, it seems that hypoxia in certain cases may be considered to be an invaluable asset to activate and/or enhance well-researched agents for therapeutic success.

If cancer cells are seen as terrorists in the human body, tumor vasculatures act as accomplices that abet them. Thus, strategies that can inhibit unwanted growth of blood vessels and block the supply of nutrients and oxygen to cancer cells may starve tumors, leading to subsequent cellular necrosis and apoptosis. In view of the vital role of oxygen, agents that can directly remove intratumoral oxygen and efficiently block rapid reoxygenation via tumor blood vessels may contribute to innovative significant antiangiogenic strategies/cancer-starvation methods, but this effect remains a large challenge. We recently prepared Mg2Si nanoparticles (MS NPs) by a special self-propagating high-temperature synthesis (SHS) approach in a mixed O2/Ar gas atmosphere. These MS NPs can be used as qualified deoxygenating agents (DOAs) for specific tumorstarving therapy (Figure 7a,b).36 The reactions for environmental oxygen scavenging are as follows: (1) in the mildly acidic tumor microenvironment, the Lewis basic Si4− ion in MS NPs can react with H+ to give the intermediate silane (SiH4) by the reaction Mg2Si + 4H+ → 2Mg2+ + SiH4; (2) reactive SiH4 is further oxidized and condenses into SiO2 microsheets according to the reaction SiH4 + 2O2 → 2H2O + SiO2. Thus, the MS NPs serve as a safe oxygen scavenger, and overall, biocompatible Mg2+, H2O, and SiO2 are the only deoxygenation products. On the basis of the total reaction, one mole of Mg2Si can consume two moles of oxygen molecules, suggesting high oxygen-consumption efficiency. Research using 29 Si solid-state magic-angle spinning (MAS) NMR spectroscopy (Figure 7c) and time-course TEM images (Figure 7d) H

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Accounts of Chemical Research evidently confirmed the stepwise transformation of intratumoral MS NPs to amorphous SiO2 microsheets, which aggregated in the tumor as an efficient capillary blocker to completely stop reoxygenation, consequently leading to highly effective tumor inhibition. Afterward, Zhang’s group developed a cancer-targeted cascade bioreactor (mCGP) by embedding glucose oxidase (GOx) and catalase in the cancer cell membrane-camouflaged porphyrin metal−organic framework for synergistic therapeutic effects of long-term cancer starvation therapy and robust PDT.37 At its core, this nanosystem attempts to cut off the energy supply within living cells and starve the cells to death, which offers a promising cancer therapy for future anticancer efforts.

Meng Zhang was born in 1991. He received his B.Eng. from Shandong University in 2014, majoring in Materials Science and Engineering. After graduation, he joined Wenbo Bu’s group at SICCAS to pursue his Ph.D degree. Zhongmin Tang was born in 1993. He received his B.Eng. from Shandong University in 2014, majoring in Materials Science and Engineering. After graduation, he joined Wenbo Bu’s group at SICCAS to pursue his Ph.D degree. Mingyuan He was born in 1940. He graduated from Shanghai East China Institute of Textile Engineering in 1966. He was elected as the Chinese Academician of Sciences in 1995 and now is a chemistry professor at ECNU. Wenbo Bu was born in 1973. He obtained his Ph.D. degree at Nanjing University of Technology in 2002. He joined SICCAS as a postdoctoral fellow with Prof. Jianlin Shi in 2002. In 2016, he joined the College of Chemistry and Molecular Engineering at ECNU and is now a full professor at ECNU and an adjunct professor at SICCAS.

5. SUMMARY AND OUTLOOK Over the past decade, tumor hypoxia has been heavily researched, as it renders solid tumors more resistant to many conventional therapeutic methods and is associated with a more malignant phenotype and poor survival of patients with tumors. Because of the rapid development of nanotechnology, well-designed nanomaterials could overcome the difficulties encountered by conventional anticancer methods, such as low drug/energy delivery efficiency, tumor nonspecificity, and hypoxia resistance, and even convert the unfavorable hypoxia features into therapeutic targets for additional advantages in the battle against tumors. Our efforts in the above areas have centered on the design and construction of suitable nanomaterials to modulate hypoxia (including countering hypoxia, disregarding hypoxia, and exploiting hypoxia) for highly efficient therapeutic outcomes. Such strategies could potentially improve the overall anticancer efficiency, but these proposed nanotherapies are still in their infancy, with some underlying problems that need to be assessed in detail, such as how to properly penetrate hypoxic regions, how to ensure nanomaterials’ biosafety and biodegradability, etc. Though nanomedicine is at an early stage, the reported results are surprising, and importantly, these advanced antitumor concepts have great reference values for chemists, materials scientists, biologists, and doctors and may lead to new insights in oncology and even breakthrough in other fields.

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ACKNOWLEDGMENTS This work was financially supported by the National Science Foundation for the Young Scientists of China (Grant 51702211), the National Funds for Distinguished Young Scientists of China (Grant 51725202), the National Natural Science Foundation of China (Grants 51872094, 81471714, and 81472794), and the Shanghai Excellent Academic Leaders Program (Grant 16XD1404000).

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]; [email protected] (W.B.). ORCID

Wenbo Bu: 0000-0001-6664-3453 Notes

The authors declare no competing financial interest. Biographies Yanyan Liu was born in 1988. She obtained her Ph.D. degree from Shanghai Institute of Ceramics, Chinese Academy of Sciences (SICCAS) under Prof. Wenbo Bu. She joined the College of Chemistry and Molecular Engineering at East China Normal University (ECNU) as a lecturer in 2017. Yaqin Jiang was born in 1995. She received her B.Eng. degree from Anhui Normal University in 2017, majoring in Material Chemistry. After graduation, she joined Wenbo Bu’s group at ECNU to pursue her Ph.D degree. I

DOI: 10.1021/acs.accounts.8b00214 Acc. Chem. Res. XXXX, XXX, XXX−XXX

Article

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DOI: 10.1021/acs.accounts.8b00214 Acc. Chem. Res. XXXX, XXX, XXX−XXX