Functional Nanomaterials for Phototherapies of ... - ACS Publications

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Functional Nanomaterials for Phototherapies of Cancer Liang Cheng, Chao Wang, Liangzhu Feng, Kai Yang, and Zhuang Liu* Institute of Functional Nano & Soft Materials (FUNSOM) & Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou 215123, China 2.5.1. Light-Controllable Drug Release Based on the Photothermal Effect of Nanocarriers 2.5.2. Photothermally Enhanced Drug Delivery 2.5.3. Gold Nanomaterials for PTT-Based Cancer Combination Therapy 2.5.4. Other Inorganic Nanomaterials for PTTBased Cancer Combination Therapy 2.5.5. Organic NIR-Absorbing Nanoagents for PTT-Based Cancer Combination Therapy 3. Photodynamic Therapy Based on Nanomaterials 3.1. Organic Nanoparticles as Nanocarriers of Photosensitizers for Photodynamic Therapy 3.2. Inorganic Nanoparticles as Nanocarriers of Photosensitizers for Photodynamic Therapy 3.2.1. Silica Nanoparticles 3.2.2. Metallic Nanoparticles 3.2.3. Magnetic Nanoparticles 3.2.4. Semiconducting QDs 3.2.5. Fullerenes and Their Derivatives 3.2.6. Other Nanocarbons 3.2.7. Two-Photon Exciting Nanoparticles 3.2.8. Scintillation Nanoparticles and SelfIlluminating Nanoparticles 3.2.9. Upconversion Nanoparticles for NearInfrared-Induced Photodynamic Therapy 3.3. Combination of Photodynamic Therapy with Other Therapeutic Approaches 3.3.1. Combination of Photodynamic Therapy with Chemotherapy 3.3.2. Combination of Photodynamic Therapy with Photothermal Therapy 4. Future Challenges and Prospects Author Information Corresponding Author Notes Biographies Acknowledgments References

CONTENTS 1. Introduction 2. Photothermal Therapy Using Nanoagents 2.1. Gold Nanostructures for Photothermal Therapy 2.1.1. The Plasmonic Absorbance of Gold Nanostructures 2.1.2. Gold Nanoparticles 2.1.3. Gold Nanorods 2.1.4. Gold Nanoshells 2.1.5. Gold Nanocages, Nanostars, and Other Nanostructures 2.1.6. Gold-Shelled Nanocomposites for Imaging-Guided Therapy 2.1.7. Toxicology Studies of Gold Nanomaterials 2.2. Carbon Nanomaterials for Photothermal Therapy 2.2.1. Carbon Nanotubes 2.2.2. Nanographene 2.2.3. Carbon-Based Composite Nanostructures 2.2.4. Toxicology Studies of Carbon Nanomaterials 2.3. Other Inorganic Nanomaterials for Photothermal Therapy 2.3.1. Pd Nanosheets 2.3.2. CuS Nanostructures 2.3.3. Other Inorganic Photothermal Nanoagents 2.4. Organic Nanoparticles for Photothermal Therapy 2.4.1. NIR-Absorbing Dye Containing Nanocomplexes 2.4.2. NIR-Absorbing Conjugated Polymers 2.4.3. Porphysomes 2.4.4. Other NIR-Absorbing Organic Nanoparticles 2.5. Combination of Photothermal Therapy with Other Therapeutic Approaches

© 2014 American Chemical Society

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1. INTRODUCTION Cancer has been one of the major threats to the lives of human beings for centuries.1 Current cancer therapies mainly include surgery, chemotherapies, and radiotherapies. While surgery in many occasions is not able to completely remove all cancer cells

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Received: September 25, 2013 Published: September 26, 2014 10869

dx.doi.org/10.1021/cr400532z | Chem. Rev. 2014, 114, 10869−10939

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Figure 1. Statistics of publications and their citations with topics including “photo”, “nano”, and “therapy”, based on Web of Science searching conducted on August 15th, 2014.

reported ones,9,10 as well as organic nanoparticles such as NIRabsorbing conjugated polymers,11,12 porphysomes,13 and nanomicelles encapsulated NIR dyes,14 have been widely explored by many research groups including ours as photothermal agents for PTT ablation of cancer cells in vitro and in vivo. In addition, the photothermal effect of nanoagents can not only be used to directly burn cancer cells, but is also helpful to trigger and/or enhance other therapeutic approaches if well-designed smart nanoplatforms are employed, aiming at the synergistic cancer killing effect. Different from PTT, which relies on photothermal heating to “cook” cancer, photodynamic therapy (PDT) uses singlet oxygen (SO) or reactive oxygen species (ROS) generated from photosensitizer (PS) molecules under light exposure to kill cancer cells.15 PDT is an externally activable treatment modality for various diseases, and has already been approved for cancer treatment in the clinic. Upon administration of PS molecules, the lesion is then selectively illuminated with light of appropriate wavelength, which, in the presence of oxygen, leads to the generation of cytotoxic oxygen species by PS molecules and consequently to cell death and tissue destruction. A wide range of PS molecules, most of which contain porphyrin structures, have been applied in the PDT. Over the past decade, nanoparticle-based PDT has emerged as an alternative to conventional PDT to effectively target cancer. PS-carrying nanoparticles could increase the water solubility of PS molecules, enhance their tumor accumulation, and thus improve the therapeutic efficacy and specificity of PDT. In addition, nanotechnology provides a platform for the integration of multiple functionalities in a single construct. Various nanomaterials such as liposomes,16 polymeric nanoparticles,17 magnetic nanoparticles,18−20 quantum dots,21 carbon-based nanomaterials,22 mesoporous silica nanoparticles,23 as well as a number of other functional nanoparticles with interesting chemical and physical properties24 have been

in the human body, chemotherapy and radiotherapy all suffer from their severe toxic side effects to normal tissues and limited specificities to cancer cells.2 Phototherapies induced by light, preferably near-infrared (NIR) light with superior tissue penetration ability, usually involve phototherapeutic agents with little toxicity in dark, and are able to selectively kill cancer cells under light irradiation, without causing much damage to normal tissues in dark. There are two levels of “selectivity” in photo therapy: (1) The well-engineered phototherapeutic agents (e.g., nanoagents) could selectively target tumor via either passive or active tumor homing. (2) The light illumination could be spatially controlled to irradiate only the diseased lesion (e.g., the tumor) without damaging normal tissues. Such dual-selectivity offered by phototherapies could significantly reduce the systemic toxicity associated with traditional chemo- or radio-therapeutic approaches. With the rapid development of nanoscience and technology in the past decade, phototherapies based on nanomaterials and nanotechnologies have attracted tremendously increasing interest (Figure 1). Photothermal therapy (PTT) employs photoabsorbing agents to generate heat from light, leading to thermal ablation of cancer cells and the subsequent cell death. Ideal photothermal agents should exhibit strong absorbance in the NIR region, which is a transparency window for biological tissues, and could efficiently transfer the absorbed NIR optical energy into heat. In addition, the agents used in PTT should be nontoxic and show high tumor-homing ability, to improve therapeutic efficacy without rendering toxic side effects. Various nanomaterials with strong NIR absorbance have shown great promise in photothermal treatment of cancer, achieving encouraging therapeutic efficacies in many in vivo animal studies. Inorganic nanomaterials including different gold nanostructures,3,4 carbon nanomaterials,5 palladium nanosheets,6 copper sulfide nanoparticles,7,8 and a few other newly 10870


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Table 1. A Summary of Functional Nanomaterials Developed for Photothermal and Photodynamic Therapy types of nanoagents photothermal therapy

photodynamic therapy

Au nanoparticles Au nanorods Au nanoshells Au nanocages Au nanostars Au nanoprisms Au−Ag alloyed metallic Au-based nanocomposites carbon nanotubes nanographene carbon nanocomposites Pd nanosheets CuS nanostructures transition-metal dichalcogenides wungsten oxide nanowires indocyanine green heptamethine indocyanine dye polyaniline nanoparticles polypyrrole nanoparticles PEDOT:PSS nanoparticles PCPDTBT, PCPDTBSe porphyrin-lipid nanodevices melanin nanoparticles silica nanoparticles metallic nanoparticles magnetic nanoparticles semiconducting QDs fullerenes and their derivatives carbon nanotubes nanographene carbon dots scintillation nanoparticles upconversion nanoparticles liposomes micelles natural degradable polymers dendrimers hollow polymer microcapsules

references 39−57 28,58−66 68,70−82 83−85 37,86,87 88,89 90,91

remarks gold nanostructures have been extensively explored as photothermal agents; their absorbance spectra could be easily tuned by controlling their sizes and morphology; gold is a rather inert element with reasonable biocompatibility

92−97,102,106−108 131−144 157,164−167,170 171− 179

carbon nanomaterials usually show broad absorbance from UV to NIR with excellent photothermal stability; the toxicity of nanocarbons is closely related to their surface chemistry

6,196−198 7,8, 199−202,204,205

those inorganic photothermal agents containing heavy metal elements are recently developed ones; many of them could be utilized for imaging-guided PTT; their potential long-term toxicity remains to be explored

9,10 214 216,218,225 14

ICG is a clinically approved agent; small molecules usually could be rapidly excreted by renal excretion

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conjugated polymers have been found to be robust photothermal agents; their biodegradation behaviors remain to be studied

11,237,242 12 238 13,243,244

those organic agents may have great biocompatibility

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many inorganic nanoparticles could be loaded with photosensitizers for photodynamic therapy; some of them (e.g., fullerene derivatives) are intrinsic PS agents; the future clinical use of those inorganic nanoagents is again limited by their long-term in vivo retention and toxicity concerns

383−387 21,393−396 400−405 22,406−409 23,410−413 414,415 420−422

able to deliver PDT without the need of external light sources

25,26,430,433,436−438,441

able to trigger PDT under NIR light via resonance energy transfer

345 351−355 356−359

organic nanocarriers for PDT have been studied for decades; some of them are already in clinical trials

360 17,361,362

developed for the delivery of PDT, showing encouraging results in vitro and in vivo. Moreover, in recent years, another unique class of optical nanomaterials, upconversion nanoparticles (UCNPs), which emit high-energy visible light under NIR excitation, have been developed to realize NIR-induced PDT for improved tissue penetration.25,26

This article would comprehensively review the recent advances regarding the development of phototherapies for cancer treatment, such as PTT, PDT, and phototriggered combined therapy, using functional nanomaterials (Table 1). A large variety of inorganic and organic NIR-absorbing nanomaterials explored for PTT cancer treatment will be summarized. 10871


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Figure 2. Plasmonic absorbance and transmission electron microscopy (TEM) images of various types of Au nanostructures. (a and e) Au nanoparticles (AuNPs). Reprinted with permission from ref 33. Copyright 2013 Elsevier. (b and f) Au nanorods (AuNRs). Reprinted with permission from ref 32. Copyright 2010 Elsevier. (c and g) Au nanocages (AuNCs). Reprinted with permission from ref 34. Copyright 2008 American Chemical Society. (d and h) Au nanostars or nanoflowers (AuNFs). Reprinted with permission from ref 37. Copyright 2012 Institute of Physics.

research groups.4,27−32 Most of these applications are based on an optical phenomenon known as localized surface plasma resonance (LSPR). The optical properties of gold nanostructures are determined by the size and the shape of the nanoparticle. Figure 2 shows the structures and the typical absorbance spectra of several types of representative gold nanostructures, icnluding gold nanoparticles (AuNPs), gold nanorods (AuNRs), gold nanocages (AuNCs), and Au nanostars or Au nanoflowers (AuNFs). Spherical AuNPs usually show the LSPR peak at ∼520 nm, with the slightly red-shifted absorbance as the increase of nanoparticle diameter.33 By changing the morphology of gold nanostructures, their LSPR peak can be tuned to the NIR region. The optical absorption of AuNSs can be tuned to the NIR range by

The combination of PTT with other therapeutic approaches such as chemotherapy and gene therapy will then be discussed. Various different types of nanoagents developed for the delivery of PDT, as well as combined PDT with other therapies, will also be reviewed. The future prospects and challenges in this rapidly growing field will be addressed at last.

2. PHOTOTHERMAL THERAPY USING NANOAGENTS 2.1. Gold Nanostructures for Photothermal Therapy

2.1.1. The Plasmonic Absorbance of Gold Nanostructures. Gold nanostructures provide a versatile, multifaceted platform for a broad range of biomedical applications for both cancer diagnosis and therapies as demonstrated by numerous 10872


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Figure 3. Development of amphiphilic plasmonic micelle-like nanoparticles (APMNs) based on self-assembled AuNPs coated with block copolymers. Depending on the lengths of polymer tethers and the sizes of AuNP cores, different structures including unimolecular micelles, clusters, as well as vesicles could be formed by self-assembly. APMNs with red-shifted absorption were then used for in vivo photothermal ablation of tumors in mice. Reprinted with permission from ref 53. Copyright 2013 American Chemical Society.

Figure 4. PEGylated AuNRs for in vivo tumor photothermal therapy. (a) A TEM image of NIR-absorbing AuNRs. (b) A schematic showing surface PEGylation on AuNRs. (c) A photo of a mouse bearing two MDA-MB-435 tumors on its opposing flanks. PEG-AuNRs or saline were iv given (20 mg/kg) to tumor-bearing mice bearing. After AuNRs had cleared from circulation (72 h after injection), the right flank was irradiated using an 810 nm diode laser (2 W/cm2; beam size indicated by dotted circle). (d) Infrared (IR) thermal images of photothermal heating for PEG-AuNR-injected (top) and saline-injected (bottom) mice under laser irradiation. (e) Photos showing AuNR-based photothermal destruction of tumors in mice. Reprinted with permission from ref 64. Copyright 2009 American Association for Cancer Research.

varying the relative size of the core and shell. AuNRs typically have two LSPR peaks,32 one for the transverse mode around

520 nm and the other for the longitudinal mode whose position strongly depends on the aspect ratio of the nanorod and can be 10873


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Figure 5. Targeted hollow gold nanoshells (HAuNS) for photothermal ablation therapy. (a) A scheme for c(KRGDf)-PEG-HAuNS bioconjugation. (b) Characterization of HAuNS by TEM (bar, 20 nm) and UV−vis−NIR spectrum. (c) Representative bioluminescence images of nude mice bearing U87-TGL tumors with different treatments. (d) Quantitative analysis of bioluminescence images beginning with treatment administration on day 8 after tumor inoculation (n = 5 per group). (e) Kaplan−Meier survival curve of tumor-bearing mice after various treatments indicated in (c) (n = 10 per group). Reprinted with permission from ref 81. Copyright 2009 American Association for Cancer Research.

finely tuned from visible to NIR region.28 AuNCs invented in 2002 by the Xia group are hollow cubic Au nanostructures with ultrathin porous walls and truncated corners.34,35 The LSPR peaks of AuNCs can be tuned to any wavelength in the range of 600−1200 nm by controlling the size or wall thickness of the AuNCs. AuNFs, or named Au nanostars, which contain multiple sharp branches with plasmonic absorbance tunable in the NIR region, have also gained wide interest in recent years.36 The extinction spectra of individual AuNFs vary greatly due to the unavoidable shape polydispersity, whereas that of a AuNFs solution typically exhibits broad visible and NIR absorbance due to the overlapping of many distinctive spectra.37,38 2.1.2. Gold Nanoparticles. With a much higher absorption cross-section than small organic dyes, AuNPs usually exhibit strong visible absorption, whose peak could be affected by the diameter and aggregation state of AuNPs. Photothermal ablation of cancer can be achieved using AuNPs under irradiation by visible lasers. In 2003, Lin and co-workers used pulsed laser to heat cancer cells treated with AuNPs, and realized highly localized photothermolysis of targeted lumphocytes cells.39 At about the same time, Zharov et al. reported a similar study on the photothermal destruction of K562 cancer cells by AuNPs.40 In this work, they detected the laser-induced bubbles during the laser irradiation of AuNPs, and investigated their formation dynamics during the pulsed laser treatment. Later, they carried out further studies and demonstrated this technique in the treatment of different types of cancer cells

using the laser-induced bubble formation mechanism under nanosecond laser pulses with AuNPs as the photothermal agent.41−43 On the basis of the approach, in vivo tumor ablation in rats with AuNPs was also realized in a recent study using pulsed laser irradiation.44 Intracellular bubble formation from AuNPs could result in individual tumor cell damage. However, rather expansive pulsed lasers are required in this technique and usually used to irradiate small localized regions. Moreover, the overall heating efficiency is relatively low due to rapid heat loss after the short irradiation pulses. The use of continuous wave (CW) laser during PTT has its advantage in terms of effective heat accumulation to induce tumor ablation in a larger area. In the study by EI-Sayed et al., AuNPs were conjugated to an anti-EGFR antibody to target two types of human head and neck cancer cells.45 It was found that the photothermal heating of AuNPs could induce cancer cell death after the irradiation with a CW laser with a wavelength of 514 nm for 4 min at the power density of at 19 W/cm2, while healthy cells showed little loss of cell viability under the same treatment. A number of other groups have also reported the use of AuNPs as a photothermal agent for effective cancer cell ablation under irradiation by CW visible lasers.46−49 Although AuNPs can be readily synthesized and have been extensively explored in the area of nanomedicine, the major limitation of using AuNPs in photothermal cancer treatment is their relatively short absorption wavelength in the visible region (∼520 nm). Because visible light would be strongly absorbed and scattered by biological tissues, the penetration depth of 10874


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Figure 6. Gold nanocages for in vitro and in vivo photothermal therapy. (a) Normalized UV−vis−NIR extinction spectra recorded from aqueous suspensions of nanostructures after titrating Ag nanocubes with different amounts of a HAuCl4 aqueous solution. (b) A scanning electron microscopy (SEM) image of AuNCs prepared by refluxing an aqueous solution containing both Ag nanocubes and HAuCl4. The inset shows a TEM image of the as-made AuNCs. (c) SK-BR-3 breast cancer cells were treated with immuno AuNCs and then irradiated by an 810 nm laser at a power density of 1.5 W/cm2 for 5 min. (c1) Calcein AM assay, and (c2) ethidium homodimer-1 (EthD-1) assay. In the control experiment, cells irradiated under the same conditions but without immuno AuNCs treatment maintained viability, as indicated by (c3) calcein fluorescence assay and (c4) the lack of intracellular EthD-1 uptake. Cells treated with immunoAuNCs but irradiated at a lower power density (0.5 W/cm2) for 5 min remained alive, as shown by (c5) calcein fluorescence assay and (c6) the lack of intracellular EthD-1 uptake. (d) Photograph of a tumor-bearing mouse under the photothermal treatment. (d1−d8) IR thermal images of (d1−d4) nanocage-injected and (d5−d8) saline-injected tumor-bearing mice at different time points: (d1, d5) 1 min, (d2, d6) 3 min, (d3, d7) 5 min, and (d4, d8) 10 min. Reprinted with permission from ref 83. Copyright 2007 American Chemical Society. Reprinted with permission from ref 85. Copyright 2010 John Wiley & Sons, Inc.

AuNP-based PPT is usually rather limited. To overcome this problem, there have been a number of recent reports taking advantage of the aggregation-induced red-shift of AuNP absorption for photothermal cancer ablation,50−57 Kim and co-workers designed and synthesized “smart” AuNPs that could be responsible for pH changes and form aggregates in acidic pH.50 When exposed to an acidic environment after cell internalization, those “smart” AuNPs began to aggregate, showing greatly red-shifted absorbance to NIR, useful for photothermal ablation of cancer cells under NIR light exposure. Recently, the same group further investigated pH-responsive assembly of AuNPs and spatiotemporally concerted drug release for synergistic cancer therapy.51 In another work, Liu et al. used a simple method to prepare AuNPs by surface modification with mixed-charge zwitterionic self-assembled monolayers, which could be stable at the pH of blood and normal tissues but aggregate instantly in response to the acidic extracellular pH of solid tumors.52 The total accumulation, retention, and cell uptake of the pH-responsive AuNPs in tumors were significantly enhanced by the pH-induced aggregation effect as compared to that of nonsensitive

PEGylated AuNPs. A preliminary photothermal tumor ablation evaluation suggested that the aggregation of AuNPs could be applied in cancer NIR PTT. Well-designed self-assemblies of AuNPs with red-shifted absorption have also been explored for applications in photothermal therapy. In recent years, Nie and co-workers reported self-assemblies of amphiphilic plasmonic micelle-like AuNPs with the help of linear block copolymers (BCPs)53 (Figure 3). In a mixture of water/tetrahydrofuran, Au micellelike nanoparticles would be assembled into various superstructures. The assemblies of Au micelle-like nanoparticles resulted in strong absorption in NIR range due to the remarkable plasmonic coupling of Au cores, thus facilitating their biomedical applications in bioimaging and photothermal cancer therapy.53−56 Another work by Liu et al. also developed a simple strategy for simultaneous assembly of small-size AuNPs to form a novel nanocomposite in the presence of gum arabic as an efficient photothermal agent for killing cancer cells.57 Therefore, although the plasmonic absorbance of individual AuNPs themselves usually locates in the visible range, their self-assembled nanostructures with red-shifted 10875


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Figure 7. Schematic representation of the synthesis of monoclonal anti-PSMA antibody- and A9 RNA aptamer-conjugated popcorn-shaped AuNFs for in situ monitoring of photothermal therapy response using surface-enhanced Raman scattering (SERS). The disappearance of SERS signals indicated the accomplishment of photothermal cancer cell ablation in this study. Reprinted with permission from ref 86. Copyright 2010 American Chemical Society.

effects of folate-conjugated AuNRs to human malignant nasopharyngeal carcinoma (KB) cells by both continuouswave NIR laser and femtosecond-pulsed laser irradiation.58 They found that the photothermolysis of KB cells with a high expression of folate receptors (FR) was much more effective than that of normal NIH/3T3 cells with a lower level of FR expression. Several other groups have also reported that AuNRs could be used as promising agents for in vitro cancer cell photothermolysis.59−63 In the case of in vivo PTT, Van Maltzahn et al. reported that polyethylene glycol (PEG) coated AuNRs (AuNR-PEG) could be used as an efficient photothermal nanoheater.64 In their work, AuNR-PEG exhibited a long blood half-life of ∼17 h after intravenous (iv) injection into tumor-bearing mice (20 mg Au/ kg) and could accumulate in tumor at ∼7% ID/g at 72 h post injection. It was found that the tumors on mice iv injected with AuNR-PEG were rapidly heated to over 70 °C by laser irradiation (810 nm, 2 W/cm2, 5 min), whereas the control

absorbance to the NIR window are promising for in vivo photothermal cancer treatment with improved tissue penetration. 2.1.3. Gold Nanorods. Among various Au nanostructures, AuNRs that can be easily synthesized by seeded growth methods have been extensively explored in PTT due to their strong optical extinction in the visible and NIR region.3 By simply increasing the aspect ratio of nanorods, the strong longitudinal plasma absorption band of AuNRs can be tuned to the longer wavelength. There have been numerous examples of methods to conjugate AuNRs with biomolecules for cell targeting or intracellular delivery. As early as 2006, El-sayed et al. demonstrated that AuNRs could be used for in vitro molecular imaging and PTT.28 Antibody-conjugated AuNRs showed a high binding affinity to the cell membrane of malignant cells over that of normal cells, allowing selective destruction of tumor cells without harming healthy cells after laser irradiation. Tong et al. also investigated the photothermal 10876


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Figure 8. Au nanoprisms for photothermal therapy. (a) A scheme of the synthetic method to produce PEGylated Au nanoprisms functionalized with glucose (Glc) and the dye TAMRA. (b) UV−vis−NIR spectra of purified solutions (nanoprisms@PEG) corresponding to the preparations with different volumes of the reductant added. (c−f) SEM images of Au nanoprisms with increasing average edge length. The scale bars are 500 nm in all cases. (g,h) Calcein AM (green staining, live cells) and EthD-1 (red staining, dead cells) costained cells after incubation with Au nanoprisms and laser irradiation. The laser spot was focused at the center in (h). Reprinted with permission from ref 88. Copyright 2012 American Chemical Society.

Figure 9. Magnetic gold nanocomposites. (a−e) Multifunctional magnetic AuNSs for magnetic resonance imaging and photothermal therapy. (a) Synthesis of the magnetic AuNSs (Mag-GNS). (b−e) TEM images of (b) amino-modified silica spheres, (c) silica spheres with Fe3O4 (magnetite) nanoparticles immobilized on their surfaces, (d) silica spheres with Fe3O4 and gold nanoparticles immobilized on their surfaces, and (e) the MagGNS. (f−j) Monodisperse superparamagnetic Fe3O4 core@hybrid@Au shell nanocomposite for bimodal imaging and photothermal therapy. (f) A schematic diagram for the fabrication of Fe3O4@hybrid@Au nanocomposite. (g−j) SEM images of Au-SSCNs (g and h) and Fe3O4 @hybrid@Au nanocomposites (i and j). Reprinted with permission from refs 92 and 94. Copyright 2006 and 2011 John Wiley & Sons, Inc.

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uptake of RGD-dAuNRs over time. They further observed the disappearance of tumors after iv injection of RGD-dAuNRs and NIR laser irradiation (808 nm, 24 W/cm2, 5 min). In another study, Choi et al. synthesized AuNRs loaded into chitosanconjugated pluronic-based nanocarriers that could selectively target the tumor.59 Those AuNRs showed a rather high tumor uptake at over 20% of injected dose per gram tissue (%ID/g), in marked contrast to PEG modified AuNRs, which exhibited the tumor uptake at only ∼7%ID/g. After iv injection of the AuNRs-loaded, chitosan-conjugated nanocarriers, and the followed NIR laser irradiation of the tumor, rather efficient in vivo thermolysis of tumors was achieved, without showing any apparent damage to the surrounding healthy tissues. 2.1.4. Gold Nanoshells. Gold nanoshells (AuNSs) are usually core/shell particles comprising a gold shell formed on top of a dielectric silica core, and can be easily synthesized by the seed-mediated shell growth.27,67,68 AuNSs are attractive in PTT because their LSPR can be easily tuned to the NIR region simply by modifying the thickness of the shell.68−70 In 2005, Halas and co-workers demonstrated that AuNSs conjugated with anti-HER2 antibody could be used for dark-field imaging and PTT of SKBR3 breast carcinoma cells.70 In 2007, the same group also investigated the use of AuNSs for in vivo enhancement of optical coherence tomography (OCT) imaging as well as effective photothermal ablation of tumors.68 In this work, thiolated PEG (PEG-SH) conjugated AuNSs were iv injected into tumor-bearing mice for OCT imaging, following which the tumors were irradiated using a NIR laser (808 nm, 4 W/cm2, 3 min) for photothermal ablation. Besides the use of silica nanoparticles as the cores to fabricate AuNSs, many other methods have been developed to synthesize AuNSs based on different core materials. Liu and co-workers reported a new approach toward the design of AuNSs on carboxylated polystyrene spheres (AuNRCPSs).71 The higher refractive index of polystyrene, as compared to silica, resulted in a somewhat narrower NIR plasma resonance absorbance peak of AuNRCPSs, enhancing their NIR-absorbing as well as photothermal efficiency. Ke et al. developed a novel multifunctional theranostic agent based on Au nanoshelled

Figure 10. Magnetic targeting enhanced photothermal cancer treatment under the guidance of multimodal imaging using PEGylated, gold-coated iron oxide nanoclusters. Reprinted with permission from ref 98. Copyright 2014 John Wiley & Sons, Inc.

mice showed the maximum surface temperature at ∼40 °C (Figure 4). Thus, tumors on mice that received AuNR-PEG through iv injection completely disappeared within 10 days after NIR laser irradiation, in marked contrast to the control groups, which showed uninhibited tumor growth. Moreover, the survival time of mice who received AuNR-PEG injection and the followed PTT treatment was over 50 days as compared to ∼33 days for control groups. Similar results using PEGylated AuNRs for in vivo PTT cancer treatment have also been reported by Dickerson et al. in another work.65 Beside simply relying on the ERP effect for tumor passive tumor, active tumor targeting with AuNR bioconjugates for effective in vivo PTT has also been achieved by a number of groups. Li et al. demonstrated in vivo tumor targeting and PTT using dendrimer-modified AuNRs (dAuNRs) conjugated with arginine-glycine-aspartic acid (RGD) peptide, which binds integrin αvβ3 overexpressed on tumor vasculatures and several types of tumor cells.66 The biodistribution data of RGDdAuNRs revealed ∼47% of the injected RGD-dAuNRs in the blood at 3 h p.i., ∼17% of the injected RGD-dAuNRs in the tumor at 6 h post injection, and the gradually increased tumor

Figure 11. Multifunctional nanoparticles (MFNPs) based on upconversion nanoparticles as the cores for imaging-guided cancer therapy. A schematic illustration showing the composition of a PEGylated MFNPs (MFNP-PEG) and the concept of in vivo imaging-guided magnetically targeted PTT. After iv injection of MFNP-PEG, a magnet was attached to the tumor to enhance the nanoparticle tumor accumulation, which was revealed by bimodal MR and upconversion imaging. In vivo PTT was further carried out to enable effective tumor ablation. Reprinted with permission from ref 107. Copyright 2012 Elsevier. 10878


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Figure 12. Single-walled carbon nanotubes (SWNTs) for in vivo NIR mediated photothermal tumor destruction. (a) Scheme of PEGylated SWNTs (PEG-SWNTs). Inset: A photo showing PEG-SWNTs stably dispersed in fetal bovine serum and phosphate buffer saline (PBS). (b) Atomic force microscope (AFM) image of individual PEG-SWNTs deposited on a SiO2 substrate. The scale bar is 500 nm. (c) A scheme showing in vivo photothermal treatment using PEG-SWNTs. (d) Photographs of a mouse bearing a xenograft KB tumor (70 mm3) after i.t. injection of PEGSWNTs (120 mg/L, 100 μL) and then exposure to the NIR laser irradiation (808 nm, 76 W/cm3) for 3 min to induce the tumor ablation. Reprinted with permission from ref 139. Copyright 2009 American Chemical Society.

microcapsules (AuNS-MCs) by the electrostatic adsorption of AuNPs as seeds on the polymeric microcapsule surfaces, followed by the formation of AuNSs by using the seedmediated growth.72 Those AuNS-MCs could be utilized for both PTT cancer ablation and photoacoustic (PA) imaging of cancer. Recently, lipid vesicles (such as liposomes) have also been used as the templates to prepare hollow AuNSs as photothermal agents.73−75 Because of their ease of functionalization, AuNSs are often conjugated with targeting ligands for targeted PTT both in vitro and in vivo.76−79 In 2009, Lu et al. investigated in vivo tumor targeting by PEGylated AuNSs conjugated with a melanocytestimulating hormone (MSH) analogue for selective photothermal ablation of melanoma tumors.80 In 2011, Lu et al. further showed that iv injection of RGD peptide conjugated AuNSs could target glioma tumors with high integrin αvβ3 expression, enabling photoacoustic tomography (PAT) and selective PTT of an orthotopic mouse xenograft model of glioma (Figure 5).81 It was also found that the photothermal treatment significantly prolonged the survival of tumor-bearing mice. AuNSs have not only been demonstrated to be an effective class of photothermal agents in preclinical animal experiments, but, more excitingly, also entered clinic trails. Recently, Cancer

Treatment Centers of America (CTCA) and Nanospetra Biosciences have carried out the first clinical trial for the treatment of lung cancers by phtotothermal therapy that uses AuNSs invented by Halas’s group at Rice University. The therapy begins with an injection of AuNSs into the patient’s bloodstream. After 12−24 h to allow enough time for the tumor accumulation of AuNSs, a NIR laser is used to heat AuNSs and destroy tumors in the patient. This clinical trial is in its phase II stage right now, to our best knowledge.82 2.1.5. Gold Nanocages, Nanostars, and Other Nanostructures. Gold nanocages (AuNCs) represent another novel class of nanostructures first developed by Xia and co-workers in 2002.34 AuNCs could be prepared by galvanic replacement between Ag nanocubes and HAuCl4 in an aqueous solution. In 2007, Xia’s group demonstrated the selective photothermal destruction of SK-BR-3 breast cancer cells in vitro using immuno-AuNCs functionalized with the anti-HER-2 antibody (Figure 6a−c).83,84 After incubation with the immuno-AuNCs, SK-BR-3 breast cancer cells were irradiated with a femtosecond laser at varying power densities for 5 min. When the AuNCs were incorporated, a well-defined area of cellular death corresponding to the laser spot was observed. Later in 2010, they switched to an in vivo tumor mouse model to examine the efficacy of AuNCs for photothermal cancer treatment in 10879


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Figure 13. In vivo tumor photothermal therapy using iv injected SWNTs with the optimized surface coating. (a) A scheme of a SWNT with PEGPMHC18 polymer coating. Right table: A list of 10 PEG-PMHC18 polymers synthesized in this work. Nine of them were successfully used to solubilize SWNTs. The 10%-5k version was found to be the optimized coating molecule that offered SWNTs long blood circulation time, efficient tumor uptake, and relatively low retention in other organs such as liver, spleen, and skin. SWNTs functionalized by 10%-5k PEG-PMHC18 polymer were thus used for the followed photothermal therapy. (b) Representative photos of tumors on mice after various treatments indicated. (c) The tumor growth curves of different groups after treatment. Reprinted with permission from ref 142. Copyright 2011 Elsevier.

mice85(Figure 6d). After iv injection of PEG-AuNCs for 3 days, the tumor on each mouse was irradiated with an 808 nm continuous-wave laser at a power density of 0.7 W/cm2 for 10 min, during which the tumors containing AuNCs were rapidly heated to over 55 °C, leading to effective ablation of those tumors. Another type of NIR-absorbing Au nanostructures utilized for PTT is Au nanostars, or Au nanoflowers (AuNFs), which were spherical nanoparticles with multiple sharp edges and a high absorption-to-scattering ration in the NIR region, favorable for photothermal heat generation.37,86 Lu et al. reported a multifunctional AuNFs-based surface-enhanced Raman scattering (SERS) assay for targeting sensing, PTT treatment, and in situ monitoring of the PTT response during the therapy process36,86 (Figure 7). When AuNFs were attached to cancerous cells, the localized heating that occurred during NIR irradiation was able to cause irreparable cellular damage. In another work, Yuan et al. showed that TAT-peptide functionalized AuNFs entered cells significantly more than bare or PEGylated AuNFs.36 After 4 h incubation of TAT-AuNFs with BT549 breast cancer cells, efficient photothermolysis was accomplished using a NIR laser under 0.2 W/cm2, which was among the lowest power densities ever reported for pulsed lasers. The photothermal ablation in vivo was demonstrated using PEGylated AuNFs on mice. Their results illustrated the

potential of AuNFs as an efficient photothermal agent in cancer therapy.87 There are some other types of Au nanostructures with NIR absorption useful for PTT. Au nanoprisms (AuNMs) are triangular shaped Au discs that have tunable optical properties in the NIR.88 Pelaz et al. described a novel and straightforward wet-chemical synthetic route to produce biocompatible singlecrystalline AuNMs,88 which could effectively ablate Vero cells after 2 min of 1064 nm NIR illumination at 30 W/cm2, that however was a rather high power density (Figure 8). Wang et al. synthesized AuNMs and compared them with AuNRs and AuNCs.89 They found that AuNMs exhibited a comparable photothermal efficiency, higher cell uptake, and lower cytotoxicity relative to AuNRs and AuNCs. Core−shell and alloyed multimetallic Au-based nanomaterials are also interesting nanomaterials in PTT. Particularly, Au− Ag nanocomposites possess sharper and stronger longitudinal LSPR bands than the corresponding Ag or Au nanostructures. Hu et al. synthesized a new class of AuxAg1−x nanostructures with dendrite morphology by using a replacement reaction between Ag dendrites and an aqueous solution of HAuCl4.90 The hollow Au0.3Ag0.7 dendrites with strong NIR absorption showed good biocompatibility and could serve as an effective photothermal agent. In a recent work, Tan and co-workers designed an aptamer-based nanostructure, which combined the high absorption efficiency of Ag−Au nanorods with the target 10880


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Figure 14. Chirality enriched SWNTs for photothermal therapy at the ultralow dose. (a) Photoluminescence emission (PLE) spectrum of SWNTs after chirality separation. Inset is the PLE spectrum of SWNTs before separation. (b) UV−vis−NIR absorbance spectra of SWNTs before and after chirality separation. Under the same weight concentration, chirality-separated (6,5)-SWNTs offered >10-fold higher absorbance at 980 nm as compared to those before separation. (c) NIR-II fluorescent images of a mouse bearing a 4T1 tumor after injection with chirality-separated (6,5)SWNTs taken at 12, 24, and 48 h post injection, showing clear SWNT accumulation in the 4T1 tumor. The left image is a optical photo of this mouse. (d and e) IR thermal images from 4T1 tumor bearing mice 48 h after injection with chirality-separated (6,5)-SWNTs (d) or as-made SWNTs (e) after 5 min of 980 nm laser irradiation at a power density of 0.6 W/cm2. (f) The tumor temperature changes on different groups of mice under 980 nm laser irradiation. C18PMH-PEG coated SWNTs at the i.v. injection dose of 0.254 mg/kg of SWNTs were used in this study. Reprinted with permission from ref 144. Copyright 2012 American Chemical Society.

particles with gold nanostructures have been proposed by a variety of groups. There have been two commonly used strategies to develop gold-based magnetic PTT agents, by coating magnetic nanospheres by a layer of gold shell, or by attaching ultrasmall magnetic nanoparticles on gold nanostructures such as AuNRs.92,94,95 Hyeon and co-workers proposed the combination of magnetic nanoparticles and AuNSs to develop a novel nanomedical platform for diagnostic MR imaging and simultaneous PTT treatment92,93(Figure 9a−e). In their work, monodispersed 7 nm Fe3O4 nanoparticles stabilized with 2-bromo-2-methylpropionic acid (BMPA) were covalently attached to amino-modified silica spheres through a direct nucleophilic substitution reaction between the bromo groups and the amino groups. Au seed nanoparticles were attached to the residual amino groups of the silica spheres. Finally, a complete Au shell with embedded Fe3O4 nanoparticles was formed around the silica sphere by the seed-mediated growth, resulting in the formation of magnetic AuNSs (Mag-AuNSs). Anti-HER2/neu antibody was linked onto the surface of MagAuNSs for targeted MR imaging and NIR PTT killing of SKBR3 breast cancer cells. In a similar approach, Lee et al. fabricated a multifunctional nanocomposite of Au shelled

specificity of molecular aptamers, and realized efficient and selective photothermal destruction of cancer cells.91 2.1.6. Gold-Shelled Nanocomposites for ImagingGuided Therapy. In the process of PTT, introducing imaging during therapy, or imaging-guided therapy, has been proposed to improve the treatment efficiency. First, the exact tumor location, size, and shape should be visualized by imaging to ensure that the whole tumor is effectively exposed to the light during PTT treatment. Second, real-time tracking of the photothermal agent after systemic administration by imaging would allow us to carry out the laser irradiation at the right time point when the photothermal agent reaches the highest accumulation in the tumor, so that the optimized therapeutic outcome could be achieved. Last, advanced imaging techniques would allow the monitoring of therapeutic responses after treatment. Therefore, to afford the PTT agents more enriched functionalities in imaging and therapy, many gold-based nanocomposites have been developed by a large number of research groups for imaging-guided PTT.92−94 Magnetic resonance (MR) imaging is one of the most powerful imaging techniques currently used in the clinic. Many multifunctional nanocomposites by coupling magnetic nano10881


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Figure 15. Imaging-guided PTT for sentinel lymph node (SLN) ablation to inhibit tumor metastasis. (a) A scheme showing the design of animal experiment. 4T1 murine breast tumor cells were subcutaneously injected on the right hind foot of each Balb/c mouse. Tumor cells would then spread from the primary tumor to its nearby SLNs to form metastatic sites. (b) NIR-II fluorescent imaging of a tumor-bearing mouse taken at different time points after injection with SWNT-PEG. The retention of SWNTs in the SLN reached its peak level at ∼90 min postinjection. (c) Morbidity-free survival of different groups of mice after various treatments indicated (7 mice per group). Reprinted with permission from ref 145. Copyright 2014 John Wiley & Sons, Inc.

outcomes (100% of tumor elimination after NIR laser treatment) was achieved in our animal experiments. Upconversion nanoparticles (UCNPs), particularly lanthanide-doped nanocrystals, which emit high-energy photons under excitation by the NIR light, have found potential applications in many different fields including biomedicine.99−103 As compared to traditional down-conversion fluorescence imaging, the NIR light excited upconversion luminescence (UCL) imaging relying on UCNPs exhibits improved tissue penetration depth, higher photochemical stability, and free of autofluorescence background, promising in biomedical imaging with high sensitivities.103−105 Multifunctional nanoparticles based on UCNPs have been also synthesized and used for imaging-guided PTT. Our group developed a novel class of multifunctional nanoparticles (MFNPs) based on UCNPs with combined optical and magnetic properties useful in multimodality imaging and therapy102,106,107(Figure 11). Ultrasmall superparamagnetic Fe3O4 nanoparticles (IONPs) were adsorbed on the surface of a NaYF4-based UCNP by electrostatic attraction, forming a UCNP−IONP complex, on top of which a thin gold shell was formed by the seed-induced reduction growth. Those UCNP@ IONP@Au MFNPs were successfully used for in vivo dualmodal imaging guided and magnetically targeted PTT, via a concept similar to that above-mentioned. Besides our design, Song and co-workers in a recent study fabricated silver-coated UCNPs (UCNP@Ag) with NIR absorption, which were also useful for UCL simultaneous optical imaging and photothermal ablation of cancer cells.108 This class of core−shell nanoparticles is expected to be an attractive theranostic agent for imaging-guided tumor ablation.

MnFe2O4 nanoparticles for synchronous MR imaging and PTT.96 To control the particle size, dispersivity, and reproducibility of the gold shell attached on the surface of the Fe3O4 nanoparticles, Shi’s group developed a simple but efficient route to construct a superparamagnetic Fe3O4 core/gold shell structured nanocomposite with tunable dimensions (100−240 nm in diameter)94(Figure 9f−j), which could serve as a theranostic agent for MR imaging-guided PTT as demonstrated in their in vivo experiments. The same group also designed uniform AuNRs-capped magnetic core/mesoporous silica shell nanoellipsoids (Au NRs-MMSNEs) by coating a uniform layer of AuNRs onto the outer surface of a magnetic core/ mesoporous silica shell nanostructure,97 based on a two-step chemical self-assembly process. The obtained multifunctional nanoellipsoids showed strong NIR absorbance and could also be used for MR imaging-guided PTT. Recently, our group designed a multimodal imaging-guided, magnetic targeting enhanced photothermal ablation cancer treatment strategy using Au shelled iron oxide nanoclusters98 (Figure 10). Such composite nanoparticles with diameters of ∼100 nm exhibit strong magnetic property and high NIR optical absorbance useful for both MR and PA imaging, respectively. Because of their rapid responses under local magnetic field together with prolonged blood circulation time, such composite nanoparticles after iv injection could be effectively attracted to the tumor, nearby which an external magnetic field was applied. Because of the remarkably enhanced tumor accumulation of nanoparticles as the result of magnetic targeting, photothermal ablation with excellent therapeutic 10882


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Figure 16. PEGylated nanographene oxide (NGO-PEG) for photothermal therapy. (a) A scheme of a NGO with PEG functionalization and Cy7 labeling. (b) An AFM image of NGO-PEG. Inset is a photo of NGO-PEG solution. (c) In vivo fluorescence images of tumor bearing mice taken 24 h post injection of Cy7 labeled NGO-PEG. Effective tumor uptake of NGO-PEG was observed in three different types of tumor models. (d−f) In vivo PTT study using intravenously injected NGO-PEG. (d) Tumor growth curves in different groups of mice after various treatments indicated. The tumor volumes were normalized to their initial sizes. (e) Survival curves of mice bearing 4T1 tumor after various treatments indicated. NGO-PEG injected mice after PTT survived over 40 days without any single death. (f) Representative photos of mice after various treatments indicated. Reprinted with permission from ref 157. Copyright 2010 American Chemical Society.

2.1.7. Toxicology Studies of Gold Nanomaterials. Considering the nonbiodegradable nature of gold nanomaterials, their long-term potential toxicity has become a concern when they are used for in vivo PTT cancer treatment. Although it is believed that gold is chemically inert, whether gold nanomaterials would have any potential negative effect in biological systems still merits particular attention. Therefore, a large number of groups have spent substantial efforts to look into the nanotoxicology of gold nanomaterials in vitro and in vivo.109 Many factors would affect the toxicity of the gold

nanostructures, such as the particle size, concentration, and surface modification. Surface properties may be crucial in regulating the cytotoxicity of those gold nanoparticles. Connor et al. used the standard methyl thiazolyl tetrazolium (MTT) assay to study the toxicity of 18 nm AuNPs with different surface coatings,110 including citrate, biotin, and CTAB. Citrate- and biotinmodified AuNPs were not toxic even at a high concentration of 250 μM, whereas CTAB-coated nanoparticles showed obvious toxicity at a low concentration of 0.05 μM. However, after being washed to remove free CTAB, the nanoparticles lost 10883


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Figure 17. Optimization of graphene-based photothermal agents. (a) AFM images of different graphene derivatives: while nGO-PEG and nRGOPEG showed similar ultrasmall sizes at about 20−30 nm, the size of RGO-PEG was about 60−70 nm. Insets are photos of the respective solutions. RGO-PEG and nRGO-PEG showed much enhanced optical absorbance as compared to nGO-PEG. (b) The blood circulation of GO derivatives measured by collecting blood from mice iv injected with 125I labeled nGO-PEG, nRGO-PEG, and RGO-PEG at various time points (n = 3). (c) The biodistribution of GO derivatives in 4T1 tumor-bearing mice 2 days after injection. The radioactivities in tissue and blood samples were determined by a gamma counter. (d) The 4T1 tumor growth curves of mice after various treatments indicated. The laser irradiation was conducted at the power density of 0.15 W/cm2 for 5 min. (e) Survival of tumor-bearing mice after various treatments indicated. Reprinted with permission from ref 169. Copyright 2012 Elsevier.

AuNPs.114 Balb/C mice were intraperitoneally injected with 3, 5, 8, 12, 17, 37, 50, and 100 nm Au NPs at a dose of 8 mg/kg/ week. It was found that the 3, 5, 50, and 100 nm AuNPs did not show harmful effects, while 8−37 nm AuNPs induced fatigue, loss of appetite, change of fur color, and weight loss in mice. Recently, Danio rerio embryos have become a popular model for toxicity experiments. Browning et al. showed that 11 nm AuNPs could be passively transferred by diffusion into the chorionic space of the embryos and would retain their randomwalk motion through chorionic space and into the inner mass of the embryos.115 Bar-Ilan et al. also obtained similar conclusions, based on experiments with 3, 10, 50, and 100 nm Ag and Au nanoparticles.116 Whereas all sizes of Ag caused toxicity in zebrafish embryos, AuNPs appeared to be safe in their experiments. In a short summary, gold nanomaterials with different morphologies have been widely explored as photothermal agents, as illustrated by the many examples discussed above. The absorbance spectra of gold nanostructures could be easily tuned by their sizes, morphologies, as well as aggregation states, providing many opportunities to manipulate their photothermal performances in cancer ablation treatment. On one hand, gold is generally regarded as a rather inert element. On the other

their toxicity, clearly suggesting that it was the coating molecules that resulted in the toxicity of AuNRs. Particle size was another important physical parameter controlling the behaviors of AuNPs in biological systems. Pan et al. examined the size-dependent toxicity of AuNPs in detail by using several kinds of cell lines treated with Au atomic clusters of 0.8, 1.2, 1.4, and 1.8 nm, as well as 15 nm nanoparticles stabilized with triphenylphosphine derivatives.111 According to the MTT assay data, the 1.4 nm Au clusters were the most toxic, while the 15 nm AuNPs were not cytotoxic even at concentrations 100-fold higher than the IC50 of the small clusters. Moreover, Chithrani and co-workers investigated the size-dependent cellular uptake of AuNPs by mammalian cells, and found that 50 nm AuNPs entered cells via receptormedicated endocytosis more efficiently than smaller nanoparticles.112 Regarding in vivo toxicology, Cho et al. studied the in vivo toxicity of 13 nm PEG-coated AuNPs at the doses of 0.17, 0.85, and 4.26 mg/kg in mice.113 After iv injection for 7 days, the nanoparticles were found to be mainly accumulated in the liver and spleen, similar to that of the majority of nanomaterials after systemic administration. Recently, Chen et al. reported a detailed study of the toxicity using various sizes of the 10884


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Figure 18. Multimodal imaging and imaging guided PTT based on PEGylated RGO-iron oxide nanocomposites (RGO-IONP-PEG). (a) A scheme showing the preparation of RGO-IONP-PEG from GO. (b) Cy5 labeled RGO-IONP-PEG could be used as a multifunctional imaging probe for triple modal fluorescence, MR, and photoacoustic imaging. (c) Using RGO-IONP-PEG as a photothermal agent, excellent in vivo tumor ablation efficacy could be achieved. (d) After treatment, MR imaging was employed to monitor the therapeutic responses. Reprinted with permission from ref 177. Copyright 2012 John Wiley & Sons, Inc.

applications of CNTs, including the use of those 1D nanomaterials for photothermal cancer treatment.131−134 Starting from 2005, PTT based on CNTs has been considered as a noninvasive, harmless, and highly efficient therapeutic method using NIR laser irradiation. In 2005, Dai and coworkers developed DNA-coated single-walled carbon nanotubes (SWNTs) for in vitro cancer cell PTT. HeLa cells were incubated with DNA-CNTs and irradiated with 808 nm laser at the power density of 1.4 W/cm2 for 2 min, which induced remarkable cell death.135 By conjugating folate acid (FA) to PEGylated SWNTs, they further demonstrated targeted photothermal destruction of FR positive cancer cells in vitro. Since then, many different groups have studied CNT-based photothermal cancer cell killing, using various targeting peptide or antibody conjugated CNTs as photothermal agents.136−138 The in vivo PTT based on CNTs was first reported by three different groups at almost the same time in 2009. Moon et al. uncovered that PEGylated SWNTs after intratumorally (i.t.) injection into the tumor could offer strong photothermal effect under irradiation by an 808 nm laser.139 It was found that

hand, it is clear that both surface chemistry and sizes of gold nanomaterials would affect their behaviors and toxicology in biological systems. Excitingly, some of those materials, such as AuNSs, have already entered the clinical trial. However, further in-depth investigations may still be necessary to understand the potential neglect effect, if any, of those nonbiodegradable gold nanomaterials to biological systems at different levels. 2.2. Carbon Nanomaterials for Photothermal Therapy

The sp2 carbon nanomaterials mainly including zero-dimensional (0D) fullerenes, 1D carbon nanotubes (CNTs), and 2D graphene have attracted a great deal of attention in various fields including biomedicine. In recent years, fullerenes, carbon nanotubes (CNTs), and graphene have been developed as nanocarries for drug delivery, as well as contrast probes for biomedical imaging.117−130 Because of their strong NIR optical absorbance, CNTs and graphene have also been utilized as photothermal agents for cancer PTT treatment in vitro and in vivo. 2.2.1. Carbon Nanotubes. In the past years, there has been a large amount of papers reporting the biomedical 10885


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Figure 19. Freestanding palladium (Pd) nanosheets for photothermal therapy. (a) A TEM image of Pd nanosheets. Inset: Photograph of an ethanol dispersion of the as-prepared Pt nanosheets in a curvette. (b) A high-resolution TEM (HRTEM) image of a Pt nanosheet flat lying on the TEM grid. (c) Selected area electron diffraction (SAED) pattern of a single Pd nanosheet (shown in the inset). (d) A TEM image of stacked Pt nanosheets perpendicular to the TEM grid. Inset: Thickness distribution of the Pd nanosheets. (e−j) Optical absorption and photothermal properties of Pd nanosheets. (e) Absorption spectra of hexagonal Pt nanosheets with average edge lengths of 21, 27, 41, and 51 nm. (f) Photothermal effect of palladium nanosheets. (g) Viability of liver cells incubated for 48 h with different concentrations of Pt nanosheets. (h) Viability of human hepatoma cells incubated with Pt nanosheets upon irradiation by an 808 nm laser with a power density of 1.4 W cm−2 for various periods. (i and j) Micrographs corresponding to 2 min (i) and 5 min (j) irradiation of cells in (h). Dead cells are stained with trypan blue. Scale bars = 50 μm. Reprinted with permission from ref 6. Copyright 2011 Nature Publishing Group.

accumulation of nanotubes in the mouse skin. The optimized PEGylation that gave SWNTs a blood circulation half-life of ∼12 h was ideal in terms of balancing skin and tumor accumulation of nanotubes (low skin but high tumor uptake). The 4T1 murine breast cancer tumor-bear mice iv treated with SWNTs with the optimized PEGylation showed remarkable tumor ablation efficacy after laser irradiation at the power density of 1 W/cm2 for 5 min (Figure 13b and c). Therefore, surface coating is highly important when SWNTs are used for biomedical applications such as PTT cancer treatment. SWNTs are not only useful as a photothermal agent for in vivo tumor PTT, but also can be used as a photoluminescent agent for in vivo tumor imaging. Dai and co-workers found that PEG-branched polymer and PEGylated phospholipid cofunctionalized SWNTs showed long blood circulation and high tumor uptake upon iv injection. Mice bearing 4T1 murine breast tumors after iv injection with SWNTs at the dose of 3.6 mg/kg were imaged under 808 nm excitation with a low power density at 0.15 W/cm2 during imaging. A lab-built photoluminescence imaging setup was used to collect emitted light within the 1.0−1.4 μm range, which was the NIR-II region as defined by Dai and co-workers. Rather strong NIR-II fluorescence signals were found in the tumors after iv injection of SWNTs, indicating the efficient tumor accumulation of nanotubes. Next, those tumors were irradiated for 5 min at 0.6 W/cm2 with the 808 nm laser, which induced 100% tumor ablation.143 This work demonstrated the use of SWNTs as an imagable photothermal agent for in vivo tumor PTT.

carcinoma KB tumors were completely destroyed after 808 nm laser irradiation at the power density of 76 W/cm3 for 3 min (Figure 12). Besides SWNTs, multiwalled carbon nanotubes (MWNTs) also exhibit strong NIR absorbance. Burke et al. injected MWNTs functionalized with pluoronic F127 (100 μg per mouse) into RENCA tumors, which were then ablated upon 1064 nm laser irradiation (3 W/cm2, 30 s).140 In another paper, Ghosh et al. reported that DNA-encased MWNTs (100 μL, 500 μg/mL) after i.t. injected into PC3 xenograft tumors could also result in complete ablation of tumors after irradiation by the 1064 nm laser at the power density of 2.5 W/cm2 for 70 s.141 Despite the encouraging in vivo PTT therapeutic effects realized in the above three reports, CNTs were directly injected into tumors in those studies. Cancer treatment upon systemic administration (e.g., iv injection) generally would have better clinical relevance. To achieve PTT using systemically injected CNTs, the surface chemistry of nanotubes should be optimized to enable highly efficient tumor targeting. In a study by our group, we synthesized a series of amphiphilic polymers by anchoring polyethylene glycol (PEG) of different lengths at various densities on poly(maleic anhydride-alt-1-octadecene) (C18PMH), obtaining a small library of C18PMH-PEG polymers to modify SWNTs142 (Figure 13a). While SWNTs with insufficient PEG coating would be rapidly cleared out from the circulating blood into reticuloendothelial systems (RES) with little tumor uptake, heavily PEGylated SWNTs showed significantly increased blood circulation half-life and high tumor uptake after iv injection, but could result in substantial 10886


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Figure 20. Hydrophilic flower-like CuS superstructures as an efficient photothermal agent for ablation of cancer cells. (a) Schematic representation of a CuS superstructure serving as laser-cavity mirrors for 980 nm laser and its photothermal conversion. (b) The temperature elevation of aqueous dispersions containing the CuS superstructures or their building blocks. (c) The temperature elevation of the aqueous dispersion of CuS superstructures with different concentration as a function of irradiation time, and water was used as a control. Inset: Plot of temperature change (ΔT) over a period of 5 min versus CuS superstructure concentration. (d) The temperature elevation of the aqueous dispersion of CuS superstructures (0.25 g L−1) coated with the chicken skin as a function of irradiation time of 980 nm laser. The inset shows a photograph of the measuring facility for recording temperature. Reprinted with permission from ref 8. Copyright 2011 John Wiley & Sons, Inc.

As-synthesized SWNTs normally contain a large number of different chiralities, each with varied absorption wavelengths. Therefore, in photothermal treatment when a NIR laser is used, only a small portion of SWNTs that are in resonance with the laser wavelength could be effectively heated. In a recent work by the same group, chirality enriched (6.5)-SWNTs with resonance absorption at 980 nm and emission near ∼1200 nm were separated by the gel filtration method and used for imaging-guided PTT (Figure 14). An extremely low dose of purified SWNTs at 0.16 mg/kg was used to achieve effective in vivo tumor ablation, in marked contrast to the dose needed for unsorted SWNTs (dose = 1.0 mg/kg).144 Remarkably lowering the dose of photothermal agent used in PTT is greatly helpful to reduce the potential toxicity concern of using those lightabsorbing nanomaterials for potential clinical applications. More than 90% of cancer deaths directly or indirectly resulted from the metastatic spread of tumor cells. At the early stage of cancer metastasis, sentinel lymph nodes (SLNs) nearby the primary tumor usually have the highest risk of being invaded by metastasizing cancer cells. In our latest work, we for the first time used PEGylated SWNTs as the theranostic agent for imaging and photothermal ablation of metastatic SLNs in an animal tumor model145 (Figure 15a). By using NIR-II fluorescent imaging, we clearly visualized the translocation of SWNTs from the injected primary tumor to the nearby SLNs (Figure 15b). Importantly, it was found that photothermal ablation of both primary tumors and SLNs could offer remarkably prolonged mouse survival as compared to mice treated by elimination of only their primary tumors (Figure

15c). This work demonstrates that imaging and ablation of SLNs with nanoagents could help to prevent cancer lymphatic metastasis, making photothermal therapy a potentially useful addition to surgery. 2.2.2. Nanographene. Motivated by the successes of using CNTs for biomedical applications, the 2D nanocarbon graphene has also opened many new opportunities in nanobiomedicine due to its unique physical and chemical properties.146−149 Since 2008, a large number of groups have reported graphene and graphene oxide (GO)-based biomedical applications including biosensing,150−152 drug and gene delivery,119,120,153−156 bioimaging,5,157−160 as well as tissue engineering scaffolds.161−163 In recent years, motivated by its high NIR absorbance, GO has also been explored as a new photothermal agent for PTT cancer treatment. In 2010, our group for the first time studied the in vivo behaviors of PEGylated nano-GO (nGO-PEG) with fluorescent labeling (Figure 16). In this work, a NIR fluorescent dye was conjugated to nGO-PEG for in vivo fluorescence imaging, which uncovered high tumor passive uptake of PEGylated nano-GO after iv injection in three different tumor modals. We then used nGO-PEG as a photothermal agent to generate heat with 808 nm laser irradiation to kill tumors, resulting in 100% tumor ablation at the laser power density of 2 W/cm2 with the nanoGO dose of 20 mg/kg.157 This was the first report of using graphene materials for in vivo cancer PTT. Later, several different groups have also studied GO-based PTT in vitro and in vivo.164−166 There was a report suggesting that GO could offer a stronger photothermal effect in comparison with CNTs 10887


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beneficial for the treatment of relatively large tumors without significantly harming nearby normal tissues. To enhance the therapeutic selectivity and realize active tumor targeting, several groups have developed tumor-targeting GO nanosheets for PTT. Dai’s group used noncovalently PEGylated nano-RGO attached with a targeting peptide ArgGly-Asp(RGD) for selective photothermal killing of U87MG cancer cells in vitro.168 In another study, Akhavan et al. also showed that an ultralow concentration (1 μg/mL) of PEGylated GO nanoribbons functionalized by RGD peptide could be used for in vitro targeted PTT.166 Recently, the same group developed an efficient in vivo photothermal agent using RGD-functionalized RGO nanomeshes in a mouse model.170 By using TiO2 nanoparticles, rGO were transformed into GO nanomeshes through photocatalytic degradation. GO nanomeshes functionalized by PEG, RGD, and Cy7 then were utilized for in vivo tumor targeting and fluorescence imaging of U87 tumors in mice. The rGO nanomeshes-PEG solution exhibited ∼4.2- and 22.4-fold higher NIR absorption at 808 nm than rGO-PEG and GO with sizes of ∼60 nm and ∼2 μm, respectively. The excellent NIR absorbance and tumor targeting of rGO nanomeshes resulted in ultraefficient PTT. 2.2.3. Carbon-Based Composite Nanostructures. To offer carbon nanomaterials additional properties and functions, various inorganic nanoparticles have been grown on the surface of nanocarbons, yielding carbon-based nanocomposites for different biomedical applications. In 2009, Kim et al. reported that Au nanoparticles could be grown on the surface of CNTs to yield Au coated CNTs (AuCNTs),171 which could not only be used as photoacoustic contrast agents for in vivo imaging, but were also useful for potential individual cancer cell killing due to the photothermal effect. In our recent work, a layer of AuNPs was in situ grown on the surface of DNA coated SWNTs, yielding SWNT-Au nanocomposite, which was then coated with folic acid (FA) modified PEG.172 The obtained SWNT-Au-FA nanocomposite could then serve as a strong surface-enhanced Raman scattering (SERS) imaging probe to detect FR positive cells. The dramatically enhanced NIR absorbance of SWNT-Au also allowed us to use them for targeted photothermal ablation of cancer cells with high FR expression. Similar to studies with CNTs, a number of inorganic nanoparticles were also coupled with nanographene to endow the obtained nanocomposites more enriched functionalities. Recently, in two separated studies, fluorescent Au nanoclusters and quantum dots were conjugated to nanographene for drug delivery, fluorescent bioimaging, and photothermal therapy.173,174 Chen and co-workers reported a novel QD-tagged RGO nanocomposite combining the capability of bioimaging with PTT.174 Interestingly, as the QD-RGO absorbed NIR irradiation to cause cell killing and PTT, the generated heat from the QD-RGO simultaneously caused a temperature increase and a marked decrease in the QD brightness, offering a method for in situ heat/temperature sensing and a real-time indictor of the PTT progress. Superparamagnetic iron oxide nanoparticles as a contrast agent of MR imaging could also be grown on the surface of GO to form magnetic GO-based nanocomposite, in which GO was usually partially reduced into RGO. Using their strong superparamagnetic properties, the obtained RGO-IONP after PEGylation could be used for magnetically targeted drug delivery, MR imaging, and PTT cancer treatment.175−178 In one of our reports, an amphiphilic C18PMH-PEG polymer was

Figure 21. Fe3O4@Cu2−xS core−shell nanostructures for dual-modal imaging and photothermal therapy. (a) Experimental design for the synthesis of Fe3O4@Cu2−xS core−shell nanostructures. (b) Photograph of the tumor-bearing mouse (tumor was marked by a dashed circle). (c) An IR thermal image of the tumor-bearing mouse treated with the Fe3O4@Cu2−xS nanoparticles after a 980 nm laser irradiation for 2 min. The irradiated area was marked by a dashed circle. (d) The temperature profiles in regions 11 and 12 marked in (c) as a function of the irradiation time. (e and f) The representative HE images of ex vivo tumor sections injected with water only (e) and an aqueous dispersion of polymer-modified Fe3O4@Cu2−xS nanoparticles (Cu content 50 ppm) (f), after photothermal ablation. Reprinted with permission from ref 202. Copyright 2013 American Chemical Society.

at the same concentration, although their results may need further explanation.167 To improve the GO-based PTT, GO could be chemically reduced into reduced graphene oxide (RGO), which showed much higher NIR absorbance as compared to GO.168,169 In a work by Dai and co-workers, a new type of ultrasmall RGO with high NIR absorbance was functionalized with PEG and used for in vitro photothermal ablation of cancer cells.168 In a later work by our group, we systematically compared the in vivo behaviors of various GO derivatives with different surface coatings and sizes using a radiolabeling method (Figure 17). We found that ultrasmall nano-RGO with noncovalent PEG coating showed relatively low RES accumulation and high tumor uptake. With 6-fold enhanced NIR absorbance and 8fold increased tumor uptake as compared to nGO-PEG, our newly developed nRGO-PEG was then used as a new photothermal agent for in vivo cancer treatment. It was uncovered that 4T1 breast cancer tumors grown on Balb/c mice after iv injection with nRGO-PEG were completely ablated after the 808 nm laser irradiation at an ultralow power density of 0.15 W/cm2 for 5 min.169 The laser power density we used (0.15W/cm2) in this work is the lowest so far in literature for in vivo PTT cancer treatment, and could be 10888


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Figure 22. CuTe nanostructures for SERS used as SERS probes and photothermal agents in vitro. TEM images of different CuTe nanostructures: (a) nanocubes, (b) nanoplates, and (c) nanorods. (d) UV−vis−NIR spectra of different CuTe nanostructures. (e) A scheme showing the use of CuTe nanocubes as a SERS probe and a photothermal agent. Reprinted with permission from ref 205. Copyright 2013 American Chemical Society.

measurement, as well as in vivo MR imaging to determine the post-therapeutic response (Figure 18c and d). In our latest work, a layer of gold was further grown on the surface of RGOIONP, yielding RGO-IONP-Au nanocomposite with strong superparamagnetism and effective X-ray absorbance, which were useful for in vivo MR and X-ray dual-modal imaging, respectively. Moreover, because of the remarkably increased NIR absorbance offered by the Au layer, GO-IONP-Au could be used as an enhanced photothermal agent for in vitro and in vivo cancer ablation.179 Therefore, graphene with the 2D structure and large surface area offers plenty of room to engineer a variety of multifunctional nanocomposites, promising for cancer theranostic applications.

introduced to functionalize RGO-IONP nanocomposite to render it great stability in physiological environments (Figure 18a). Utilizing the high NIR absorbance, strong superparamagnetic property, as well as an extra fluorescent label, RGO-IONP-PEG could be used as a multifunctional nanoprobe for in vivo multimodal PA, MR, and fluorescence imaging, respectively, all of which revealed high uptake of RGO-IONPPEG in 4T1 tumors after i.v. injection (Figure 18b). We then carried out an in vivo PTT experiment. Mice bearing 4T1 tumors were iv injected with RGO-IONP-PEG at the dose of 20 mg/kg and irradiated with 808 nm laser at the power density of 0.5 W/cm2 for 5 min. Highly efficient tumor ablation efficacy was achieved, as evidenced by both caliper-based tumor size 10889


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Like CNTs, GO without surface coating after intravenous injection would mainly accumulate in the lung and induce obvious pulmonary toxicity.190−192 However, appropriate surface functionalization would significantly decrease the pulmonary toxicity induced by GO. In a recent work, Multu and co-workers193 found that while as-made GO without surface coating resulted in severe and persistent lung injury, pluronic functionalized GO with excellent dispersity exhibited remarkably decreased lung toxicity without inducing obvious inflammation after inhalation, similar to their experimental results related to CNTs.134 In our group, we have also systematically studied the in vivo behaviors and toxicity of PEGylated GO and its derivatives via different administration routes including oral feeding, intraperitoneal (i.p.) injection, and iv injection. Radiolabeling was used to study the in vivo behaviors of PEGylated GO and its derivatives. 125I-labeled nGO-PEG via iv injection mainly accumulated in the RES organs including liver and spleen.194 More importantly, we found that nGO-PEG via iv injection could be gradually excreted from the mouse body via urine and feces, and did not obviously affect liver and kidney functions within 3 months at a high dose (20 mg/kg). No appreciable damage or inflammation was observed in examined major organs and tissues. Moreover, our group has also systematically studied the in vivo behaviors and long-term toxicity of GO and PEGylated GO derivatives after oral and i.p. administration.195 It was shown that GO and PEGylated GO derivatives after oral administration could not be absorbed by organs and were rapidly excreted. In contrast, PEGylated GO derivatives, but not uncoated GO, could be engulfed by phyagocytes in the RES system after i.p. administration by a size and surface modification related manner. No significant toxicity was noticed in our systematic serum biochemistry assay, complete blood panel test, and histological analysis. Therefore, developing suitable surface coatings and controlling sizes are important to the development of nanocarbon agents with low toxicity for PTT applications. Different from gold nanostructures, which usually exhibit well-defined absorbance peak or band, carbon nanotubes (except chirality enriched SWNTs) and nanographene would show rather broad absorbance spectra all of the way from UV to NIR. Regarding their mass extinction coefficient at the NIR wavelength, chirality enriched SWNTs is the highest, followed by noncovalently functionalized SWNTs without chirality separation, RGO, and then GO. Those carbon nanomaterials show rather high photothermal stability, better than typical gold nanostructures (e.g., AuNRs, AuNCs), which could be “melted” under high-power photothermal heating and lose their NIR absorbance. The potential long-term toxicity of carbon nanomaterials, which again is closely associated with their surface chemistry and sizes, has been under certain debate and may be the main concern hampering their future clinical use.

Figure 23. PEGylated WS2 nanosheets as a multifunctional theranostic agent for in vivo dual-modal CT/photoacoustic imaging guided photothermal therapy. Reprinted with permission from ref 211. Copyright 2014 John Wiley & Sons, Inc.

2.2.4. Toxicology Studies of Carbon Nanomaterials. Although carbon nanomaterials including CNTs and GO have received considerable attention in biomedical applications, the safety of carbon nanomaterials in biological systems should be carefully examined. Numerous groups have deliberatively explored the toxicology of carbon nanomaterials, but conclusions seem to be somewhat controversial.180−185 In recent years, it has been widely acknowledged that the toxicity of carbon nanomaterials to cells and animals could be closely dependent on their surface chemistry, sizes, doses, and administration routes.186 According to the literature, pristine CNTs without appropriate surface functionalization have been shown to induce toxicity in various manners. However, when CNT are properly functionalized (e.g., with biocompatible polymers such as PEG), their toxicity could be dramatically reduced, to be even not appreciable. In several early reports, pristine CNTs without any surface coating after intratracheal instillation into mice or rats187−189 would induce severe pulmonary toxicity and inflammation. On the other hand, in a recent work, Mutlu et al. found that nanoscale dispersed SWNTs coated by Pluronic F 108NF after intratracheal instillation would be engulfed by macrophages and gradually cleared over time, without showing obvious pulmonary toxicity.134 Thus, the pulmonary toxicity induced by CNTs is heavily dependent on the surface coating of CNTs. Moreover, the in vivo toxicity of CNTs after iv injection has also been reported by many groups. They found that well-functionalized nanotubes (e.g., PEG functionalization) after iv injection into mice mainly accumulated in liver and spleen, and would be gradually excreted via the biliary and renal pathways, without inducing obvious toxicity.131,135 In addition to their surface coating, the length of CNTs also plays an important role regarding the in vivo toxicity of nanotubes. Short CNTs may be easily enveloped by macrophages, while long nanotubes may induce severe inflammation and DNA damage. In a work by Poland et al., it was found that long MWNTs (length 10−50 μm) without surface coating intraperitoneally injected into the abdominal cavity of mice could induce inflammation and the formation of lesions known as granulomas. However, shorter MWNTs (length 1−20 μm) did not induce an obvious toxic effect.133 Therefore, the toxicology of CNTs is obviously determined by the surface chemistry and sizes of nanotubes.

2.3. Other Inorganic Nanomaterials for Photothermal Therapy

2.3.1. Pd Nanosheets. Besides Au and carbon nanomaterials, which have been extensively explored in photothermal cancer treatment, a number of other inorganic nanomaterials with strong NIR absorbance have also shown promises as effective photothermal agents. Palladium (Pd) nanosheets represent another class of noble-metal nanostructures with tunable LSPR peaks in the NIR region. In 2009, Zheng and coworkers reported the synthesis of freestanding hexagonal Pd 10890


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Figure 24. PEGylated WO3−x nanowires as a new NIR photothermal agent for efficient ablation of cancer cells in vivo. (a and b) TEM (a) and HRTEM (b) images of W18O49 nanowires. (c) UV−vis−NIR absorption spectrum of an aqueous dispersion containing 2 g/L W18O19 nanowires. Inset: Photo of a aqueous dispersion. (d) Plots of the temperature within the irradiated tumor areas in two mice injected, respectively, with saline solution and W18O19 nanowires solution (2 g/L), as a function of irradiation time. The inset is the corresponding full-body IR thermal image of these two mice at 180 s. (e and f) H&E-stained histological images of the corresponding ex vivo tumor sections after laser irradiation for 10 min. Reprinted with permission from ref 214. Copyright 2013 John Wiley & Sons, Inc.

positive charges on the sheet surface. As the result of the enhanced cellular uptake, those silica-coated Pd nanosheets offered markedly enhanced photothermal cancer cell killing efficacy in vitro. The same group also fabricated silver-coated Pd (Ag@Pd) core−shell nanoplates using uniform Pd nanosheets as the seeds.198 The bimetallic nanoplates exhibited tunable SPR properties over a wide spectral range and outstanding photothermal stability. After being incubated with silica-coated Pd@Ag nanoplates, ∼100% of the liver cancer cells were killed after 5 min irradiation with an 808 nm laser at a power density of 1.4 W/cm2. 2.3.2. CuS Nanostructures. Copper sulfide (CuS) nanocrystals as a kind of copper chalcogenide-based nanomaterials have been demonstrated to be a new type of photothermal therapeutic agent. Usually, CuS nanoparticles were synthesized

nanosheets, which showed blue color and exhibited a welldefined and tunable surface plasmon resonance peak in the NIR region (Figure 19).6,196 Under the NIR laser (808 nm, 1 W) irradiation, the temperature of the solution containing 27 ppm Pd nanosheet rose from 28.0 to 48.7 °C. In comparison, the temperature of the solution in the absence of Pd nanosheets increased by only 0.5 °C. As compared to Ag and Au nanostructures, their Pd nanosheets exhibited much improved photothermal stability, and could be used to induce a strong photothermal effect to destruct cancer cells. The 2D ultrathin nature of the Pd nanosheets prevented them from effective cell entry to certain extent. To promote cellular uptake of those nanosheets, Zheng and co-workers altered the ultrathin feature of the Pd nanosheets by coating with silica197 to enlarge the sheet thickness and introduce 10891


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Figure 25. Indocyanine green (ICG) as near-infrared dual-functional targeting probes for optical imaging and photothermal therapy. (a) Selfassembly process of ICG-PL-PEG probe and the subsequent antibody (mAb) conjugation. (b) Photograph of a mouse bearing U87-MG tumor. (c) IR thermal images of mice bearing U87-MG tumors under different treatments. (d) Histological staining of the excised tumors 12 h after different treatments indicated. Targeted photothermal therapy enabled by antibody conjugated ICG-PL-PEG probe resulted in significant tumor cell damage after laser ablation. Reprinted with permission from refs 216 and 225. Copyright 2011 and 2012 American Chemical Society.

However, one of the limitations of CuS nanoparticles as a photothermal agent was their relatively low photothermal conversion efficiency. Hu and co-workers reported hydrophilic flower-like CuS superstructures as an efficient 980 nm laserdriven photothermal agent for ablation of cancer cells8 (Figure 20). The as-synthesized CuS superstructures exhibited a high NIR photothermal conversion efficiency that was improved by approximate 50% from that of their corresponding CuS nanoparticle building blocks. Under 980 nm illumination, the CuS nanoflowers showed almost complete cell killing at a low power density (0.5 W/cm2) when incubated with HeLa cells. Importantly, cancer cells in vivo can be efficiently killed by the photothermal effect of CuS superstructures under the irradiation of 980 nm laser using a conservative and safe power density at 0.51 W/cm2 over a short period time (5−10 min). However, it should be noted that the size of those CuS superstructures at ∼1 μm may be too large for in vivo use.

by wet chemistry methods and had an optical absorption band in the NIR range with a maximum absorbance at 900−1000 nm. Li and co-workers found that the aqueous solution of CuS nanoparticles under irradiation by a NIR laser beam at 808 nm would show a rapid temperature increase.199 As the result, the CuS nanoparticle-induced photothermal destruction of HeLa cells occurred in a laser dose- and nanoparticle concentrationdependent manner, and displayed minimal dark cytotoxicity effect. The same group also synthesized and evaluated a novel chelator-free64Cu labeling method to radiolabel CuS nanoparticles, obtaining64(Cu)CuS nanoparticles suitable for both positron emission tomography (PET) imaging and photothermal cancer treatment.7 Recently, they further demonstrated that CuS nanoparticles could be used as a new class of photoacoustic imaging contrast agent for deep tissue imaging under 1064 nm excitation,200 suggesting the great potential of using CuS nanoparticles for imaging guided PTT. 10892


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Figure 26. PEGylated nanoparticles encapsulating a nonfluorescent NIR organic dye as a highly effective photothermal agent for in vivo cancer therapy. (a) A scheme showing the structure of PEGylated nanomicelles containing IR825 dye molecules. (b) The blood circulation curves of IR825PEG and IR825-PEG-Cy5.5 after iv injection as determined by measuring either IR825 absorbance or Cy5.5 fluorescence, respectively. (c) In vivo fluorescence images of a 4T1 tumor bearing Balb/c mouse taken at different time points post injection of IR825-PEG-Cy5.5. (d) IR thermal images of 4T1 tumor-bear mice without (upper row) or with (lower row) iv injection IR825-PEG (10 mg/kg, 24 h p.i.) under the 808 nm laser irradiation taken at different time intervals. (e) The growth of 4T1 tumors in different groups of mice after various treatments indicated. (f) Survival curves of mice after various treatments as indicated in (e). Reprinted with permission from ref 14. Copyright 2013 John Wiley & Sons, Inc.

et al. presented the integration of iron oxide nanoparticles with a CuS shell for the preparation of multifunctional Fe3O4@ Cu2−xS core−shell nanoparticles202(Figure 21). This new class of nanoparticles featured ultrasmall particle size, superparamagnetic property, low toxicity, and a highly efficient photothermal effect. The tumors treated with the Fe3O4@ Cu2−xS nanoparticles could be visualized by T2-weighted MR imaging, and showed typical signs of cell damage under a lowpower density laser irradiation (0.6 W/cm2), such as cell shrinkage, loss of contact, and nuclear damage. Those results

Therefore, the same group in a later work reported the development of hydrophilic Cu9S5 plate-like nanocrystals with a mean size of ∼70 nm × 13 nm as a novel photothermal agent.201 The aqueous dispersion of these Cu9S5 nanoplates exhibited an intense absorbance in the NIR, and its temperature could be increased by 15.1 °C within 7 min under the irradiation of 980 nm laser with a power density of 0.51 W/cm2 due to the effective photothermal conversion. Nanoparticles with combined optical and magnetic functionalities are important for biomedical applications. Recently, Tian 10893


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metal dichalcogenides (TMDCs), such as MoS2, MoSe2, WS2, and WSe2, all consist of a hexagonal layer of metal atoms (M) sandwiched between two layers of chalcogen atoms (X) within stoichiometry MX2. The common feature of these materials is the layered structure with strong covalent bonding within each layer and weak van der Waals forces between different MX2 layers. For their special characteristics, TMDCs have become the rising star in recent years, offering great opportunities in physics, chemistry, and materials science.206−210 Chou et al. for the first time uncovered that MoS2 nanosheets could serve as a new NIR photothermal agent, with approximately 7.8 times greater NIR absorbance relative to GO on a per mass basis.10 The extinction coefficient of MoS2 nanosheets at 800 nm was 29.2 L/g·cm, which was higher than that of AuNRs (13.9 L/g· cm) and comparable to that of RGO (24.6 L/g·cm). In another work, bismuth selenide (Bi2Se3) nanoplates were used as a theranostic platform for simultaneous cancer imaging and therapy upon local administration into tumors.9 Recently, our group developed a novel PTT agent based on WS2 nanosheets for multimodal imaging and in vivo photothermal ablation of tumors in a mouse model211 (Figure 23). Using the thiol chemistry method, the surface of WS2 nanosheets was coated with PEG to acquire improved physiological stability and biocompatibility. Utilizing the strong X-ray attenuation ability and high NIR optical absorbance of WS2, we were able to image tumors by X-ray computed tomography (CT) and photoacoustic tomography, respectively. Highly effective in vivo photothermal ablation of tumors under NIR laser was then realized, after either intratumoral injection with a low dose of WS2-PEG or intravenous injection with a moderate dose of this nanoagent into 4T1 tumor-bearing mice. In another latest report by our group, we found that twodimensional MoS2-PEG nanosheets could not only be utilized as a photothermal agent, but also act as a drug delivery carrier to load various types of aromatic drug molecules with high loading capacities, enabling combined photothermal + chemotherapy both in vitro and in vivo.212 Besides transition metal sulfides, transition metal oxides are also interesting candidates with LSPR properties. Among them, tungsten oxide (WO3−x) nanocrystals are of great interest because of their strong NIR absorbance.213 In a recent work,

Figure 27. A schematic illustration to show the formation of HSAIR825 complex, as well as its unique optical behavior. HSA-IR825, which is prepared by simply mixing HSA and IR825, shows a high QY under 600 nm excitation useful for fluorescence imaging, together with a low QY under 808 nm excitation ideal for photothermal therapy. Reprinted with permission from ref 232. Copyright 2014 Elsevier.

suggest the promise of developing a copper chalcogenide nanoplatform for cancer theranostic applications. There have been several other types of copper-containing NIR-absorbing nanomaterials developed for PTT cancer treatment. Copper selenide nanocrystals (CuSe), similar to CuS nanoparticles, have also been explored for cancer imaging and PTT.199,203 Hessel et al. synthesized Cu2−xSe nanocrystals with an average diameter of ∼16 nm and an intense NIR absorbance peak, which enabled significant photothermal heating to kill cancer cells in vitro under laser irradiation.204 Recently, Li et al. reported a procedure to prepare highly monodispersed CuTe nanocubes, nanoplates, and nanorods based on the reaction of a copper salt with trioctylphosphine telluride in the presence of lithium bis(trimethylsilyl) amide and oleylamine205 (Figure 22). It was found that CuTe nanocubes, in particular, displayed a strong NIR optical absorption associated with localized surface plasmon resonance. The preliminary results showed that those CuTe nanocubes could be used as SERS probes as well as photothermal agents. 2.3.3. Other Inorganic Photothermal Nanoagents. There have been other types of inorganic nanomaterials also showing great potential as photothermal agents. Transition-

Figure 28. Convertible organic nanoparticles for NIR photothermal ablation of cancer cells. Polyaniline nanoparticles with visible absorbance at their native EB state would be converted into the ES state with NIR absorbance in the presence of intracellular acidic or oxidative conditions, useful for photothermal ablation of cancer cells. Reprinted with permission from ref 236. Copyright 2011 John Wiley & Sons, Inc. 10894


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Figure 29. Polypyrrole (PPy) organic nanoparticles for in vitro photothermal therapy. (a) Schematic to illustrate the synthesis of PVA-coated PPy nanoparticles. (b) IR thermal images of 4T1 tumor-bearing mice i.t. injected with PPy nanoparticles exposed to the 808 nm laser at different power densities. (c) Change of tumor temperatures on mice i.t. injected with PPy nanoparticles under the 808 nm laser irradiation at different power densities. (d) Tumor growth in different groups of mice after various treatments indicated. A low laser power density at 0.25 W/cm2 was sufficient to induce complete tumor ablation. Reprinted with permission from ref 11. Copyright 2012 John Wiley & Sons, Inc.

photothermal conversion efficiency in the NIR region, those PB nanoparticles could rapidly and efficiently convert the 808 nm laser energy into thermal energy, and the photothermal stability of PB nanoparticles was much higher as compared to other photothermal agents. All of those results demonstrated that PB nanoparticles could act as a promising photothermal agent for PTT treatment of cancers. In a short summary, a wide range of inorganic nanomaterials with high absorbance in the NIR have been extensively used in PTT, showing encouraging therapeutic results both in vitro and in vivo. However, most of these inorganic PTT agents are nonbiodegradable and usually would retain in the body for long periods, raising concerns regarding their potential long-term toxicity. Before these therapeutic strategies are tested in cancer patients, much more effort should be focused on the in vivo behaviors of those inorganic nanomaterials, including their pharmacodynamics, pharmacokinetics, and potential long-term toxicity. Moreover, it would be interesting and important to compare the above-mentioned various different PTT agents

Chen et al. reported the preparation of ultrathin PEGylated W18O19 nanowires by a simple solvothermal route214(Figure 24). The nanowires exhibited strong NIR absorption and could be used as a 980 nm laser-driven photothermal agent for the efficient photothermal ablation of cancer. However, whether and how those metal sulfides or metal oxides containing heavy elements (e.g., W, Mo, Bi) would be degraded, excreted, and do any long-term harmful effects require further systematic investigations. Another inorganic PTT agent was Prussian blue (PB) nanoparticles.215 Prussian blue, as an ancient dye, has been approved by the US FDA for the treatment of radioactive exposure and demonstrated good biosafety in the human body based on sufficient clinical trials. The PB nanoparticles were simply synthesized by mixing aqueous solutions of FeCl3 and K4(Fe(CN)6) in the presence of citric acid, which acted as the surface capping agent to prevent PB nanoparticles from aggregation and mediate the size of PB nanoparticles.215 Because of the high molar extinction coefficient and good 10895


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Figure 30. PEDOT:PSS organic stealth nanoparticles for in vivo photothermal therapy of cancer. (a) A scheme showing the fabrication process of PEGylated PEDOT:PSS nanoparticles (PEDOT:PSS-PEG). (b) UV−vis−NIR spectra of PEDOT:PSS and PEDOT:PSS-PEG solutions at the concentration of 0.02 mg/mL. Inset: A photo of PEDOT:PSS (left) and PEDOT:PSS-PEG (right) solutions at the concentration of 0.1 mg/mL in water. (c) The heating curves of pure water and PEDOT:PSS-PEG (0.1 mg/mL) under 808 nm laser irradiation at a power density of 1 W/cm2. (d) The growth of 4T1 tumors in different groups of mice after treatment. (e) Survival curves of mice after various treatments as indicated in (d). (f) Representative photos of a PEDOT:PSS-PEG injected mouse at day 0 before PTT treatment and at day 10 after treatment. In the in vivo treatment study, PEDOT:PSS-PEG at a dose of 10 mg/kg was iv injected into mice. Reprinted with permission from ref 12. Copyright 2012 American Chemical Society.

cancer treatment due to the potential long-term toxicity concern. Recently, significant attention has been paid to the development of NIR-absorbing organic materials as photothermal agents in PTT cancer treatment. 2.4.1. NIR-Absorbing Dye Containing Nanocomplexes. Organic dyes with high quantum yields (QY) are generally preferred in fluorescent optical imaging. However, their photothermal efficiency could be low because a part or even a majority of the absorbed optical energy is emitted from those dye molecules as fluorescence instead of heat. Organic dyes with high NIR absorption coefficients but low QYs, on the other hand, may offer the best photothermal efficiency because the thermal effect would prevail in the energy dissipation process of those molecules after light excitation.

side-by-side, to tell the advantages and limitations of each agent, as well as identify the most promising ones with high photothermal conversion efficiency, optimized in vivo behaviors, and minimal long-term toxicity. 2.4. Organic Nanoparticles for Photothermal Therapy

As discussed in the above section, a variety of NIR-absorbing inorganic nanomaterials have been widely explored by many research groups as photothermal agents, showing high efficacies for PTT treatment of cancers in many preclinical animal experiments. However, most of these currently used inorganic photothermal agents, some of which even contain heavy metal elements, are nonbiodegradable and would retain in the body for long periods, hampering their further applications in clinical 10896


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Figure 31. Porphysome nanovesicles generated by bilayers of porphyrin-conjugated phospholipids as a multimodal biophotonic theranostic agent. (a) Schematic representation of a pyropheophorbide-lipid porphysome. (b) TEM images of negatively stained porphysomes containing 5% PEGlipid and 95% pyropheophorbide-lipid. Reprinted with permission from ref 13. Copyright 2011 Nature Publishing Group.

thermal ablation of U87MG tumors after treatment with the 808 nm NIR light (2 W/cm2, 10 min)225(Figure 25b−d), in comparison to free ICG at the same dose. With a similar structure of ICG, heptamenthine near-infrared dye has also been used as an NIR imaging probe.226−228 Luo et al. recently reported the chemical synthesis and biological characterization of a new heptamethine dye (IR808 DB),229 natively with multifunctional characteristics of cancer targeting, near-infrared fluorescence imaging, and efficient photothermal anticancer activity. Peng et al. synthesized a multifunctional micelle containing an 188Re-labeled radionucleotide for singlephoton emission computed tomography (SPECT) imaging and a IR-780 iodide NIR dye for fluorescent imaging and PTT.230 Their results showed that 188Re-labeled IR-780 injected into HCT-116 tumors and treated with NIR light resulted in 82.6% of tumor growth inhibition 27 days after treatment. In our recent work, we synthesized a NIR-absorbing heptamethine indocyanine dye, IR825, which showed a super high NIR absorption peak at ∼825 nm and a rather low QY (75%). Despite the disadvantage of low efficiency in using QDs for PDT as compared to conventional PS molecules, QDs show exceptional photostability, which offers cumulative effects in PDT. For example, Anas et al. found that prolonged photoactivation of a QD-plasmid DNA conjugate at 512 nm resulted in the breakage and damage of DNA393 due to the photosensitized production of ROS. Their results suggest that QDs are promising PS drugs for nucleus targeted PDT if combined with intranuclear delivery of QDs in cancer cells. In another work, Chen et al. reported that CdSe QDs could effectively eliminate nasopharyngeal carcinoma cells under light exposure.394 They demonstrated that TGA-coated QDs, when partially oxidized, functioned like PS agents to perform PDT in tumor cells via the so-called Type I photoreaction mechanism, in which electrons were trapped at the QD surface and the dwell time was long enough to promote electron transfer to nearby oxygen molecules. Another study reported by Juzenas et al. found that NIR photoactivation of QDs in cancer cells results in the production of ROS and reactive nitrogen species (RNS) such as superoxide and peroxynitrite, respectively.395 They employed dihydrorhodamine 123 as a sensor for the PDT process, and found that ROS and RNS generated by QDs resulted in the breakage of lysosomes. To utilize the photostability of QDs and improve the production of 1O2, several QD−PS hybrids have been developed as a new generation of PS agents for PDT. In such hybrid QD−PS systems, the excited singlet (1PS*) and triplet (3PS*) states of PS drugs are indirectly generated by nonradioactive energy transfer, also known as fluorescence resonance energy transfer (FRET). Because of the indirect photoactivation, photobleaching of PS drugs could be minimized. The concept of FRET-based production of 1O2 by QD−PS hybrid systems was also first demonstrated by Samia et al.21 In their study, CdSe QDs with an average diameter of 5 nm were linked to a silicon Pc photosensitizer (Pc4). In this system, the QD acted as the primary energy donor if light with the wavelength between 400 and 500 nm was used for excitation. Their results demonstrated that CdSe QDs could be used to sensitize either a PDT agent via the FRET mechanism or molecular oxygen through a triplet energy transfer (TET) mechanism. Since then, many researchers have explored a variety of covalent and noncovalent QD−PS systems composed of CdSe, CdSe/CdS/ZnS, CdSe/ZnS, and CdTe

Figure 52. Vascular targeted nanoparticles for imaging and photodynamic therapy treatment of brain tumors. (a) Schematic representation and characterization of a multifunctional nanoparticles. (b) SEM images of those nanoparticles. (c) Monitoring of therapeutic efficacy using multifunctional nanoparticles in 9L brain tumors by MR imaging. (C1) A representative control of a mouse bearing a 9L tumor; (C2) a tumor-bearing mice exposed to light only; (C3) iv administration of Photofrin plus laser light; (C4) nontargeted nanoparticles containing Photofrin plus laser light; (C5) targeted nanoparticles containing Photofrin plus laser light. The image shown in (C6) was from the same tumor shown in (C5), which was treated with the F3-targeted nanoparticle but at day 40 after treatment. (d) Kaplan−Meier survival plot for the tumor-bearing mice after various treatments indicated. Reprinted with permission from ref 383. Copyright 2006 American Association for Cancer Research.

carriers.386 In our latest work, PEGylated iron oxide nano clusters (IONCs) were loaded with Ce6, obtaining IONCPEG-Ce6 as a theranostic agent for dual-mode imaging guided and magnetic-targeting enhanced in vivo PDT387(Figure 53). Interestingly, Ce6 after being loaded on IONC-PEG exhibited a red-shifted absorbance/excitation peak from ∼650 to ∼700 nm, the latter of which located in the NIR region with improved tissue penetration. With strong magnetism of and long bloodcirculation time, IONC-PEG-Ce6 showed strong magnetic field (MF)-induced tumor homing ability, as evidenced by in vivo dual modal fluorescence and MR imaging. In vivo PDT experiment using IONC-PEG-Ce6 under magnetic tumor targeting further demonstrated great therapeutic efficacy, achieving remarkably delayed tumor growth after just a single 10919


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Figure 53. Magnetic targeting enhanced and NIR-induced in vivo PDT based on PEGylated iron oxide nanoclusters (IONC-PEG). (a) Schematic illustration for the synthesis and structure of IONC-PEG-Ce6. (b) A schematic drawing to illustrate in vivo magnetic tumor targeting. (c) In vivo fluorescence image of a mouse bearing two 4T1 tumors after iv injection with IONC-PEG-Ce6. (d) In vivo T2-weighted MR images of a mouse taken before injection (upper) and 24 h post injection (bottom) of IONC-PEG-Ce6. (e) Tumor growth in different groups after various treatments indicated. (f) Representative photos of mice after various treatments. Reprinted with permission from ref 387. Copyright 2013 Elsevier.

QDs as energy donors, and various chromophores such as porphyrins, phthalocyanines, inorganic complexes, and other organic dyes as energy acceptors.389 As a typical example, Tsay et al. covalently conjugated Rose Bengal and Ce6 onto the surface of green- and red-emitting CdSe/CdS/ZnS QDs through a lysine-terminated peptide linker396(Figure 54). By using two color excitations, the conjugate could be simultaneously used for fluorescence imaging and singlet oxygen generation. The intrinsic ROS production ability and excellent photostability of QDs promise their use in PDT. Careful design of QD or QD−PS conjugates to enable effective delivery of QDs and QD−PS complexes into tumors, efficient generation of ROS, and image-guided PDT would be essential if QDs are employed in photodynamic cancer treatment. However, the potential cytotoxicity of QDs containing heavy metal elements could be a majority obstacle toward the real clinical use of those nanoparticles in patients. 3.2.5. Fullerenes and Their Derivatives. Fullerene, discovered in 1985, is typically composed of 60 carbon atoms arranged in a soccer-ball structure. Fullerenes with 70, 72, 76, 82, 84, and even up to 100 carbon atoms are also commonly obtained. The condensed aromatic rings present in fullerenes lead to an extended π-conjugated system of molecular orbitals and therefore to significant absorption of visible light.

Fullerenes are found to be able to generate ROS upon illumination, suggesting a possible role of them in PDT.397−399 As pristine fullerenes are highly hydrophobic, surfaces functionalized with some functional groups attached to fullerenes are thus needed to make them more soluble in water and biological solutions. Phototoxicity of fullerenes has been demonstrated in many studies. As early as in 1993, Tokuyama et al. used carboxylic acid-functionalized fullerenes in HeLa cells and demonstrated the phototoxic effect of fullerenes.400 Burlaka et al. used pristine C60 aggregates with sizes of ∼10 μm to induce phototoxicity in Ehrlich carcinoma cells or rat thymocytes under irradiation by a mercury lamp.401 In another work, Yang et al. reported three C60 derivatives attached with two to four malonic acid groups (DMAC60, TMAC60, and QMAC60) as photodynamic agents to kill HeLa cells.402 In vivo PDT for tumor treatment has also been demonstrated using fullerenes as the photodynamic agent. Tabata et al. for the first time demonstrated fullerene-based PDT of tumors in animal experiments.403 In this work, fullerene was functionalized with PEG, only not to acquire water solubility, but also to enable preferential accumulation and prolonged retention of fullerene in the tumor tissue. As compared to the commercial agent Photofrin, C60-PEG conjugate following intravenous injection offered a stronger tumor suppressive effect under exposure to the visible light. In a 10920


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Figure 54. Singlet oxygen production by peptide-coated QD-photosensitizer conjugates for photodynamic therapy. (a) Scheme showing the conjugation of Rose Bengal (RB) to peptide-coated QDs (pcQD) and the proposed mechanism for singlet oxygen generation via FRET. (b) UV−vis absorption spectra of 545 nm emitting pcQDs conjugated with RB at ratios of 1:1, 1:2, and 1:5. (c) Scheme showing the conjugation of Ce6 to pcQDs and the proposed mechanism for singlet oxygen generation via FRET. (d) UV−vis absorption spectra of Ce6-conjugated pcQDs and Ce6 alone (black). Reprinted with permission from ref 396. Copyright 2007 American Chemical Society.

excited with light with short wavelengths in the UV or blue regions, which has very limited tissue penetration. Future studies will include synthesis of new fullerene derivatives, particularly those with light-harvesting antennae to broaden the range of activating light that can be used, hence increasing light penetration depth into deep lesions. 3.2.6. Other Nanocarbons. Other carbon nanomaterials, including CNTs, graphene, and carbon dots, have also been used for the delivery of PDT. In 2009, Naveen et al. reported the direct observation of 1O2 production upon nonlinear excitation of SWNTs functionalized with −COOH and/or chitosan.22 It was demonstrated that 1O2 formation was influenced by several factors including surface functionalization/modification and the existence of residual iron catalyst. 1 O2 emission signals observed from SWNTs upon irradiation at 532 nm were via a two-photon process. The relative quantum yield of 1O2 production at excitation wavelength of 532 nm was found to be 0.00, 0.07−0.13, and 0.24−0.53 for highly functionalized, partially functionalized, and nonfunctionalized SWNT samples, respectively. However, because surface functionalization usually is critical to develop SWNTs suitable for bioapplications, it might not be that practical to use the intrinsic photoinduced 1O2 generation ability of SWNT samples in real PDT applications. On the other hand, researchers have found that instead of acting as a PS agent, SWNTs could in fact quench 1O2 generation of PS molecules attached to the nanotube surface.

later work by Tabata and coauthors, they introduced a therapeutic and diagnostic hybrid system based on C60.404 After chemical conjugation of PEG to C60 to form C60-PEG, diethylenetridiethylenetriaminepentaacetic acid (DTPA) was subsequently conjugated to the terminal group of PEG to form C60-PEG-DTPA, which was then mixed with gadolinium acetate solution to obtain Gd3+-chelated C60-PEG (C60-PEGGd). Following iv injection of C60-PEG-Gd plus light irradiation, the PDT efficacy was observed at the time when the tumor accumulation was detected by the Gd-enhanced T1MR imaging, demonstrating the promise of using those fullerene conjugates for cancer theranostic applications. In another study, Hamblin and coauthors uncovered that i.p. injection with mono(dimethylpyrolidinium) (BF4) fullerene and white light irradiation exhibited a significant therapeutic effect in a challenging mouse model of disseminated abdominal cancer405(Figure 55). In this work, the tumor model was generated by using engineered bioluminescent tumor cells. Intraperitoneal injection of N-methylpyrrolidinium-fullerene formulated in cremophor-EL micelles followed by white-light illumination delivered through the peritoneal wall (after creation of a skin flap) produced a statistically significant reduction in bioluminescence signals from the mouse abdomen, and offered an obvious survival advantage in mice. Fullerene derivatives have been demonstrated to be effective PS agents in photodynamic cancer treatment. However, the major disadvantage of fullerenes in PDT is that they have to be 10921


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Figure 55. Photodynamic therapy mediated by fullerene-based nanocarriers in a mouse model of abdominal dissemination of colon adenocarcinoma. (a) Chemical structure of BF4 and chemical structure of photofrin. (b) UV−vis−NIR absorption spectra of BF4 in DMSO:water 1:9 (black solid) and Photofrin in PBS (red solid), as well as fluorescence emission spectra under broadband white (black dashes), green light (green dashes), and red light (red dashes) excitations. (c) Bioluminescence imaging of CT26-Luc tumors growing in a representative control mouse (upper panel) and a representative PDT treated mouse (lower panel). (d) Quantitative analysis of bioluminescence signals in control and PDT-treated mice showing the inhibition of tumor development in mouse abdominal after treatment. Reprinted with permission from ref 405. Copyright 2011 Elsevier.

Figure 56. Regulation of singlet oxygen generation (SOG) using SWNTs. (a) A scheme showing the complex formed between a SWNT and aptamer-photosensitizer (AP) conjugates for target controllable PDT. (b) The SOG signal of different samples. (c) The SOG signal plotted as a function of thrombin concentration. (d) SOG specificity. Reprinted with permission from ref 406. Copyright 2008 American Chemical Society.

great quenchers to singlet oxygen generation (SOG), while in

Zhu et al. designed a novel PDT system containing protein binding aptamers, photosensitizers, and SWNTs.406 In their design, a photosensitizer was covalently attached to one end of the DNA aptamer that wrapped onto the SWNT surface (Figure 56). In the absence of its target protein, SWNTs were

the presence of its target, the binding of target thrombin would disturb the DNA interaction with SWNTs and cause the DNA aptamer to fall off from the SWNT surface, resulting in the 10922


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Figure 57. Photothermally enhanced photodynamic therapy delivered by nanographene oxide. (a) Schematic drawing showing Ce6 loading on NGO-PEG. Red, Ce6; black, NGO; blue, six-arm PEG. (b) Scheme of the experimental design in photothermally enhanced PDT. Ce6 after being loaded on NGO-PEG showed enhanced cellular uptake, which could be further promoted under mild photothermal heating of NGO induced by the NIR light. Reprinted with permission from ref 123. Copyright 2012 American Chemical Society.

GO-based nanocarriers to realize selective PDT of cancer cells.412,413 In our work, we showed that PEGylated nano-GO could serve as a multifunctional nanocarrier to load photosensitizer Ce6 for photothermally enhanced PDT23(Figure 57). Again, Ce6 was loaded on PEG-functionalized nano-GO via supramolecular π−π stacking. We found that the obtained nGOPEG-Ce6 complex offered a remarkably improved cancer cell photodynamic destruction effect as compared to that of free Ce6, due to the greatly increased cellular uptake of Ce6 when it was loaded on nGO-PEG. More importantly, we showed that the photothermal effect of nGO could be utilized to promote the delivery of Ce6 molecules by a mild local heating when exposed to a NIR laser at a low power density, further enhancing the PDT efficacy against cancer cells. Carbon dots (C-dots) and graphene quantum dots (GQDs) with ultrasmall sizes have recently emerged as novel carbon nanomaterials showing great potential in nanomedicine and bioapplications. Several groups have explored their potential use as PDT agents. Chen and collaborators designed photosensitizer-conjugated C-dots for NIR fluorescence imaging guided PDT treatment.414 C-dots were employed for improved PDT by two different excitation pathways: (1) indirect excitation by FRET from the C-dots to Ce6; and (2)

restoration of SOG.. Their results demonstrated that SOG could be regulated by a target protein. Several other teams have also studied CNT-based PDT delivery.407−409 For example, in a recent work, Erbas et al. studied the use of noncovalent functionalized SWNTs as the delivery agent for Bodipy-based PS agent in PDT.409 Pyrenylfunctionalized distyryl-Bodipy sensitizer was noncovalently attached to SWNTs by π−π stacking interactions, and was shown to generate singlet oxygen when excited at 660 nm with a red LED array. Graphene exhibits the unique 2-D structure and exceptional physical and chemical properties, which lead to many potential applications including PDT. Dong et al. first reported the graphene-based PDT.410 Zinc phthalocyanine (ZnPc), a widely used PS molecule, was loaded on the surface of nGO-PEG via π−π stacking and hydrophobic interactions. They found that the obtained nGO-PEG-ZnPC exhibited significant cytotoxicity toward MCF-7 cells under Xe light irradiation. Cui and his coworkers reported the use of FA conjugated GO loaded with Ce6 for folate-targeted PDT.411 Those nanocarriers could selectively deliver Ce6 to MGC803 cells overexpressing the folate receptor, and achieve effective cancer cell photodynamic destruction under the 633 nm laser irradiation. Several other groups have also demonstrated the delivery of PS molecules by 10923


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Figure 58. Hypocrellin B (HB)-loaded gold nanocages (AuNCs) with high two-photon efficiency for photothermal/photodynamic cancer therapy. (a) Schematic illustration of the formulation of lipid-HB-AuNCs and the process of the combinational treatments of two-photon photodynamic/ photothermal therapy for suppressing tumor cell growth in a synergistic manner in vitro. (b−e) images of HeLa cells’ cellular uptake of lipid-HBAuNCs after 6 h incubation: (b) one-photon fluorescent image of well-distributed lipid-HB in the whole cytoplasm; (c) two-photon luminescence image of AuNCs scattered in the cytoplasm and on the membrane; (d) the overlapped image; and (e) x−y top view at a given z and two other images of the respective x−z and y−z side views along the green and red lines. (f) HeLa cell viability in vitro measured by MTT assay (n = 3) with dependence on nanomedicine concentration. (g) HeLa cell viability in vitro measured by MTT assay (n = 3) under irradiation for different times. (h) HeLa cell viability in vitro measured by MTT assay (n = 3) at different optical doses. (i) HeLa cell viability in vitro measured by MTT assay (n = 3) under different conditions. Reprinted with permission from ref 416. Copyright 2012 American Chemical Society.

therapy416(Figure 58). The hybrid conjugate comprised an AuNC as a support core, mixed lipid layers with the incorporation of the two-photon photodynamic therapeutic agent hypocrellin B (HB), and a hydrophilic PEG shell. They demonstrated that under two-photon illumination (790 nm 85.5 pJ per pulse, 300s), the photodynamic anticancer treatment was dramatically enhanced by the photothermal effect. MSNs have also been utilized as a nanocarrier for twophoton photodynamic agents. Gary-Bobo et al. prepared MSN containing a porphyrin for efficient TPA-PDT in vivo.372 They demonstrated that a single intravenous injection with MSNmannose to nude mice (n = 4) bearing HCT-116 xenografts was sufficient to treat those tumors after two-photon irradiation at 760 nm for three periods of 3 min (Ti:sapphire laser generating 150 fs wide pulses at a 76 MHz rate). Thirty days after treatment, PDT-treated tumors showed a remarkable growth delay as compared to saline controls. In another work, Cheng et al. demonstrated MSN coencapsulating TPA dyes and

direct excitation of the Ce6. Their results indicated that the synthesized multifunctional nanocarrier platform was effective for enhanced PDT of gastric cancer tumor in vivo. In another work, Trajkovic and collaborators studied cytotoxicity of GQDs under light irradiation.415 They found that GQDs irradiated with blue light (470 nm, 1 W) could generate ROS including singlet oxygen, and were able to kill U251 human glioma cells by causing oxidative stress. Their data indicate the potential usefulness of GQDs in PDT. 3.2.7. Two-Photon Exciting Nanoparticles. Two-photon absorption (TPA) is the simultaneous absorption of two photons of identical or different frequencies to excite a molecule from one state (usually the ground state) to a higher energy electronic state. Using TPA materials, the window for excitation can be extended into the infrared region, thereby making the process more viable to be used to treat deep lesions. Liang et al. constructed a new bioconjugate nanostructure by using photosensitizer-incorporated mixed lipid-coated AuNCs for two-photon photothermal/photodynamic cancer 10924


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Figure 59. Luciferase-immobilized quantum dots for self-illuminated photodynamic therapy. (a) Schematic representation of Renilla luciferase 8 (RLuc8)-immobilized QDs-655 for BRET-based PDT. (b) Relative tumor growth curves from different treatment groups. (c) Photos of A549 tumors taken from mice after various treatments. (d) H&E stained histological sections of tumors from different groups. Reprinted with permission from ref 422. Copyright 2013 Elsevier.

substrate for the PS immobilization.421 Upon the ionizing radiation, the scintillation nanoparticles could illuminate visible light, which were then absorbed by PS molecules to generate ROS. The utilization of scintillation nanoparticles for PDT has several advantages as compared to traditional PDT and radiation therapy, as in such a method the high-energy radiation can penetrate deep tissues, and radiation doses can be markedly reduced from that needed for radiation therapy. Another approach is the development of self-illuminating nanoparticles, which undergo the bioluminescence process and emit light from chemical energy to trigger PDT. Recently, Hsu et al. developed Renilla luciferase-immobilized QD-655 (QDRLuc8),422 which was used for bioluminescence resonance energy transfer (BRET)-mediated PDT (Figure 59). When the substrate coelenterazine was added, the bioluminescent QDRLuc8 conjugate exhibited self-illumination at 655 nm, which could activate the attached PS molecules. Both in vitro and in vivo results revealed the great potential for BRET-mediated PDT using QD-RLuc8 conjugates without an external light source for cancer therapy. The use of X-ray excited nanoparticles or self-illuminating nanoparticles to trigger PDT could circumvent the tissue penetration limit of light, which is the major disadvantage in current phototherapies of cancer. However, the development of such techniques is still at its infant stage. The efficiency of this type of strategies may need further significant improvement. 3.2.9. Upconversion Nanoparticles for Near-InfraredInduced Photodynamic Therapy. Upconversion nanoparticles (UCNPs) are usually lanthanide-doped nanocrystals, which emit high energy photons under lower energy radiation (NIR light), and have shown potential applications in many different fields including biomedicine.102,423,424 As compared to traditional down-conversion fluorescence, the NIR light excited upconversion luminescence (UCL) of UCNPs exhibits improved tissue penetration depth, higher photochemical stability, and is free of autofluorescence background, making them widely explored new nanoprobes in biomedical imaging

photosensitizers could enable high-energy transfer rates for two-photon activated PDT.417 By control of donor−acceptor (D−A) ratios, the well-ordered mesoporous structure of MSNs enhanced the energy transfer rate up to an unprecedented 93%. They observed an efficient and controllable energy transfer mechanism via the facile modification of two-photon antenna molecules and photosensitizers on different topological domains in MSNs. The cytotoxicity induced by the singlet oxygen was demonstrated in both in vitro and in vivo breast cancer models. By intratumor injection of nanoparticles to nude mice bearing MDA-MB-231 breast tumors and then irradiation with a 920 nm femtosecond laser at a total energy of 150 J cm−2, the death of cancer cell was examined by H&E stain and caspase-3 immunohistogram. Two-photon excited PDT is able to increase the penetration depth of the PDT illumination light in tissue and allow for treatment of thicker malignancies. However, this technique requires the use of a pulsed laser as the light source to excite focused small areas to obtain sufficient instant energy needed for two-photon excitation, and thus may have limited value for real clinical applications. 3.2.8. Scintillation Nanoparticles and Self-Illuminating Nanoparticles. In PDT, because most of the PS molecules are excited by visible light, the short light penetration depth has been a major limitation. A few reports have explored some revolutionary PDTs strategies, which do not require external light irradiation. Scintillation nanoparticles such as LaF3:Ce3+, LuF3:Ce3+, CaF2:Mn2+, CaF2:Eu2+, BaFBr:Eu2+, BaFBr:Mn2+, and CaPO4:Mn2+ could emit visible luminescence upon exposure to ionizing irradiation such as X-ray, which shows remarkably better tissue penetration ability as compared to visible light.418,419 Liu et al. reported that LaF3:Tb3+-mesotetra(4-carboxy-phenyl) porphyrin (mTCP) nanoparticles could be activated by X-ray irradiation with the energy transferred from LaF3+:Tb3+ nanoparticles to mTCP to generate ROS.420 Chen et al. also utilized scintillation luminescent nanoparticles (BaFBr:Eu +, Mn+)URE as a 10925


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Figure 60. Near-infrared light induced in vivo photodynamic therapy of cancer based on upconversion nanoparticles (UCNPs). (a) A schematic drawing showing Ce6 physically adsorbed on the surface of PEGylated UCNPs via hydrophobic interactions to form a UCNP−Ce6 complex. (b) The growth of 4T1 tumors on different groups of mice after various treatments indicated. (c) The survival curves of mice in 60 days after various treatments indicated. A 980 nm laser at the power density of 0.5 W/cm2 was introduced for tumor irradiation. (d) Biodistribution of yttrium in various organs of UCNP−Ce6 injected mice after PDT treatment. ICP-AES was employed to quantitatively determine the Y3+ levels. Reprinted with permission from ref 25. Copyright 2011 Elsevier.

in recent years.99−103,425−429 Different from the two-photon excited PDT, which requires the pulsed laser with high instant energy as the excitation light and can only treat small areas using the focused laser beam, continuous lasers with much lower instant energy densities can be applied to illuminate large lesion areas in UCNP-based PDT. Many groups have demonstrated in vitro PDT using UCNPPS nanocomplexes.25,26,424,430−432 In an early study by Zhang et al., UCNPs were coated with a porous, thin layer of silica doped with merocyanine-540 photosensitizer, and conjugated with a tumor-targeting antibody for the targeted PDT to kill MCF-7/ AZ breast cancer cells.26 Liu et al. used folic acid (FA) to functionalized UCNP-RB nanoconjugates.431 A covalent bonding strategy was used to construct a highly efficient NIR

photosensitizing nanoplatform for simultaneous PDT and imaging. The first in vivo UCNP-based PDT study in animal experiments was demonstrated by our team25(Figure 60). In our study, we noncovalently incorporated Ce6 onto PEGylatedamphiphilic polymer-coated UCNPs. By directly injecting UCNP-Ce6 into 4T1 tumors grown on BABL/C mice, an obvious tumor regression effect was observed after tumors were exposed to a 980 nm light at 0.5 W/cm2 for 30 min. Moreover, we found that UCNPs injected into tumors after PDT treatment could be gradually cleared out from mouse organs after 2 months as determined by ex vivo inductively coupled plasma-atomic emission spectrometry (ICP-AES) assay. In a side-by-side comparison experiment, we uncovered that the 10926


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Figure 61. UCNPs for in vivo tumor-targeted photodynamic therapy. (a) The fluorescence emission spectrum of UCNPs under 980 nm NIR laser excitation and the absorption spectra of ZnPc and MC540 photosensitizers. (b) A schematic drawing showing mesoporous-silica-coated UCNPs coloaded with ZnPc and MC540 for PDT. (c) A schematic diagram showing UCNP-based targeted PDT in a mouse model of melanoma. (d) Change in tumor size as a function of time after various treatments indicated. (e) Representative photos of mice from different treatment groups before PDT and 7 days after PDT. Reprinted with permission from ref 430. Copyright 2012 Nature Publishing Group.

Figure 62. Multifunctional theranostic red blood cells for magnetic field enhanced in vivo combination therapy of cancer. The scheme showing the preparation steps of theranostic RBCs modified with IONPs, Ce6, DOX, and PEG. Reprinted with permission from ref 434. Copyright 2014 John Wiley & Sons, Inc.

NIR-induced PDT using UCNP−Ce6 nanocomplex showed

UCNP-based PDT based on systemic administration has also been demonstrated in a few recent studies.390,392,395,430,432,435,436 Hyeon and co-workers reported an in vivo PDT effect through the systemic administration of UCNP−Ce6 followed by the 980 nm irradiation.430 In their design, NaGdY4-based UCNPs after PEGylation were loaded

much deeper tissue penetration in comparison to traditional visible light induced PDT when free Ce6 was used. A few other groups have also demonstrated in vivo PDT using UCNP-PS complexes by local administration.433,434 10927


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Figure 63. AuNR-photosensitizer complex for NIR fluorescence imaging and photodynamic/photothermal therapy in vivo. (a) Schematic diagram of the AuNR−AlPcS4 complex for NIR fluorescence imaging and tumor phototherapy. (b) Tumor-to-background ratio (TBR) determined by in vivo NIR fluorescence imaging at 1, 4, and 24 h post injection. (c−e) In vivo PDT and PTT. (c) IR thermal images captured after 1 min of light illumination, and (d) thermographic monitoring in the tumors of GNR-AlPcS4-injected and PBS-injected mice. (e) Tumor growth in different groups of mice after various treatments indicated. Reprinted with permission from ref 457. Copyright 2011 American Chemical Society.

layer (LbL) self-assembly strategy was employed to load multiple layers of Ce6 conjugated polymers onto UCNPs via electrostatic interactions. By further coating with an outer layer of charge-reversible polymer, the obtained nanoparticles were negatively charged and PEG coated under pH 7.4, and could be converted to have a positively charged naked surface at pH 6.8. As the result, significantly enhanced in vitro cell internalization and in vivo tumor retention of those nanoparticles were observed, leading to the remarkably improved NIR-induced PDT efficacy both in vitro and in vivo. Our results suggest the great potential of tumor acidity-targeted in vivo dual modal imaging and therapy using environmentally responsive nanoagents. UCNPs with the unique upconversion optical properties have significant potential in biomedical imaging and phototherapy. However, there remain a number of challenges in this field. The low quantum yield of UCL emission of UCNPs (less than 1% for most of UCNPs) has been an important issue to be addressed. Better design of UCNP structure,437,438 and the use of upconversion nanocapsules based on triplet−triplet annihilation,439 may be helpful to promote the QY of UCNPs for more effective PDT. Moreover, the potential toxicity and long-term fates of various types of UCNPs, although having been investigated in a number of recent reports,440−442 still need to be better understood.

with Ce6 molecules by both physical adsorption and chemical conjugation. Nude mice bearing U87MG tumors were injected with UCNP−Ce6 through the tail vein. Obvious tumor accumulation of UCNP−Ce6 nanoparticles was revealed by dual-modal upconversion luminescence imaging and T1weighted MR imaging. Under the 980 nm irradiation, tumor growth of UCNP−Ce6 injected mice was significantly inhibited as compared to other control groups. In another recent study, Zhang and co-workers demonstrated in vivo tumor-targeted PDT using UCNPs loaded with dual types of PS molecules436(Figure 61). In their study, UCNPs were coated with mesoporous silica and coloaded with ZnPc and merocya-nine 540 (MC540), which were two widely used PS molecules with different excitation wavelengths to allow full usage of the green and red emission light from UCNPs. After that, UCNPs were PEGylated and conjugated with folic acid for targeted PDT. Mice bearing B16-F0 melanoma tumors were iv injected with ZnPc/MC540 coloaded FA-PEG-UCNPs and then irradiated with a 980 nm laser at 4 h post injection. They found a significant reduction in tumor growth of the treatment group as compared to control mice treated with PBS. Gu and collaborators developed tumor targeted UCNP-PS nanoconstructs with high ZnPc loading capacity for deeppenetrating PDT in vivo.435 Folate-modified amphiphilic chitosan (FASOC) was coated on the surface of UCNPs to anchor the ZnPc close to UCNPs, thereby facilitating resonance energy transfer from UCNPs to ZnPc. In comparison with conventional PDT depending on red light irradiation, the NIR-induced PDT based on their nanoconstructs possessed higher tumor inhibition ratio for the treatment of deep-seated tumors. In our latest study, we developed charge-reversible Mn2+doped UCNPs for pH-sensitive in vivo PDT.434 A layer-by-

3.3. Combination of Photodynamic Therapy with Other Therapeutic Approaches

Apart from being explored as a monotherapy of cancer, PDT could be integrated with chemotherapy, PTT, and some other treatment modalities for cancer combination therapy. The unique UCL emission of UCNPs under NIR light also has the 10928


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which were used together for combination therapy of tumors in mice, showing an effective tumor regression effect after treatment.444 A following work by the same group found that the combination therapeutic effects could be significantly improved by conjugating the copolymer with an antibody to allow higher tumor accumulation.447 After that, Peng et al. demonstrated that the amphiphilic 4-armed star-shaped chlorin-core diblock methoxy poly(ethylene glycol) (mPEG) and poly(-caprolactone) (PCL) copolymers could form a micelle structure, which could be utilized for the loading of anticancer drug (paclitaxel) in the core via the hydrophobic interaction. Using those micelles, an effective synergistic treatment effect on MCF-7 cancer cells was observed.448 Recently, Khdair and co-workers prepared DOX and methylene blue coencapsulated nanoparticles based on an anionic surfactant (Aerosol-OT, AOT) and a naturally occurring polysaccharide polymer (sodium alginate) via the multiple emulsification cross-linking technique. The obtained nanoparticles were used for the treatment of multidrug resistance (MDR) mouse tumor models, showing significantly inhibited tumor growth and improved animal survival after the combined photodynamic and chemo-therapies.449 Additionally, various inorganic nanoparticles have also been explored for combined chemotherapy and PDT.230,449−451 In 2011, Wang and co-workers fabricated hematoporphyrin doped hollow silica nanocages and used them for DOX loading. Those nanoparticles with two types of therapeutic agents loaded were robust in killing cancer cells by combining chemotherapy and PDT.451 More recently, a work by Miao et al. indicated that GO with PEGylation (pGO) could also be utilized for simultaneously loading of DOX and Ce6. The fabricated Ce6/DOX/pGO exhibited a superior antitumor effect in mouse xenografts in comparison with those treated by Ce6/pGO or DOX/pGO, respectively, under PDT treatment conditions.450 Besides systematic nanoparticle-based drug delivery systems, red blood cells (RBCs) with inherent biocompatibility and long systemic circulation represent an interesting class of drug carriers. In a very recent work, our group developed a multifunctional drug delivery system based on RBCs for magnetic field (MF)-enhanced combination therapy of cancer452(Figure 62). In our design, IONPs coated with PS molecules, Ce6, are attached onto the membrane of RBCs, in which a chemotherapy drug DOX is loaded. After further PEG coating, we obtained DOX@RBC-IONP-Ce6-PEG with long blood circulation time and strong responses to the external MF. Those theranostic RBCs were then used for in vivo MFenhanced cancer treatment in a mouse tumor model using rather low doses of therapeutic agents, achieving a great synergistic tumor growth inhibition effect after the combined photodynamic and chemotherapy is conducted. This work highlights the promise of a smartly designed RBC-based drug delivery system as a safe and multifunctional platform for combination therapy of cancer. 3.3.2. Combination of Photodynamic Therapy with Photothermal Therapy. Recently, NIR-absorbing nanomaterials, which could simultaneously work as the photosensitizer carrier and as heat generator, have been explored to combine PDT with PTT together for synergistic cancer killing.123,453 As described in detail in the earlier part of this Review, our group demonstrated the use of PEGylated nano-GO with Ce6 loading for photothermally enhanced delivery of PDT.123 After that, Sahu and co-workers indicated that Pluronic block copolymer functionalized GO could also be utilized for the loading of

Figure 64. Photosensitizer-loaded Au vesicles with strong plasmonic coupling effect for imaging-guided photothermal/photodynamic therapy. (a) Scheme of Ce6-loaded plasmonic Au vesicles (GVs) for triple modal fluorescence/thermal/photoacoustic imaging guided synergistic photothermal/photodynamic cancer therapy. (b) In vivo NIR fluorescence image of MDA-MB-435 tumor-bearing mice taken at pre injection and post injection of GV-Ce6. (c) IR thermal images of tumor-bearing mice exposed to 671 nm laser (2.0 W/cm2) for 6 min at post injection of GV-Ce6. (d) Tumor growth curves of different groups of tumor-bearing mice after different treatments. Reprinted with permission from ref 56. Copyright 2013 American Chemical Society.

potential to be employed to trigger a few other therapeutic mechanisms (Table 2). 3.3.1. Combination of Photodynamic Therapy with Chemotherapy. The combination of PDT with chemotherapy has a long histology in both preclinical research and clinical tumor treatment applications.443,444 Many polymer-based drug delivery systems that are capable of delivering both chemotherapy drugs and photodynamic PS molecules have been widely explored by different groups.445,446 As an early example, in 1996, Peterson and co-workers synthesized N-(2hydroxypropyl)methacrylamide (HPMA) copolymer-Adriamycin conjugate and HPMA copolymer-meso-chlorin e6 monoethylene diamine disodium salt (Mce6) conjugate, both of 10929


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a large variety of research groups, as well as photodynamic therapeutic approaches relying on different mechanisms by utilizing the unique properties of functional nanostructures, are summarized in detail. Explorations regarding the combination therapy of cancer by integrating phototherapeutic methods with other traditional therapies to achieve the synergistic cancer killing effect are further discussed. However, despite the tremendous amount of exciting results reported in the past few years in this field, there are still many challenges ahead toward further clinical applications of those functional nanomaterials in phototherapies of cancer. (i) One of the most important issues is the potential longterm safety concerns of the nanomaterials, especially those inorganic ones that are not biodegradable and would retain inside the body for long periods of time after administration. Although a large number of reports have demonstrated that many inorganic nanomaterials, such as gold and carbon nanomaterials, if with appropriate surface coatings and sizes, are not noticeably toxic in vitro and in vivo in the tested dose ranges, it could still be extremely tough for those nanoagents to finally get FDA approval for clinical use. The recent preliminary success in the clinical trial of gold nanoshells would shine some light on this direction though. Nevertheless, the development of biocompatible and biodegradable nanoagents for photothermal and photodynamic therapy of cancer could thus have a much higher clinical value. (ii) Another major challenge in phototherapy of cancer is the limited light penetration depth. For photothermal therapy, NIR absorbing photothermal agents are absolutely preferred over those with visible absorption considering the reduced light absorbance and scattering in the NIR window. Regarding photodynamic therapy, the visible light used in traditional PDT is not the ideal light source. Although progress has been made in the development of NIR-induced PDT (e.g., by using UCNPs or two-photon excitation PDT agents), great efforts are still required to develop new generations of PDT agents that can be more effectively excited by the NIR light. (iii) Even if NIR light is used to trigger phototherapy, the effective penetration depth of NIR light is still usually limited to be no deeper than 1 cm. For some types of cancers, such as skin cancers, oral cancer, esophageal cancer, and even stomach cancers, light can be induced to locally irradiate the tumors with the help of certain facilities (e.g., gastroscopy, endoscopy). For other types of cancers with tumors located deeply inside the body, effective phototherapy would require the appropriate design of medical devices (e.g., with optical fibers) that can deliver light into those deep lesions. Moreover, it would be greatly beneficial for clinicians if some imaging functions can be integrated into such medical devices to real-time track the location of phototherapeutic agents, to ensure all of the tumor mass is effectively exposed to the light, and to monitor the therapeutic responses at the real time (e.g., temperature elevation of the tumor and its surrounding tissues during photothermal therapy). Such phototherapy medical devices, if designed by a team with experts from different backgrounds, may greatly promote the development of phototherapy in clinical cancer treatment. (iv) Different from traditional chemotherapy, phototherapy uses light to locally irradiate the tumor. Therefore, imagingguided therapy becomes extremely meaningful and important in phototherapy: (1) Before phototherapy, careful whole-body imaging should be carried out to find out the exact tumor location, size, and shape, to ensure the efficient light exposure

methylene blue via the electrostatic interaction. The obtained nanocomplex exhibited a superior synergistic anticancer effect in mouse xenografts when used in combination with PTT.454 More recently, Wang and co-workers prepared a multifunctional nanoplatform by covalently grafting GO with UCNPs, obtaining GO-UCNP composite, which was demonstrated to be effective for the loading of photosensitizer ZnPC to realize a synergistic treatment effect of cancer cells in vitro by combining PTT with PDT.455 Besides, Wang and colleagues fabricated an aptamer switch probe conjugated AuNRs for the targeted delivery of Ce6 and observed a synergistic therapeutic effect of cancer cells under combined treatment with both PDT and PTT.456 In another piece of work by Jang and cowaorkers, it was demonstrated that Al(III) phthalocyanine chloride tetrasulfonic acid (AlPcS4) loaded AuNRs could contribute to a strong reduced tumor growth effect (95% inhibition) in mouse xenografts after being combinedly treated with PDT and PTT, while the tumor growth inhibition effect was 79% for those only receiving PDT treatment457(Figure 63). In the above-mentioned studies, two different lasers are independently used to trigger PDT and PTT separately. For operation convenience and patient comfort, it would be helpful to find new strategies to realize combined PDT and PTT under a single laser irradiation. In 2008, Zhang et al. fabricated BSA stabilized single-wall carbon nanohorns (SWNHs) with holes opened for the photosensitizer (ZnPc) loading. The obtained nanocomplex offered greatly improved therapeutic effects by combining PDT and PTT under the irradiation of a 670 nm laser both in vitro and in vivo, in comparison single PDT or PTT therapy delivered by ZnPc or SWNHs alone, respectively.458 Similarly, by using the photosensitizers (e.g., ICG, Ce6) with strong absorption in NIR region, several interesting works have demonstrated that various NIRabsorbing nanostructures (e.g., AuNRs, AuNFs) could be used for photosensitizer delivery and showed excellent synergistic therapeutic effects under the single wavelength laser irradiation.453,459,460 More recently, Lin and colleagues fabricated a Ce6 loaded gold vesicle with strong NIR light absorbance in the NIR region of 650−850 nm. Using this nanoagent upon intratumoral injection, effective combined PDT and PTT under the 671 nm laser irradiation was achieved, resulting in remarkable tumor regression after treatment56(Figure 64). By utilizing the two-photon technique, Gao et al. prepared a lipid-coated AuNC for the delivery of a photosensitizer (hypocrellin B), achieving effective cancer treatment effect by combined PDT and PTT.461 Apart from utilizing the inorganic NIR-absorbing nanostructures as the heat generator for combined PDT and PTT, Peng and colleagues exploited a traditional hydrophobic photosensitizer (phthalocyanine, PC) with a strong NIR light absorption as both ROS and heat generator for combined PDT and PTT after being loaded in hollow silica nanoparticles (HSNs).462 It was found that the asprepared PC-HSNs exhibited an effective combined therapeutic effect both in vitro and in vivo after being irradiated with a 730 nm laser, showing an outstanding potential for further exploration of the new-generation combination therapy for cancers.

4. FUTURE CHALLENGES AND PROSPECTS In this Review, we have systematically reviewed the recent advances in phototherapies of cancer using functional nanomaterials. Photothermal therapy studies based on various inorganic and organic NIR-absorbing nanoagents reported by 10930


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Biographies

of the whole tumor. (2) To achieve the highest photo therapeutic efficacy, the light irradiation has to be applied when the phototherapeutic agent reaches the highest accumulation in the tumor, as the tumor homing of any agent is a dynamic process. Thus, the real-time track of the phototherapeutic agent after administration by imaging is important to achieve the optimized therapeutic outcome. (3) After treatment is accomplished, advanced imaging techniques are required to determine the therapeutic response as early as possible. In this regard, it would be ideal if a phototherapeutic agent could also have the imaging capability. Therefore, a well-engineered nanoplatform that offers both therapy and imaging functionalities could have important clinical values and be of great interest to the future development of phototherapies. (v) Each therapeutic approach could have its own advantages and limitations. Although phototherapy does have its great potential, it is still not realistic to expect that phototherapy by itself would win the fight against cancer. There is almost no doubt that future cancer therapies would very much likely rely on the combination of a set of different treatment approaches, which may include surgery, chemotherapy, radiotherapy, gene therapy, as well as photothermal and photodynamic therapies discussed in this Review. Therefore, the development of multifunctional nanocarriers that enable different therapeutic mechanisms for cancer combination therapy may bring great opportunities to the new generation of cancer therapy. Besides the above-mentioned challenges and prospects, there are also a number of in-depth basic mechanism questions that remain to be addressed in the future development of phototherapy for cancer treatment. For example, how the immune system would respond to photothermal or photodynamic killing of tumor cells, what would be the effect of the tumor residues after photothermal ablation, what could be the most optimized therapeutic condition for photodynamic therapy in which oxygen is involved, and how to realize the most effective synergistic effect when phototherapy is combined with other therapeutic methods all merit further careful investigations. Moreover, whether phototherapy would bring any potential therapeutic advantages to overcome multidrug resistance of tumor cells and prevent tumor metastasis, which are two killing factors of cancer, would be of great importance. Nevertheless, it is believed that phototherapies based on functional nanoagents, due to their unique advantages such as minimal side effects and high efficacies, would play increasingly important roles in the fight against cancer.

Dr. Liang Cheng received his Ph.D. degree from the Institute of Functional Nano & Soft Materials (FUNSOM) at Soochow University in 2012. His Ph.D. thesis was focused on the biomedical applications of upconversion nanoparticles under the supervision of Prof. Zhuang Liu. He is now an associate professor in Prof. Liu’s group. His current research interest is the development of multifunctional nanostructures for applications in cancer theranostics, partially for imaging-guided photothermal therapy of cancer.

Chao Wang was born in Jiangsu, China, in 1987. He received his B.S. degree from Soochow University in 2010. Since then, he has studied as a Ph.D. candidate under the guidance of Prof. Zhuang Liu in FUNSOM at Soochow University. His current research directions include photodynamic therapy based on UCNPs and the applications of UCNPs for cell tracking and cell therapies.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

Liangzhu Feng received his B.S. degree from Soochow University in 2010. Since then, he has been pursuing his Ph.D. degree at FUNSOM of Soochow University under the supervision of Prof. Zhuang Liu. His

Notes

The authors declare no competing financial interest. 10931


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REFERENCES

research interest is focused on the light-controllable drug and gene delivery systems using functionalized nanographene.

(1) Ferrari, M. Nat. Rev. Cancer 2005, 5, 161. (2) Peer, D.; Karp, J. M.; Hong, S.; Farokhzad, O. C.; Margalit, R.; Langer, R. Nat. Nanotechnol. 2007, 2, 751. (3) Nikoobakht, B.; El-Sayed, M. A. Chem. Mater. 2003, 15, 1957. (4) Xia, Y.; Li, W.; Cobley, C. M.; Chen, J.; Xia, X.; Zhang, Q.; Yang, M.; Cho, E. C.; Brown, P. K. Acc. Chem. Res. 2011, 44, 914. (5) Yang, K.; Feng, L.; Shi, X.; Liu, Z. Chem. Soc. Rev. 2013, 42, 530. (6) Huang, X.; Tang, S.; Mu, X.; Dai, Y.; Chen, G.; Zhou, Z.; Ruan, F.; Yang, Z.; Zheng, N. Nat. Nanotechnol. 2011, 6, 28. (7) Zhou, M.; Zhang, R.; Huang, M.; Lu, W.; Song, S.; Melancon, M. P.; Tian, M.; Liang, D.; Li, C. J. Am. Chem. Soc. 2010, 132, 15351. (8) Tian, Q.; Tang, M.; Sun, Y.; Zou, R.; Chen, Z.; Zhu, M.; Yang, S.; Wang, J.; Wang, J.; Hu, J. Adv. Mater. 2011, 23, 3542. (9) Li, J.; Jiang, F.; Yang, B.; Song, X.-R.; Liu, Y.; Yang, H.-H.; Cao, D.-R.; Shi, W.-R.; Chen, G.-N. Sci. Rep. 2013, 3, 1998. (10) Chou, S. S.; Kaehr, B.; Kim, J.; Foley, B. M.; De, M.; Hopkins, P. E.; Huang, J.; Brinker, C. J.; Dravid, V. P. Angew. Chem., Int. Ed. 2013, 52, 4160. (11) Yang, K.; Xu, H.; Cheng, L.; Sun, C.; Wang, J.; Liu, Z. Adv. Mater. 2012, 24, 5586. (12) Cheng, L.; Yang, K.; Chen, Q.; Liu, Z. ACS Nano 2012, 6, 5605. (13) 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. Nat. Mater. 2011, 10, 324. (14) Cheng, L.; He, W.; Gong, H.; Wang, C.; Chen, Q.; Cheng, Z.; Liu, Z. Adv. Funct. Mater. 2013, 23, 5893. (15) Dolmans, D. E. J. G. J.; Fukumura, D.; Jain, R. K. Nat. Rev. Cancer 2003, 3, 380. (16) Jiang, F.; Lilge, L.; Grenier, J.; Li, Y.; Wilson, M. D.; Chopp, M. Lasers Surg. Med. 1998, 22, 74. (17) Son, K. J.; Yoon, H. J.; Kim, J. H.; Jang, W. D.; Lee, Y.; Koh, W. G. Angew. Chem., Int. Ed. 2011, 50, 11968. (18) Banerjee, R.; Katsenovich, Y.; Lagos, L.; McIintosh, M.; Zhang, X.; Li, C. Z. Curr. Med. Chem. 2010, 17, 3120. (19) Duguet, E.; Vasseur, S.; Mornet, S.; Devoisselle, J. M. Nanomedicine (London, U. K.) 2006, 1, 157. (20) Yu, M. K.; Park, J.; Jon, S. Drug Delivery Transl. Res. 2012, 2, 3. (21) Samia, A. C. S.; Chen, X. B.; Burda, C. J. Am. Chem. Soc. 2003, 125, 15736. (22) Gandra, N.; Chiu, P. L.; Li, W. B.; Anderson, Y. R.; Mitra, S.; He, H. X.; Gao, R. M. J. Phys. Chem. C 2009, 113, 5182. (23) Tu, H. L.; Lin, Y. S.; Lin, H. Y.; Hung, Y.; Lo, L. W.; Chen, Y. F.; Mou, C. Y. Adv. Mater. 2009, 21, 172. (24) Cell, J. P.; Spring, B. Q.; Rizvi, I.; Evans, C. L.; Samkoe, K. S.; Verma, S.; Pogue, B. W.; Hasan, T. Chem. Rev. 2010, 110, 2795. (25) Wang, C.; Tao, H.; Cheng, L.; Liu, Z. Biomaterials 2011, 32, 6145. (26) Zhang, P.; Steelant, W.; Kumar, M.; Scholfield, M. J. Am. Chem. Soc. 2007, 129, 4526. (27) Bardhan, R.; Lal, S.; Joshi, A.; Halas, N. J. Acc. Chem. Res. 2011, 44, 936. (28) Huang, X.; El-Sayed, I. H.; Qian, W.; El-Sayed, M. A. J. Am. Chem. Soc. 2006, 128, 2115. (29) Qin, Z.; Bischof, J. C. Chem. Soc. Rev. 2012, 41, 1191. (30) Boisselier, E.; Astruc, D. Chem. Soc. Rev. 2009, 38, 1759. (31) Dykman, L.; Khlebtsov, N. Chem. Soc. Rev. 2012, 41, 2256. (32) Huang, X.; El-Sayed, M. A. J. Adv. Res. 2010, 1, 13. (33) Kim, J.; Park, J.; Kim, H.; Singha, K.; Kim, W. J. Biomaterials 2013, 34, 7168. (34) Skralak, S. E.; Chen, J.; Sun, Y.; Lu, X.; Au, L.; Cobley, C. M.; Xia, Y. Acc. Chem. Res. 2008, 41, 1587. (35) Skrabalak, S. E.; Chen, J.; Au, L.; Lu, X.; Li, X.; Xia, Y. Adv. Mater. 2007, 19, 3177. (36) Yuan, H.; Fales, A. M.; Vo-Dinh, T. J. Am. Chem. Soc. 2012, 134, 11358. (37) Navarro, J. R. G.; Manchon, D.; Lerouge, F.; Blanchard, N. P.; Marotte, S.; Leverrier, Y.; Marvel, J.; Chaput, F.; Micouin, G.;

Dr. Kai Yang graduated in 2006 from the Anhui Polytechnic University with a B.S. degree in Biological Engineering. He obtained his Masters Degree from the School of Medicine at Soochow University in 2009, and completed his Ph.D. degree in FUNSOM at Soochow University under the supervision of Prof. Zhuang Liu at the end of 2013. His dissertation title is biomedical applications of nanographene. He is now an associate professor at the School of Radiation Medicine and Protection, Medical College of Soochow University.

Dr. Zhuang Liu received his B.S. degree from Peking University (China) in 2004 and Ph.D. degree from Stanford University (U.S.) in 2008. In 2009, Dr. Liu joined the Institute Functional Nano & Soft Materials (FUNSOM) at Soochow University in China. He is now a professor working in the field of nanobiotechnology and nanomedicine to develop various functional nanomaterials and nanotechnologies for cancer diagnosis and therapy, particular for phototherapy of cancer.Dr. Liu has authored over 120 peer-reviewed papers, many of which were published in top chemistry, materials, and biomedicine journals (total citation >12 000, H-index = 50).

ACKNOWLEDGMENTS This work was partially supported by the National Natural Science Foundation of China (51302180, 51222203, 51132006), the National “973” Program of China (2011CB911002, 2012CB932601), the Project Funded by the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions, the Jiangsu Key Laboratory for Carbon-Based Functional Materials , and the National Natural Science Foundation of Jiangsu Province (BK20130005, BK20130305). L.C. was supported by the Postdoctoral Research Program of Jiangsu Province (1202044C) and the Postdoctoral Science Foundation of China (2013M531400). 10932


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Gabudean, A.-M.; Mosset, A.; Cottancin, E.; Baldeck, P. L.; Kamada, K.; Parola, S. Nanotechnology 2012, 23, 465602. (38) Hao, F.; Nehl, C. L.; Hafner, J. H.; Nordlander, P. Nano Lett. 2007, 7, 729. (39) Pitsillides, C. M.; Joe, E. K.; Wei, X.; Anderson, R. R.; Lin, C. P. Biophys. J. 2003, 84, 4023. (40) Zharov, V. P.; Galitovsky, V.; Viegas, M. Appl. Phys. Lett. 2003, 83, 4897. (41) Zharov, V. P.; Galitovskaya, E.; Viegas, M. Proc. SPIE 2004, 5319, 291. (42) Zharov, V. P.; Galitovskaya, E. N.; Johnson, C.; Kelly, T. Lasers Surg. Med. 2005, 37, 219. (43) Zharov, V. P.; Kim, J.-W.; Curiel, D. T.; Everts, M. Nanomedicine (N. Y., NY, U. S.) 2005, 1, 326. (44) Hleb, E. Y.; Hafner, J. H.; Myers, J. N.; Hanna, E. Y.; Rostro, B. C.; Zhdanok, S. A.; Lapotko, D. O. Nanomedicine 2008, 3, 647. (45) El-Sayed, I. H.; Huang, X.; El-Sayed, M. A. Cancer Lett. 2006, 239, 129. (46) Li, J.-L.; Wang, L.; Liu, X.-Y.; Zhang, Z.-P.; Guo, H.-C.; Liu, W.M.; Tang, S.-H. Cancer Lett. 2009, 274, 319. (47) Maksimova, I. L.; Akchurin, G. G.; Khlebtsov, B. N.; Terentyuk, G. S.; Akchurin, G. G.; Ermolaev, I. A.; Skaptsov, A. A.; Soboleva, E. P.; Khlebtsov, N. G.; Tuchin, V. V. Med. Laser Appl. 2007, 22, 199. (48) Wu, Y. J.; Chen, C. H.; Chang, H. S. W.; Chen, W. C.; Chen, J. J. J. In 5th Kuala Lumpur International Conference on Biomedical Engineering 2011; Osman, N., Abas, W., Wahab, A., Ting, H.-N., Eds.; Springer: Berlin, Heidelberg, 2011; Vol. 35, p 380. (49) Khlebtsov, B.; Zharov, V.; Melnikov, A.; Tuchin, V.; Khlebtsov, N. Nanotechnology 2006, 17, 5167. (50) Nam, J.; Won, N.; Jin, H.; Chung, H.; Kim, S. J. Am. Chem. Soc. 2009, 131, 13639. (51) Nam, J.; La, W.-G.; Hwang, S.; Ha, Y. S.; Park, N.; Won, N.; Jung, S.; Bhang, S. H.; Ma, Y.-J.; Cho, Y.-M.; Jin, M.; Han, J.; Shin, J.Y.; Wang, E. K.; Kim, S. G.; Cho, S.-H.; Yoo, J.; Kim, B.-S.; Kim, S. ACS Nano 2013, 7, 3388. (52) Liu, X.; Chen, Y.; Li, H.; Huang, N.; Jin, Q.; Ren, K.; Ji, J. ACS Nano 2013, 7, 6244. (53) He, J.; Huang, X.; Li, Y.-C.; Liu, Y.; Babu, T.; Aronova, M. A.; Wang, S.; Lu, Z.; Chen, X.; Nie, Z. J. Am. Chem. Soc. 2013, 135, 7974. (54) He, J.; Liu, Y.; Babu, T.; Wei, Z.; Nie, Z. J. Am. Chem. Soc. 2012, 134, 11342. (55) He, J.; Zhang, P.; Babu, T.; Liu, Y.; Gong, J.; Nie, Z. Chem. Commun. 2013, 49, 576. (56) Lin, J.; Wang, S.; Huang, P.; Wang, Z.; Chen, S.; Niu, G.; Li, W.; He, J.; Cui, D.; Lu, G.; Chen, X.; Nie, Z. ACS Nano 2013, 7, 5320. (57) Liu, C.-P.; Lin, F.-S.; Chien, C.-T.; Tseng, S.-Y.; Luo, C.-W.; Chen, C.-H.; Chen, J.-K.; Tseng, F.-G.; Hwu, Y.; Lo, L.-W.; Yang, C.S.; Lin, S.-Y. Macromol. Biosci. 2013, 13, 1314. (58) Tong, L.; Zhao, Y.; Huff, T. B.; Hansen, M. N.; Wei, A.; Cheng, J.-X. Adv. Mater. 2007, 19, 3136. (59) Choi, W. I.; Kim, J.-Y.; Kang, C.; Byeon, C. C.; Kim, Y. H.; Tae, G. ACS Nano 2011, 5, 1995. (60) Li, J. L.; Day, D.; Gu, M. Adv. Mater. 2008, 20, 3866. (61) Tong, L.; Wei, Q.; Wei, A.; Cheng, J.-X. Photochem. Photobiol. 2009, 85, 21. (62) Tong, L.; Zhao, Y.; Huff, T. B.; Hansen, M. N.; Wei, A.; Cheng, J. X. Adv. Mater. 2007, 19, 3136. (63) Norman, R. S.; Stone, J. W.; Gole, A.; Murphy, C. J.; SaboAttwood, T. L. Nano Lett. 2007, 8, 302. (64) Maltzahn, G. v.; Park, J.-H.; Agrawal, A.; Bandaru, N. K.; Das, S. K.; Sailor, M. J.; Bhatia, S. N. Cancer Res. 2009, 69, 3892. (65) Dickerson, E. B.; Dreaden, E. C.; Huang, X.; El-Sayed, I. H.; Chu, H.; Pushpanketh, S.; McDonald, J. F.; El-Sayed, M. A. Cancer Lett. 2008, 269, 57. (66) Li, Z.; Huang, P.; Zhang, X.; Lin, J.; Yang, S.; Liu, B.; Gao, F.; Xi, P.; Ren, Q.; Cui, D. Mol. Pharmaceutics 2010, 7, 94. (67) Lin, A.; Hirsch, L.; Lee, M.-H.; Barton, J.; Halas, N.; West, J.; Drezek, R. Technol. Cancer Res. Treat. 2004, 3, 33.

(68) Gobin, A. M.; Lee, M. H.; Halas, N. J.; James, W. D.; Drezek, R. A.; West, J. L. Nano Lett. 2007, 7, 1929. (69) Wang, Y.; Xie, X.; Wang, X.; Ku, G.; Gill, K. L.; O’Neal, D. P.; Stoica, G.; Wang, L. V. Nano Lett. 2004, 4, 1689. (70) Loo, C.; Lowery, A.; Halas, N.; West, J.; Drezek, R. Nano Lett. 2005, 5, 709. (71) Liu, H.; Chen, D.; Tang, F.; Du, G.; Li, L.; Meng, X.; Liang, W.; Zhang, Y.; Teng, X.; Li, Y. Nanotechnology 2008, 19, 455101. (72) Ke, H.; Wang, J.; Dai, Z.; Jin, Y.; Qu, E.; Xing, Z.; Guo, C.; Yue, X.; Liu, J. Angew. Chem., Int. Ed. 2011, 50, 3017. (73) Bégu, S.; Pouëssel, A. A.; Lerner, D. A.; Tourné-Péteilh, C.; Devoisselle, J. M. J. Controlled Release 2007, 118, 1. (74) Chu, M.; Liu, G. Mater. Lett. 2006, 60, 11. (75) Wu, C.; Yu, C.; Chu, M. Int. J. Nanomed. 2011, 6, 807. (76) Fekrazad, R.; Hakimiha, N.; Farokhi, E.; Rasaee, M. J.; Ardestani, M. S.; Kalhori, K. A.; Sheikholeslami, F. Int. J. Nanomed. 2011, 6, 2749. (77) Day, E. S. E.; Zhang, L. L.; Thompson, P. A. P.; Zawaski, J. A. J.; Kaffes, C. C. C.; Gaber, M. W. M.; Blaney, S. M. S.; West, J. L. J. Nanomedicine 2012, 7, 1133. (78) Melancon, M. P.; Elliott, A. M.; Shetty, A.; Huang, Q.; Stafford, R. J.; Li, C. J. Controlled Release 2011, 156, 265. (79) Xie, H.; Diagaradjane, P.; Deorukhkar, A. A.; Goins, B.; Bao, A.; Phillips, W. T.; Wang, Z.; Schwartz, J.; Krishnan, S. Int. J. Nanomed. 2011, 6, 259. (80) Lu, W.; Xiong, C.; Zhang, G.; Huang, Q.; Zhang, R.; Zhang, J. Z.; Li, C. Clin. Cancer Res. 2009, 15, 876. (81) Lu, W.; Melancon, M. P.; Xiong, C.; Huang, Q.; Elliott, A.; Song, S.; Zhang, R.; Flores, L. G.; Gelovani, J. G.; Wang, L. V.; Ku, G.; Stafford, R. J.; Li, C. Cancer Res. 2011, 71, 6116. (82) http://www.nanospectra.com/index.html. (83) Chen, J.; Wang, D.; Xi, J.; Au, L.; Siekkinen, A.; Warsen, A.; Li, Z.-Y.; Zhang, H.; Xia, Y.; Li, X. Nano Lett. 2007, 7, 1318. (84) Au, L.; Zheng, D.; Zhou, F.; Li, Z.-Y.; Li, X.; Xia, Y. ACS Nano 2008, 2, 1645. (85) Chen, J.; Glaus, C.; Laforest, R.; Zhang, Q.; Yang, M.; Gidding, M.; Welch, M. J.; Xia, Y. Small 2010, 6, 811. (86) Lu, W.; Singh, A. K.; Khan, S. A.; Senapati, D.; Yu, H.; Ray, P. C. J. Am. Chem. Soc. 2010, 132, 18103. (87) Yuan, H.; Khoury, C. G.; Wilson, C. M.; Grant, G. A.; Bennett, A. J.; Vo-Dinh, T. Nanomedicine (N. Y., NY, U. S.) 2012, 8, 1355. (88) Pelaz, B.; Grazu, V.; Ibarra, A.; Magen, C.; del Pino, P.; de la Fuente, J. M. Langmuir 2012, 28, 8965. (89) Wang, Y.; Black, K. C. L.; Luehmann, H.; Li, W.; Zhang, Y.; Cai, X.; Wan, D.; Liu, S.-Y.; Li, M.; Kim, P.; Li, Z.-Y.; Wang, L. V.; Liu, Y.; Xia, Y. ACS Nano 2013, 7, 2068. (90) Hu, K.-W.; Huang, C.-C.; Hwu, J.-R.; Su, W.-C.; Shieh, D.-B.; Yeh, C.-S. Chem.Eur. J. 2008, 14, 2956. (91) Huang, Y.-F.; Sefah, K.; Bamrungsap, S.; Chang, H.-T.; Tan, W. Langmuir 2008, 24, 11860. (92) Kim, J.; Park, S.; Lee, J. E.; Jin, S. M.; Lee, J. H.; Lee, I. S.; Yang, I.; Kim, J.-S.; Kim, S. K.; Cho, M.-H.; Hyeon, T. Angew. Chem., Int. Ed. 2006, 118, 7918. (93) Kim, J.; Piao, Y.; Hyeon, T. Chem. Soc. Rev. 2009, 38, 372. (94) Dong, W.; Li, Y.; Niu, D.; Ma, Z.; Gu, J.; Chen, Y.; Zhao, W.; Liu, X.; Liu, C.; Shi, J. Adv. Mater. 2011, 23, 5392. (95) Wang, C.; Chen, J.; Talavage, T.; Irudayaraj, J. Angew. Chem., Int. Ed. 2009, 121, 2797. (96) Lee, J.; Yang, J.; Ko, H.; Oh, S.; Kang, J.; Son, J.; Lee, K.; Lee, S. W.; Yoon, H. G.; Suh, J. S.; Huh, Y. M.; Haam, S. Adv. Funct. Mater. 2008, 18, 258. (97) Ma, M.; Chen, H.; Chen, Y.; Wang, X.; Chen, F.; Cui, X.; Shi, J. Biomaterials 2012, 33, 989. (98) Li, Z.; Yin, S.; Cheng, L.; Yang, K.; Li, Y.; Liu, Z. Adv. Funct. Mater. 2014, 24, 2312. (99) Zhou, J.; Liu, Z.; Li, F. Chem. Soc. Rev. 2012, 41, 1323. (100) Wang, F.; Liu, X. Chem. Soc. Rev. 2009, 38, 976. (101) Chatterjee, D. K.; Gnanasammandhan, M. K.; Zhang, Y. Small 2010, 6, 2781. 10933


Chemical Reviews

Review

(102) Cheng, L.; Wang, C.; Liu, Z. Nanoscale 2013, 5, 23. (103) Liu, Y.; Tu, D.; Zhu, H.; Chen, X. Chem. Soc. Rev. 2013, 42, 6924. (104) Wang, F.; Deng, R.; Wang, J.; Wang, Q.; Han, Y.; Zhu, H.; Chen, X.; Liu, X. Nat. Mater. 2011, 10, 968. (105) Cheng, L.; Yang, K.; Zhang, S.; Shao, M.; Lee, S.; Liu, Z. Nano Res. 2010, 3, 722. (106) Cheng, L.; Yang, K.; Li, Y.; Chen, J.; Wang, C.; Shao, M.; Lee, S.-T.; Liu, Z. Angew. Chem., Int. Ed. 2011, 50, 7385. (107) Cheng, L.; Yang, K.; Li, Y.; Zeng, X.; Shao, M.; Lee, S.-T.; Liu, Z. Biomaterials 2012, 33, 2215. (108) Dong, B.; Xu, S.; Sun, J.; Bi, S.; Li, D.; Bai, X.; Wang, Y.; Wang, L.; Song, H. J. Mater. Chem. 2011, 21, 6193. (109) Murphy, C. J.; Gole, A. M.; Stone, J. W.; Sisco, P. N.; Alkilany, A. M.; Goldsmith, E. C.; Baxter, S. C. Acc. Chem. Res. 2008, 41, 1721. (110) Connor, E. E.; Mwamuka, J.; Gole, A.; Murphy, C. J.; Wyatt, M. D. Small 2005, 1, 325. (111) Pan, Y.; Neuss, S.; Leifert, A.; Fischler, M.; Wen, F.; Simon, U.; Schmid, G.; Brandau, W.; Jahnen-Dechent, W. Small 2007, 3, 1941. (112) Chithrani, B. D.; Ghazani, A. A.; Chan, W. C. W. Nano Lett. 2006, 6, 662. (113) Cho, W.-S.; Cho, M.; Jeong, J.; Choi, M.; Cho, H.-Y.; Han, B. S.; Kim, S. H.; Kim, H. O.; Lim, Y. T.; Chung, B. H.; Jeong, J. Toxicol. Appl. Pharmacol. 2009, 236, 16. (114) Chen, Y.-S.; Hung, Y.-C.; Liau, I.; Huang, G. S. Nanoscale Res. Lett. 2009, 4, 858. (115) Browning, L. M.; Lee, K. J.; Huang, T.; Nallathamby, P. D.; Lowman, J. E.; Nancy Xu, X.-H. Nanoscale 2009, 1, 138. (116) Bar-Ilan, O.; Albrecht, R. M.; Fako, V. E.; Furgeson, D. Y. Small 2009, 5, 1897. (117) Chen, C. Y.; Xing, G. M.; Wang, J. X.; Zhao, Y. L.; Li, B.; Tang, J.; Jia, G.; Wang, T. C.; Sun, J.; Xing, L.; Yuan, H.; Gao, Y. X.; Meng, H.; Chen, Z.; Zhao, F.; Chai, Z. F.; Fang, X. H. Nano Lett. 2005, 5, 2050. (118) Liu, Z.; Sun, X.; Nakayama, N.; Dai, H. ACS Nano 2007, 1, 50. (119) Liu, Z.; Robinson, J. T.; Sun, X. M.; Dai, H. J. J. Am. Chem. Soc. 2008, 130, 10876. (120) Sun, X.; Liu, Z.; Welsher, K.; Robinson, J. T.; Goodwin, A.; Zaric, S.; Dai, H. Nano Res. 2008, 1, 203. (121) Liu, Z.; Chen, K.; Davis, C.; Sherlock, S.; Cao, Q.; Chen, X.; Dai, H. Cancer Res. 2008, 68, 6652. (122) Huang, P.; Xu, C.; Lin, J.; Wang, C.; Wang, X.; Zhang, C.; Zhou, X.; Guo, S.; Cui, D. Theranostics 2011, 1, 240. (123) Tian, B.; Wang, C.; Zhang, S.; Feng, L.; Liu, Z. ACS Nano 2011, 5, 7000. (124) Liu, Z.; Fan, A.; Rakhra, K.; Sherlock, S.; Goodwin, A.; Chen, X.; Yang, Q.; Felsher, D.; Dai, H. Angew. Chem., Int. Ed. 2009, 48, 7668. (125) Liu, Z.; Robinson, J. T.; Tabakman, S. M.; Yang, K.; Dai, H. Mater. Today 2011, 14, 316. (126) Liu, Z.; Tabakman, S.; Welsher, K.; Dai, H. Nano Res. 2009, 2, 85. (127) Liu, Z. A.; Yang, K.; Lee, S. T. J. Mater. Chem. 2011, 21, 586. (128) He, S.; Song, B.; Li, D.; Zhu, C.; Qi, W.; Wen, Y.; Wang, L.; Song, S.; Fang, H.; Fan, C. Adv. Funct. Mater. 2010, 20, 453. (129) Loh, K. P.; Bao, Q.; Eda, G.; Chhowalla, M. Nat. Chem. 2010, 2, 1015. (130) Tang, L. A. L.; Wang, J.; Loh, K. P. J. Am. Chem. Soc. 2010, 132, 10976. (131) Liu, Z.; Cai, W. B.; He, L. N.; Nakayama, N.; Chen, K.; Sun, X. M.; Chen, X. Y.; Dai, H. J. Nat. Nanotechnol. 2007, 2, 47. (132) Liu, Z.; Davis, C.; Cai, W.; He, L.; Chen, X.; Dai, H. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 1410. (133) Poland, C. A.; Duffin, R.; Kinloch, I.; Maynard, A.; Wallace, W. A. H.; Seaton, A.; Stone, V.; Brown, S.; MacNee, W.; Donaldson, K. Nat. Nanotechnol. 2008, 3, 423. (134) Mutlu, G. M.; Budinger, G. R. S.; Green, A. A.; Urich, D.; Soberanes, S.; Chiarella, S. E.; Alheid, G. F.; McCrimmon, D. R.; Szleifer, I.; Hersam, M. C. Nano Lett. 2010, 10, 1664.

(135) Kam, N. W. S.; O’Connell, M.; Wisdom, J. A.; Dai, H. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 11600. (136) Chakravarty, P.; Marches, R.; Zimmerman, N. S.; Swafford, A. D.-E.; Bajaj, P.; Musselman, I. H.; Pantano, P.; Draper, R. K.; Vitetta, E. S. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 8697. (137) Wang, C.-H.; Huang, Y.-J.; Chang, C.-W.; Hsu, W.-M.; Peng, C.-A. Nanotechnology 2009, 20, 315101. (138) Shao, N.; Lu, S.; Wickstrom, E.; Panchapakesan, B. Nanotechnology 2007, 18, 315101. (139) Moon, H. K.; Lee, S. H.; Choi, H. C. ACS Nano 2009, 3, 3707. (140) Burke, A.; Ding, X.; Singh, R.; Kraft, R. A.; Levi-Polyachenko, N.; Rylander, M. N.; Szot, C.; Buchanan, C.; Whitney, J.; Fisher, J.; Hatcher, H. C.; D’Agostino, R., Jr.; Kock, N. D.; Ajayan, P. M.; Carroll, D. L.; Akman, S.; Torti, F. M.; Torti, S. V. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 12897. (141) Ghosh, S.; Dutta, S.; Gomes, E.; Carroll, D.; D’Agostino, R., Jr.; Olson, J.; Guthold, M.; Gmeiner, W. H. ACS Nano 2009, 3, 2667. (142) Liu, X.; Tao, H.; Yang, K.; Zhang, S.; Lee, S.-T.; Liu, Z. Biomaterials 2011, 32, 144. (143) Robinson, J. T.; Welsher, K.; Tabakman, S. M.; Sherlock, S. P.; Wang, H.; Luong, R.; Dai, H. Nano Res. 2010, 3, 779. (144) Diao, S.; Hong, G.; Robinson, J. T.; Jiao, L.; Antaris, A. L.; Wu, J. Z.; Choi, C. L.; Dai, H. J. Am. Chem. Soc. 2012, 134, 16971. (145) Liang, C.; Diao, S.; Wang, C.; Gong, H.; Liu, T.; Hong, G.; Shi, X.; Dai, H.; Liu, Z. Adv. Mater. 2014, DOI: 10.1002/adma.201401825. (146) Georgakilas, V.; Otyepka, M.; Bourlinos, A. B.; Chandra, V.; Kim, N.; Kemp, K. C.; Hobza, P.; Zboril, R.; Kim, K. S. Chem. Rev. 2012, 112, 6156. (147) Chen, D.; Feng, H.; Li, J. Chem. Rev. 2012, 112, 6027. (148) Geim, A. K. Science 2009, 324, 1530. (149) Allen, M. J.; Tung, V. C.; Kaner, R. B. Chem. Rev. 2009, 110, 132. (150) Zhang, C.; Yuan, Y.; Zhang, S.; Wang, Y.; Liu, Z. Angew. Chem., Int. Ed. 2011, 50, 6851. (151) Liu, C.; Wang, Z.; Jia, H.; Li, Z. Chem. Commun. 2011, 47, 4661. (152) Zhou, M.; Zhai, Y.; Dong, S. Anal. Chem. 2009, 81, 5603. (153) Zhang, L.; Lu, Z.; Zhao, Q.; Huang, J.; Shen, H.; Zhang, Z. Small 2011, 7, 460. (154) Wang, Y.; Wang, K.; Zhao, J.; Liu, X.; Bu, J.; Yan, X.; Huang, R. J. Am. Chem. Soc. 2013, 135, 4799. (155) Feng, L.; Yang, X.; Shi, X.; Tan, X.; Peng, R.; Wang, J.; Liu, Z. Small 2013, 9, 1989. (156) Feng, L.; Zhang, S.; Liu, Z. Nanoscale 2011, 3, 1252. (157) Yang, K.; Zhang, S.; Zhang, G.; Sun, X.; Lee, S.-T.; Liu, Z. Nano Lett. 2010, 10, 3318. (158) Hong, H.; Yang, K.; Zhang, Y.; Engle, J. W.; Feng, L.; Yang, Y.; Nayak, T. R.; Goel, S.; Bean, J.; Theuer, C. P.; Barnhart, T. E.; Liu, Z.; Cai, W. ACS Nano 2012, 6, 2361. (159) Hong, H.; Zhang, Y.; Engle, J. W.; Nayak, T. R.; Theuer, C. P.; Nickles, R. J.; Barnhart, T. E.; Cai, W. Biomaterials 2012, 33, 4147. (160) Shi, S.; Yang, K.; Hong, H.; Valdovinos, H. F.; Nayak, T. R.; Zhang, Y.; Theuer, C. P.; Barnhart, T. E.; Liu, Z.; Cai, W. Biomaterials 2013, 34, 3002. (161) Fan, H.; Wang, L.; Zhao, K.; Li, N.; Shi, Z.; Ge, Z.; Jin, Z. Biomacromolecules 2010, 11, 2345. (162) Lee, W. C.; Lim, C. H. Y. X.; Shi, H.; Tang, L. A. L.; Wang, Y.; Lim, C. T.; Loh, K. P. ACS Nano 2011, 5, 7334. (163) Xu, Y.; Sheng, K.; Li, C.; Shi, G. ACS Nano 2010, 4, 4324. (164) Zhang, W.; Guo, Z.; Huang, D.; Liu, Z.; Guo, X.; Zhong, H. Biomaterials 2011, 32, 8555. (165) Li, M.; Yang, X.; Ren, J.; Qu, K.; Qu, X. Adv. Mater. 2012, 24, 1722. (166) Akhavan, O.; Ghaderi, E.; Emamy, H. J. Mater. Chem. 2012, 22, 20626. (167) Markovic, Z. M.; Harhaji-Trajkovic, L. M.; TodorovicMarkovic, B. M.; Kepić, D. P.; Arsikin, K. M.; Jovanović, S. P.; Pantovic, A. C.; Dramićanin, M. D.; Trajkovic, V. S. Biomaterials 2011, 32, 1121. 10934


Chemical Reviews

Review

(197) Tang, S.; Huang, X.; Zheng, N. Chem. Commun. 2011, 47, 3948. (198) Huang, X.; Tang, S.; Liu, B.; Ren, B.; Zheng, N. Adv. Mater. 2011, 23, 3420. (199) Li, Y.; Lu, W.; Huang, Q.; Li, C.; Chen, W. Nanomedicine 2010, 5, 1161. (200) Ku, G.; Zhou, M.; Song, S.; Huang, Q.; Hazle, J.; Li, C. ACS Nano 2012, 6, 7489. (201) Tian, Q.; Jiang, F.; Zou, R.; Liu, Q.; Chen, Z.; Zhu, M.; Yang, S.; Wang, J.; Wang, J.; Hu, J. ACS Nano 2011, 5, 9761. (202) Tian, Q.; Hu, J.; Zhu, Y.; Zou, R.; Chen, Z.; Yang, S.; Li, R.-W.; Su, Q.; Han, Y.; Liu, X. J. Am. Chem. Soc. 2013, 135, 8571. (203) Derfus, A. M.; Chan, W. C. W.; Bhatia, S. N. Nano Lett. 2003, 4, 11. (204) Hessel, C. M.; P. Pattani, V.; Rasch, M.; Panthani, M. G.; Koo, B.; Tunnell, J. W.; Korgel, B. A. Nano Lett. 2011, 11, 2560. (205) Li, W.; Zamani, R.; Rivera Gil, P.; Pelaz, B.; Ibáñez, M.; Cadavid, D.; Shavel, A.; Alvarez-Puebla, R. A.; Parak, W. J.; Arbiol, J.; Cabot, A. J. Am. Chem. Soc. 2013, 135, 7098. (206) Ramakrishna Matte, H. S. S.; Gomathi, A.; Manna, A. K.; Late, D. J.; Datta, R.; Pati, S. K.; Rao, C. N. R. Angew. Chem., Int. Ed. 2010, 122, 4153. (207) Zeng, Z.; Yin, Z.; Huang, X.; Li, H.; He, Q.; Lu, G.; Boey, F.; Zhang, H. Angew. Chem., Int. Ed. 2011, 50, 11093. (208) Zeng, Z.; Sun, T.; Zhu, J.; Huang, X.; Yin, Z.; Lu, G.; Fan, Z.; Yan, Q.; Hng, H. H.; Zhang, H. Angew. Chem., Int. Ed. 2012, 51, 9052. (209) Coleman, J. N.; Lotya, M.; O’Neill, A.; Bergin, S. D.; King, P. J.; Khan, U.; Young, K.; Gaucher, A.; De, S.; Smith, R. J.; Shvets, I. V.; Arora, S. K.; Stanton, G.; Kim, H.-Y.; Lee, K.; Kim, G. T.; Duesberg, G. S.; Hallam, T.; Boland, J. J.; Wang, J. J.; Donegan, J. F.; Grunlan, J. C.; Moriarty, G.; Shmeliov, A.; Nicholls, R. J.; Perkins, J. M.; Grieveson, E. M.; Theuwissen, K.; McComb, D. W.; Nellist, P. D.; Nicolosi, V. Science 2011, 331, 568. (210) Huang, X.; Zeng, Z.; Zhang, H. Chem. Soc. Rev. 2013, 42, 1934. (211) Cheng, L.; Liu, J.; Gu, X.; Gong, H.; Shi, X.; Liu, T.; Wang, C.; Wang, X.; Liu, G.; Xing, H.; Bu, W.; Sun, B.; Liu, Z. Adv. Mater. 2014, 26, 1886. (212) Liu, T.; Wang, C.; Gu, X.; Gong, H.; Cheng, L.; Shi, X.; Feng, L.; Sun, B.; Liu, Z. Adv. Mater. 2014, 26, 3433. (213) Manthiram, K.; Alivisatos, A. P. J. Am. Chem. Soc. 2012, 134, 3995. (214) Chen, Z.; Wang, Q.; Wang, H.; Zhang, L.; Song, G.; Song, L.; Hu, J.; Wang, H.; Liu, J.; Zhu, M.; Zhao, D. Adv. Mater. 2013, 25, 2095. (215) Fu, G.; Liu, W.; Feng, S.; Yue, X. Chem. Commun. 2012, 48, 11567. (216) Zheng, X.; Xing, D.; Zhou, F.; Wu, B.; Chen, W. R. Mol. Pharmaceutics 2011, 8, 447. (217) de la Zerda, A.; Bodapati, S.; Teed, R.; May, S. Y.; Tabakman, S. M.; Liu, Z.; Khuri-Yakub, B. T.; Chen, X.; Dai, H.; Gambhir, S. S. ACS Nano 2012, 6, 4694. (218) Yu, J.; Javier, D.; Yaseen, M. A.; Nitin, N.; Richards-Kortum, R.; Anvari, B.; Wong, M. S. J. Am. Chem. Soc. 2010, 132, 1929. (219) Kim, C.; Favazza, C.; Wang, L. V. Chem. Rev. 2010, 110, 2756. (220) Patel, R. H.; Wadajkar, A. S.; Patel, N. L.; Kavuri, V. C.; Nguyen, K. T.; Liu, H. J. Biomed. Opt. 2012, 17, 046003. (221) Mordon, S.; Devoisselle, J. M.; Soulie-Begu, S.; Desmettre, T. Microvasc. Res. 1998, 55, 146. (222) Saxena, V.; Sadoqi, M.; Shao, J. J. Photochem. Photobiol., B 2004, 74, 29. (223) Yaseen, M. A.; Yu, J.; Wong, M. S.; Anvari, B. Biotechnol. Prog. 2007, 23, 1431. (224) Yu, J.; Yaseen, M. A.; Anvari, B.; Wong, M. S. Chem. Mater. 2007, 19, 1277. (225) Zheng, X.; Zhou, F.; Wu, B.; Chen, W. R.; Xing, D. Mol. Pharmaceutics 2012, 9, 514. (226) Luo, S.; Zhang, E.; Su, Y.; Cheng, T.; Shi, C. Biomaterials 2011, 32, 7127.

(168) Robinson, J. T.; Tabakman, S. M.; Liang, Y.; Wang, H.; Sanchez Casalongue, H.; Vinh, D.; Dai, H. J. Am. Chem. Soc. 2011, 133, 6825. (169) Yang, K.; Wan, J.; Zhang, S.; Tian, B.; Zhang, Y.; Liu, Z. Biomatreials 2012, 33, 2206. (170) Akhavan, O.; Ghaderi, E. Small 2013, 9, 3593. (171) Kim, J.-W.; Galanzha, E. I.; Shashkov, E. V.; Moon, H.-M.; Zharov, V. P. Nat. Nanotechnol. 2009, 4, 688. (172) Wang, X.; Wang, C.; Cheng, L.; Lee, S.-T.; Liu, Z. J. Am. Chem. Soc. 2012, 134, 7414. (173) Wang, C.; Li, J.; Amatore, C.; Chen, Y.; Jiang, H.; Wang, X.-M. Angew. Chem., Int. Ed. 2011, 50, 11644. (174) Hu, S.-H.; Chen, Y.-W.; Hung, W.-T.; Chen, I. W.; Chen, S.-Y. Adv. Mater. 2012, 24, 1748. (175) Ma, X.; Tao, H.; Yang, K.; Feng, L.; Cheng, L.; Shi, X.; Li, Y.; Guo, L.; Liu, Z. Nano Res. 2012, 5, 199. (176) Chen, W.; Yi, P.; Zhang, Y.; Zhang, L.; Deng, Z.; Zhang, Z. ACS Appl. Mater. Interfaces 2011, 3, 4085. (177) Yang, K.; Hu, L.; Ma, X.; Ye, S.; Cheng, L.; Shi, X.; Li, C.; Li, Y.; Liu, Z. Adv. Mater. 2012, 24, 1868. (178) Yang, X.; Zhang, X.; Ma, Y.; Huang, Y.; Wang, Y.; Chen, Y. J. Mater. Chem. 2009, 19, 2710. (179) Shi, X.; Gong, H.; Li, Y.; Wang, C.; Cheng, L.; Liu, Z. Biomaterials 2013, 34, 4786. (180) Singh, R.; Pantarotto, D.; Lacerda, L.; Pastorin, G.; Klumpp, C.; Prato, M.; Bianco, A.; Kostarelos, K. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 3357. (181) Prencipe, G.; Tabakman, S. M.; Welsher, K.; Liu, Z.; Goodwin, A. P.; Zhang, L.; Henry, J.; Dai, H. J. J. Am. Chem. Soc. 2009, 131, 4783. (182) Warheit, D. B.; Laurence, B. R.; Reed, K. L.; Roach, D. H.; Reynolds, G. A. M.; Webb, T. R. Toxicol. Sci. 2004, 77, 117. (183) Mutlu, G. k. M.; Budinger, G. R. S.; Green, A. A.; Urich, D.; Soberanes, S.; Chiarella, S. E.; Alheid, G. F.; McCrimmon, D. R.; Szleifer, I.; Hersam, M. C. Nano Lett. 2010, 10, 1664. (184) Kagan, V. E.; Konduru, N. V.; Feng, W.; Allen, B. L.; Conroy, J.; Volkov, Y.; Vlasova, I. I.; Belikova, N. A.; Yanamala, N.; Kapralov, A.; Tyurina, Y. Y.; Shi, J.; Kisin, E. R.; Murray, A. R.; Franks, J.; Stolz, D.; Gou, P.; Klein-Seetharaman, J.; Fadeel, B.; Star, A.; Shvedova, A. A. Nat. Nanotechnol. 2010, 5, 354. (185) Poland, C. A.; Duffin, R.; Kinloch, I.; Maynard, A.; Wallace, W. A. H.; Seaton, A.; Stone, V.; Brown, S.; MacNee, W.; Donaldson, K. Nat. Nanotechnol. 2008, 3, 423. (186) Liu, Z.; Tabakman, S.; Welsher, K.; Dai, H. Nano Res. 2009, 2, 85. (187) Lam, C. W.; James, J. T.; McCluskey, R.; Hunter, R. L. Toxicol. Lett. 2004, 77, 126. (188) Warheit, D. B.; Laurence, B. R.; Reed, K. L.; Roach, D. H.; Reynolds, G. A. M.; Webb, T. R. Toxicol. Lett. 2004, 77, 117. (189) Shvedova, A. A.; Kisin, E. R.; Mercer, R.; Murray, A. R.; Johnson, V. J.; Potapovich, A. I.; Tyurina, Y. Y.; Gorelik, O.; Arepalli, S.; Schwegler-Berry, D.; Hubbs, A. F.; Antonini, J.; Evans, D. E.; Ku, B. K.; Ramsey, D.; Maynard, A.; Kagan, V. E.; Castranova, V.; Baron, P. Am. J. Physiol.: Lung Cell. Mol. Physiol. 2005, 289, 698. (190) Wang, K.; Ruan, J.; Song, H.; Zhang, J.; Wo, Y.; Guo, S.; Cui, D. Nanoscale Res. Lett. 2011, 6, 291. (191) Zhang, X.; Yin, J.; Peng, C.; Hu, W.; Zhu, Z.; Li, W.; Fan, C.; Huang, Q. Carbon 2011, 49, 986. (192) Schinwald, A.; Murphy, F. A.; Jones, A.; MacNee, W.; Donaldson, K. ACS Nano 2012, 6, 736. (193) Duch, M. C.; Budinger, G. R. S.; Liang, Y. T.; Soberanes, S.; Urich, D.; Chiarella, S. E.; Campochiaro, L. A.; Gonzalez, A.; Chandel, N. S.; Hersam, M. C.; Mutlu, G. M. Nano Lett. 2011, 11, 5201. (194) Yang, K.; Wan, J. M.; Zhang, S. A.; Zhang, Y. J.; Lee, S. T.; Liu, Z. A. ACS Nano 2011, 5, 516. (195) Yang, K.; Gong, H.; Shi, X.; Wan, J.; Zhang, Y.; Liu, Z. Biomaterials 2013, 34, 2787. (196) Huang, X.; Tang, S.; Yang, J.; Tan, Y.; Zheng, N. J. Am. Chem. Soc. 2011, 133, 15946. 10935


Chemical Reviews

Review

(259) Waldow, S. M.; Morrison, P. R.; Grossweiner, L. I. Lasers Surg. Med. 1988, 8, 510. (260) Lal, S.; Clare, S. E.; Halas, N. J. Acc. Chem. Res. 2008, 41, 1842. (261) Wu, G.; Mikhailovsky, A.; Khant, H. A.; Fu, C.; Chiu, W.; Zasadzinski, J. A. J. Am. Chem. Soc. 2008, 130, 8175. (262) Leung, S. J.; Kachur, X. M.; Bobnick, M. C.; Romanowski, M. Adv. Funct. Mater. 2011, 21, 1113. (263) Leung, S. J.; Romanowski, M. ACS Nano 2012. (264) Croissant, J.; Zink, J. I. J. Am. Chem. Soc. 2012, 134, 7628. (265) Kotaidis, V.; Plech, A. Appl. Phys. Lett. 2005, 87, 213102. (266) Lukianova-Hleb, E.; Hu, Y.; Latterini, L.; Tarpani, L.; Lee, S.; Drezek, R. A.; Hafner, J. H.; Lapotko, D. O. ACS Nano 2010, 4, 2109. (267) Angelatos, A. S.; Radt, B.; Caruso, F. J. Phys. Chem. B 2005, 109, 3071. (268) Skirtach, A. G.; Dejugnat, C.; Braun, D.; Susha, A. S.; Rogach, A. L.; Parak, W. J.; Möhwald, H.; Sukhorukov, G. B. Nano Lett. 2005, 5, 1371. (269) Skirtach, A. G.; Muñoz Javier, A.; Kreft, O.; Köhler, K.; Piera Alberola, A.; Möhwald, H.; Parak, W. J.; Sukhorukov, G. B. Angew. Chem., Int. Ed. 2006, 45, 4612. (270) Anderson, L. J. E.; Hansen, E.; Lukianova-Hleb, E. Y.; Hafner, J. H.; Lapotko, D. O. J. Controlled Release 2010, 144, 151. (271) Delcea, M.; Sternberg, N.; Yashchenok, A. M.; Georgieva, R.; Bäumler, H.; Möhwald, H.; Skirtach, A. G. ACS Nano 2012, 6, 4169. (272) Troutman, T. S.; Barton, J. K.; Romanowski, M. Adv. Mater. 2008, 20, 2604. (273) Troutman, T. S.; Leung, S. J.; Romanowski, M. Adv. Mater. 2009, 21, 2334. (274) Yavuz, M. S.; Cheng, Y.; Chen, J.; Cobley, C. M.; Zhang, Q.; Rycenga, M.; Xie, J.; Kim, C.; Song, K. H.; Schwartz, A. G.; Wang, L. V.; Xia, Y. Nat. Mater. 2009, 8, 935. (275) Zhong, Y.; Wang, C.; Cheng, L.; Meng, F.; Zhong, Z.; Liu, Z. Biomacromolecules 2013, 14, 2411. (276) Zhang, Z.; Wang, L.; Wang, J.; Jiang, X.; Li, X.; Hu, Z.; Ji, Y.; Wu, X.; Chen, C. Adv. Mater. 2012, 24, 1418. (277) Wang, Y.; Wang, K.; Zhao, J.; Liu, X.; Bu, J.; Yan, X.; Huang, R. J. Am. Chem. Soc. 2013, 135, 4799. (278) Wang, Y.; Huang, R.; Liang, G.; Zhang, Z.; Zhang, P.; Yu, S.; Kong, J. Small 2014, 10, 109. (279) Fang, W.; Yang, J.; Gong, J.; Zheng, N. Adv. Funct. Mater. 2012, 22, 842. (280) Dong, K.; Liu, Z.; Li, Z.; Ren, J.; Qu, X. Adv. Mater. 2013, 25, 4452. (281) Wu, W.; Shen, J.; Banerjee, P.; Zhou, S. Biomaterials 2010, 31, 7555. (282) Yang, X.; Liu, X.; Liu, Z.; Pu, F.; Ren, J.; Qu, X. Adv. Mater. 2012, 24, 2890. (283) Luo, Y.-L.; Shiao, Y.-S.; Huang, Y.-F. ACS Nano 2011, 5, 7796. (284) Braun, G. B.; Pallaoro, A.; Wu, G.; Missirlis, D.; Zasadzinski, J. A.; Tirrell, M.; Reich, N. O. ACS Nano 2009, 3, 2007. (285) Chen, C.-C.; Lin, Y.-P.; Wang, C.-W.; Tzeng, H.-C.; Wu, C.H.; Chen, Y.-C.; Chen, C.-P.; Chen, L.-C.; Wu, Y.-C. J. Am. Chem. Soc. 2006, 128, 3709. (286) Chithrani, B. D.; Chan, W. C. W. Nano Lett. 2007, 7, 1542. (287) Gratton, S. E. A.; Ropp, P. A.; Pohlhaus, P. D.; Luft, J. C.; Madden, V. J.; Napier, M. E.; DeSimone, J. M. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 11613. (288) Kam, N. W. S.; Liu, Z.; Dai, H. Angew. Chem., Int. Ed. 2006, 118, 591. (289) Hong, G.; Wu, J. Z.; Robinson, J. T.; Wang, H.; Zhang, B.; Dai, H. Nat. Commun. 2012, 3, 700. (290) Sherlock, S. P.; Tabakman, S. M.; Xie, L.; Dai, H. ACS Nano 2011, 5, 1505. (291) Feng, L.; Yang, X.; Shi, X.; Tan, X.; Peng, R.; Wang, J.; Liu, Z. Small 2013, 9, 1989. (292) Shi, S.; Zhu, X.; Zhao, Z.; Fang, W.; Chen, M.; Huang, Y.; Chen, X. J. Mater. Chem. B 2013, 1, 1133. (293) Kim, H.; Kim, W. J. Small 2014, 10, 117.

(227) Zhang, C.; Wang, S.; Xiao, J.; Tan, X.; Zhu, Y.; Su, Y.; Cheng, T.; Shi, C. Biomaterials 2010, 31, 1911. (228) Zhang, C.; Liu, T.; Su, Y.; Luo, S.; Zhu, Y.; Tan, X.; Fan, S.; Zhang, L.; Zhou, Y.; Cheng, T. Biomaterials 2010, 31, 6612. (229) Luo, S.; Tan, X.; Qi, Q.; Guo, Q.; Ran, X.; Zhang, L.; Zhang, E.; Liang, Y.; Weng, L.; Zheng, H.; Cheng, T.; Su, Y.; Shi, C. Biomaterials 2013, 34, 2244. (230) Peng, C.-L.; Shih, Y.-H.; Lee, P.-C.; Hsieh, T. M.-H.; Luo, T.Y.; Shieh, M.-J. ACS Nano 2011, 5, 5594. (231) Song, X.; Gong, H.; Liu, T.; Cheng, L.; Wang, C.; Sun, X.; Liang, C.; Liu, Z. Small 2014, DOI: 10.1002/smll.201401025. (232) Chen, Q.; Wang, C.; Zhan, Z.; He, W.; Cheng, Z.; Li, Y.; Liu, Z. Biomaterials 2014, 35, 8206. (233) Cheng, Y.-J.; Yang, S.-H.; Hsu, C.-S. Chem. Rev. 2009, 109, 5868. (234) Zhan, X.; Zhu, D. Polym. Chem. 2010, 1, 409. (235) Burroughes, J. H.; Bradley, D. D. C.; Brown, A. R.; Marks, R. N.; Mackay, K.; Friend, R. H.; Burns, P. L.; Holmes, A. B. Nature 1990, 347, 539. (236) Yang, J.; Choi, J.; Bang, D.; Kim, E.; Lim, E.-K.; Park, H.; Suh, J.-S.; Lee, K.; Yoo, K.-H.; Kim, E.-K.; Huh, Y.-M.; Haam, S. Angew. Chem., Int. Ed. 2011, 50, 441. (237) Zha, Z.; Yue, X.; Ren, Q.; Dai, Z. Adv. Mater. 2013, 25, 777. (238) MacNeill, C. M.; Coffin, R. C.; Carroll, D. L.; LeviPolyachenko, N. H. Macromol. Biosci. 2013, 13, 28. (239) George, P. M.; Lyckman, A. W.; LaVan, D. A.; Hegde, A.; Leung, Y.; Avasare, R.; Testa, C.; Alexander, P. M.; Langer, R.; Sur, M. Biomaterials 2005, 26, 3511. (240) Ramanaviciene, A.; Kausaite, A.; Tautkus, S.; Ramanavicius, A. J. Pharm. Pharmacol. 2007, 59, 311. (241) Au, K. M.; Lu, Z.; Matcher, S. J.; Armes, S. P. Adv. Mater. 2011, 23, 5792. (242) Chen, M.; Fang, X.; Tang, S.; Zheng, N. Chem. Commun. 2012, 48, 8934. (243) Ng, K. K.; Lovell, J. F.; Vedadi, A.; Hajian, T.; Zheng, G. ACS Nano 2013, 7, 3484. (244) Jin, C. S.; Lovell, J. F.; Chen, J.; Zheng, G. ACS Nano 2013, 7, 2541. (245) Liu, T. W.; MacDonald, T. D.; Shi, J.; Wilson, B. C.; Zheng, G. Angew. Chem., Int. Ed. 2012, 51, 13128. (246) Liu, Y.; Ai, K.; Liu, J.; Deng, M.; He, Y.; Lu, L. Adv. Mater. 2013, 25, 1353. (247) Calgüneri, M.; Pay, S.; Calişkaner, Z.; Apraş, S.; Kiraz, S.; Ertenli, I.; Cobankara, V. Clin. Exp. Rheumatol. 1999, 17, 699. (248) O’Shaughnessy, J.; Miles, D.; Vukelja, S.; Moiseyenko, V.; Ayoub, J. P.; Cervantes, G.; Fumoleau, P.; Jones, S.; Lui, W. Y.; Mauriac, L.; Twelves, C.; Van Hazel, G.; Verma, S.; Leonard, R. J. Clin. Oncol. 2002, 20, 2812. (249) Rosenberg, S. A.; Lotze, M. T.; Yang, J. C.; Linehan, W. M.; Seipp, C.; Calabro, S.; Karp, S. E.; Sherry, R. M.; Steinberg, S.; White, D. E. J. Clin. Oncol. 1989, 7, 1863. (250) Coley, H. M. Cancer Treat. Rev. 2008, 34, 378. (251) Fidler, I. J. Nat. Rev. Cancer 2003, 3, 453. (252) Sargent, D. J.; Wieand, H. S.; Haller, D. G.; Gray, R.; Benedetti, J. K.; Buyse, M.; Labianca, R.; Seitz, J. F.; O’Callaghan, C. J.; Francini, G.; Grothey, A.; O’Connell, M.; Catalano, P. J.; Blanke, C. D.; Kerr, D.; Green, E.; Wolmark, N.; Andre, T.; Goldberg, R. M.; De Gramont, A. J. Clin. Oncol. 2005, 23, 8664. (253) Lee, S.-M.; Kim, H. J.; Ha, Y.-J.; Park, Y. N.; Lee, S.-K.; Park, Y.-B.; Yoo, K.-H. ACS Nano 2012, 7, 57. (254) Kah, J. C. Y.; Wan, R. C. Y.; Wong, K. Y.; Mhaisalkar, S.; Sheppard, C. J. R.; Olivo, M. Lasers Surg. Med. 2008, 40, 584. (255) Chen, W.; Carubelli, R.; Liu, H.; Nordquist, R. Mol. Biotechnol. 2003, 25, 37. (256) Sherlock, S.; Dai, H. Nano Res. 2011, 4, 1248. (257) Matsushita-Ishiodori, Y.; Ohtsuki, T. Acc. Chem. Res. 2012, 45, 1039. (258) Melancon, M. P.; Zhou, M.; Li, C. Acc. Chem. Res. 2011, 44, 947. 10936


Chemical Reviews

Review

(294) Lukianova-Hleb, E. Y.; Belyanin, A.; Kashinath, S.; Wu, X.; Lapotko, D. O. Biomaterials 2012, 33, 1821. (295) Lukianova-Hleb, E. Y.; Mutonga, M. B. G.; Lapotko, D. O. ACS Nano 2012, 6, 10973. (296) Lukianova-Hleb, E. Y.; Ren, X.; Zasadzinski, J. A.; Wu, X.; Lapotko, D. O. Adv. Mater. 2012, 24, 3831. (297) Lukianova-Hleb, E. Y.; Samaniego, A. P.; Wen, J.; Metelitsa, L. S.; Chang, C.-C.; Lapotko, D. O. J. Controlled Release 2011, 152, 286. (298) Zhang, Z.; Wang, J.; Chen, C. Adv. Mater. 2013, 25, 3869. (299) Dreaden, E. C.; Mackey, M. A.; Huang, X.; Kang, B.; El-Sayed, M. A. Chem. Soc. Rev. 2011, 40, 3391. (300) Ghosh, P.; Han, G.; De, M.; Kim, C. K.; Rotello, V. M. Adv. Drug Delivery Rev. 2008, 60, 1307. (301) Sperling, R. A.; Rivera Gil, P.; Zhang, F.; Zanella, M.; Parak, W. J. Chem. Soc. Rev. 2008, 37, 1896. (302) You, J.-O.; Guo, P.; Auguste, D. T. Angew. Chem., Int. Ed. 2013, 52, 4141. (303) Alkilany, A. M.; Thompson, L. B.; Boulos, S. P.; Sisco, P. N.; Murphy, C. J. Adv. Drug Delivery Rev. 2012, 64, 190. (304) Chang, Y.-T.; Liao, P.-Y.; Sheu, H.-S.; Tseng, Y.-J.; Cheng, F.Y.; Yeh, C.-S. Adv. Mater. 2012, 24, 3309. (305) Yang, J.; Shen, D.; Zhou, L.; Li, W.; Li, X.; Yao, C.; Wang, R.; El-Toni, A. M.; Zhang, F.; Zhao, D. Chem. Mater. 2013, 25, 3030. (306) Huang, P.; Bao, L.; Zhang, C.; Lin, J.; Luo, T.; Yang, D.; He, M.; Li, Z.; Gao, G.; Gao, B.; Fu, S.; Cui, D. Biomaterials 2011, 32, 9796. (307) Yang, X.; Liu, Z.; Li, Z.; Pu, F.; Ren, J.; Qu, X. Chem.Eur. J. 2013, 19, 10388. (308) Shen, S.; Tang, H.; Zhang, X.; Ren, J.; Pang, Z.; Wang, D.; Gao, H.; Qian, Y.; Jiang, X.; Yang, W. Biomaterials 2013, 34, 3150. (309) Kim, A. R.; Shin, S. W.; Cho, S.-W.; Lee, J. Y.; Kim, D.-I.; Um, S. H. Adv. Healthcare Mater. 2013, 2, 1252. (310) Cheng, F.-Y.; Su, C.-H.; Wu, P.-C.; Yeh, C.-S. Chem. Commun. 2010, 46, 3167. (311) Yang, J.; Lee, J.; Kang, J.; Oh, S. J.; Ko, H.-J.; Son, J.-H.; Lee, K.; Suh, J.-S.; Huh, Y.-M.; Haam, S. Adv. Mater. 2009, 21, 4339. (312) Lee, S.-M.; Park, H.; Yoo, K.-H. Adv. Mater. 2010, 22, 4049. (313) Liu, H.; Chen, D.; Li, L.; Liu, T.; Tan, L.; Wu, X.; Tang, F. Angew. Chem., Int. Ed. 2011, 123, 921. (314) Liu, H.; Liu, T.; Wu, X.; Li, L.; Tan, L.; Chen, D.; Tang, F. Adv. Mater. 2012, 24, 755. (315) You, J.; Zhang, G.; Li, C. ACS Nano 2010, 4, 1033. (316) Melancon, M. P.; Lu, W.; Yang, Z.; Zhang, R.; Cheng, Z.; Elliot, A. M.; Stafford, J.; Olson, T.; Zhang, J. Z.; Li, C. Mol. Cancer Ther. 2008, 7, 1730. (317) Zhang, J. Z. J. Phys. Chem. Lett. 2010, 1, 686. (318) You, J.; Shao, R.; Wei, X.; Gupta, S.; Li, C. Small 2010, 6, 1022. (319) You, J.; Zhang, R.; Xiong, C.; Zhong, M.; Melancon, M.; Gupta, S.; Nick, A. M.; Sood, A. K.; Li, C. Cancer Res. 2012, 72, 4777. (320) You, J.; Zhang, R.; Zhang, G.; Zhong, M.; Liu, Y.; Van Pelt, C. S.; Liang, D.; Wei, W.; Sood, A. K.; Li, C. J. Controlled Release 2012, 158, 319. (321) Yang, H.-W.; Lu, Y.-J.; Lin, K.-J.; Hsu, S.-C.; Huang, C.-Y.; She, S.-H.; Liu, H.-L.; Lin, C.-W.; Xiao, M.-C.; Wey, S.-P.; Chen, P.-Y.; Yen, T.-C.; Wei, K.-C.; Ma, C.-C. M. Biomaterials 2013, 34, 7204. (322) Zha, Z.; Zhang, S.; Deng, Z.; Li, Y.; Li, C.; Dai, Z. Chem. Commun. 2013, 49, 3455. (323) Song, G.; Wang, Q.; Wang, Y.; Lv, G.; Li, C.; Zou, R.; Chen, Z.; Qin, Z.; Huo, K.; Hu, R.; Hu, J. Adv. Funct. Mater. 2013, 23, 4281. (324) Gong, H.; Cheng, L.; Xiang, J.; Xu, H.; Feng, L.; Shi, X.; Liu, Z. Adv. Funct. Mater. 2013, 23, 6059. (325) Wang, C.; Xu, H.; Liang, C.; Liu, Y.; Li, Z.; Yang, G.; Cheng, L.; Li, Y.; Liu, Z. ACS Nano 2013, 7, 6782. (326) Zheng, M.; Yue, C.; Ma, Y.; Gong, P.; Zhao, P.; Zheng, C.; Sheng, Z.; Zhang, P.; Wang, Z.; Cai, L. ACS Nano 2013, 7, 2056. (327) Castano, A. P.; Mroz, P.; Hamblin, M. R. Nat. Rev. Cancer 2006, 6, 535. (328) Moan, J.; Peng, Q. Anticancer Res. 2003, 23, 3591.

(329) 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.; Korbelik, M.; Moan, J.; Mroz, P.; Nowis, D.; Piette, J.; Wilson, B. C.; Golab, J. Ca-Cancer J. Clin. 2011, 61, 250. (330) Dougherty, T. J.; Gomer, C. J.; Henderson, B. W.; Jori, G.; Kessel, D.; Korbelik, M.; Moan, J.; Peng, Q. J. Natl. Cancer Inst. 1998, 90, 889. (331) Dolmans, D. E.; Fukumura, D.; Jain, R. K. Nat. Rev. Cancer 2003, 3, 380. (332) Lovell, J. F.; Liu, T. W. B.; Chen, J.; Zheng, G. Chem. Rev. 2010, 110, 2839. (333) Li, W. T. Handb. Biophotonics 2013, DOI: 10.1002/ 9783527643981.bphot030. (334) Bechet, D.; Couleaud, P.; Frochot, C.; Viriot, M. L.; Guillemin, F.; Barberi-Heyob, M. Trends Biotechnol. 2008, 26, 612. (335) Yoon, H. J.; Jang, W. D. J. Porphyrins Phthalocyanines 2013, 17, 16. (336) Vanderesse, R.; Frochot, C.; Barberi-Heyob, M.; Richeter, S.; Raehm, L.; Durand, J.-O. Intracellular Delivery; Springer: New York, 2011; p 511. (337) Vargas, A.; Eid, M.; Fanchaouy, M.; Gurny, R.; Delie, F. Eur. J. Pharm. Biopharm. 2008, 69, 43. (338) Torchilin, V. P. Nat. Rev. Drug Discovery 2005, 4, 145. (339) Bala, I.; Hariharan, S.; Kumar, M. N. V. R. Crit. Rev. Ther. Drug Carrier Syst. 2004, 21, 387. (340) Gillies, E. R.; Frechet, J. M. J. Drug Discovery Today 2005, 10, 35. (341) Huang, Y.-Y.; Sharma, S. K.; Dai, T.; Chung, H.; Yaroslavsky, A.; Garcia-Diaz, M.; Chang, J.; Chiang, L. Y.; Hamblin, M. R. Nanotechnol. Rev. 2012, 1, 111. (342) van Nostrum, C. F. Adv. Drug Delivery Rev. 2004, 56, 9. (343) Derycke, A. S. L.; de Witte, P. A. M. Adv. Drug Delivery Rev. 2004, 56, 17. (344) Dragicevic-Curic, N.; Fahr, A. Expert Opin. Drug Delivery 2012, 9, 1015. (345) Zacks, D. N.; Ezra, E.; Terada, Y.; Michaud, N.; Connolly, E.; Gragoudas, E. S.; Miller, J. W. Invest. Ophthalmol. Visual Sci. 2002, 43, 2384. (346) Kabanov, A. V.; Batrakova, E. V.; Alakhov, V. Y. J. Controlled Release 2002, 82, 189. (347) Zhang, J. X.; Hansen, C. B.; Allen, T. M.; Boey, A.; Boch, R. J. Controlled Release 2003, 86, 323. (348) Zhang, G.-D.; Nishiyama, N.; Harada, A.; Jiang, D.-L.; Aida, T.; Kataoka, K. Macromolecules 2003, 36, 1304. (349) Le Garrec, D.; Taillefer, J.; Van Lier, J.; Lenaerts, V.; Leroux, J.C. J. Drug Targeting 2002, 10, 429. (350) Yamazaki, A.; Winnik, F. M.; Cornelius, R. M.; Brash, J. L. Biochim. Biophys. Acta, Biomembr. 1999, 1421, 103. (351) Li, B. H.; Moriyama, E. H.; Li, F. G.; Jarvi, M. T.; Allen, C.; Wilson, B. C. Photochem. Photobiol. 2007, 83, 1505. (352) Master, A. M.; Rodriguez, M. E.; Kenney, M. E.; Oleinick, N. L.; Sen Gupta, A. J. Pharm. Sci. 2010, 99, 2386. (353) Peng, C. L.; Shieh, M. J.; Tsai, M. H.; Chang, C. C.; Lai, P. S. Biomaterials 2008, 29, 3599. (354) Knop, K.; Mingotaud, A. F.; El-Akra, N.; Violleau, F.; Souchard, J. P. Photochem. Photobiol. Sci. 2009, 8, 396. (355) Roby, A.; Erdogan, S.; Torchilin, V. P. Cancer Biol. Ther. 2007, 6, 1136. (356) Duncan, R. Nat. Rev. Cancer 2006, 6, 688. (357) MaHam, A.; Tang, Z. W.; Wu, H.; Wang, J.; Lin, Y. H. Small 2009, 5, 1706. (358) Yoon, H. Y.; Koo, H.; Choi, K. Y.; Lee, S. J.; Kim, K.; Kwon, I. C.; Leary, J. F.; Park, K.; Yuk, S. H.; Park, J. H.; Choi, K. Biomaterials 2012, 33, 3980. (359) Zhen, Z.; Tang, W.; Guo, C.; Chen, H.; Lin, X.; Liu, G.; Fei, B.; Chen, X.; Xu, B.; Xie, J. ACS Nano 2013, 7, 6988. (360) Nishiyama, N.; Nakagishi, Y.; Morimoto, Y.; Lai, P. S.; Miyazaki, K.; Urano, K.; Horie, S.; Kumagai, M.; Fukushima, S.; 10937


Chemical Reviews

Review

Cheng, Y.; Jang, W. D.; Kikuchi, M.; Kataoka, K. J. Controlled Release 2009, 133, 245. (361) Bedard, M. F.; Sadasivan, S.; Sukhorukov, G. B.; Skirtach, A. J. Mater. Chem. 2009, 19, 2226. (362) Hota, R.; Baek, K.; Yun, G.; Kim, Y.; Jung, H.; Park, K. M.; Yoon, E.; Joo, T.; Kang, J.; Park, C. G.; Bae, S. M.; Ahn, W. S.; Kim, K. Chem. Sci. 2013, 4, 339. (363) Vivero-Escoto, J. L.; Huxford-Phillips, R. C.; Lin, W. B. Chem. Soc. Rev. 2012, 41, 2673. (364) Couleaud, P.; Morosini, V.; Frochot, C.; Richeter, S.; Raehm, L.; Durand, J. O. Nanoscale 2010, 2, 1083. (365) Hocine, O.; Gary-Bobo, M.; Brevet, D.; Maynadier, M.; Fontanel, S.; Raehm, L.; Richeter, S.; Loock, B.; Couleaud, P.; Frochot, C.; Charnay, C.; Derrien, G.; Smaihi, M.; Sahmoune, A.; Morere, A.; Maillard, P.; Garcia, M.; Durand, J. O. Int. J. Pharm. (Amsterday, Neth.) 2010, 402, 221. (366) Yan, F.; Kopelman, R. Photochem. Photobiol. 2003, 78, 587. (367) Tang, W.; Xu, H.; Kopelman, R.; Philbert, M. A. Photochem. Photobiol. 2005, 81, 242. (368) Hulchanskyy, T. Y.; Roy, I.; Goswami, L. N.; Chen, Y.; Bergey, E. J.; Pandey, R. K.; Oseroff, A. R.; Prasad, P. N. Nano Lett. 2007, 7, 2835. (369) Zhou, J. H.; Zhou, L.; Dong, C.; Feng, Y. Y.; Wei, S. H.; Shen, J.; Wang, X. S. Mater. Lett. 2008, 62, 2910. (370) Zhou, L.; Ning, Y. W.; Wei, S. H.; Feng, Y. Y.; Zhou, J. H.; Yu, B. Y.; Shen, J. J. Mater. Sci.: Mater. Med. 2010, 21, 2095. (371) Mamaeva, V.; Sahlgren, C.; Linden, M. Adv. Drug Delivery Rev. 2013, 65, 689. (372) Gary-Bobo, M.; Mir, Y.; Rouxel, C.; Brevet, D.; Basile, I.; Maynadier, M.; Vaillant, O.; Mongin, O.; Blanchard-Desce, M.; Morere, A.; Garcia, M.; Durand, J. O.; Raehm, L. Angew. Chem., Int. Ed. 2011, 50, 11425. (373) Gary-Bobo, M.; Mir, Y.; Rouxel, C.; Brevet, D.; Basile, I.; Maynadier, M.; Vaillant, O.; Mongin, O.; Blanchard-Desce, M.; Morère, A.; Garcia, M.; Durand, J.-O.; Raehm, L. Angew. Chem., Int. Ed. 2011, 123, 11627. (374) Khlebtsov, N.; Bogatyrev, V.; Dykman, L.; Khlebtsov, B.; Staroverov, S.; Shirokov, A.; Matora, L.; Khanadeev, V.; Pylaev, T.; Tsyganova, N.; Terentyuk, G. Theranostics 2013, 3, 167. (375) Dykman, L. A.; Khlebtsov, N. G. Acta Nat. 2011, 3, 34. (376) Hone, D. C.; Walker, P. I.; Evans-Gowing, R.; FitzGerald, S.; Beeby, A.; Chambrier, I.; Cook, M. J.; Russell, D. A. Langmuir 2002, 18, 2985. (377) Cheng, Y.; C. Samia, A.; Meyers, J. D.; Panagopoulos, I.; Fei, B.; Burda, C. J. Am. Chem. Soc. 2008, 130, 10643. (378) Obaid, G.; Chambrier, I.; Cook, M. J.; Russell, D. A. Angew. Chem., Int. Ed. 2012, 51, 6158. (379) Oo, M. K. K.; Yang, X.; Du, H.; Wang, H. Nanomedicine (London, U. K.) 2008, 3, 777. (380) Oo, M. K. K.; Yang, Y. M.; Hu, Y.; Gomez, M.; Du, H.; Wang, H. J. ACS Nano 2012, 6, 1939. (381) Vankayala, R.; Sagadevan, A.; Vijayaraghavan, P.; Kuo, C. L.; Hwang, K. C. Angew. Chem., Int. Ed. 2011, 50, 10640. (382) Long, R.; Mao, K. K.; Ye, X. D.; Yan, W. S.; Huang, Y. B.; Wang, J. Y.; Fu, Y.; Wang, X. S.; Wu, X. J.; Xie, Y.; Xiong, Y. J. J. Am. Chem. Soc. 2013, 135, 3200. (383) Reddy, G. R.; Bhojani, M. S.; McConville, P.; Moody, J.; Moffat, B. A.; Hall, D. E.; Kim, G.; Koo, Y. E. L.; Woolliscroft, M. J.; Sugai, J. V.; Johnson, T. D.; Philbert, M. A.; Kopelman, R.; Rehemtulla, A.; Ross, B. D. Clin. Cancer Res. 2006, 12, 6677. (384) Lai, C. W.; Wang, Y. H.; Lai, C. H.; Yang, M. J.; Chen, C. Y.; Chou, P. T.; Chan, C. S.; Chi, Y.; Chen, Y. C.; Hsiao, J. K. Small 2008, 4, 218. (385) Zeng, L. Y.; Ren, W. Z.; Xiang, L. C.; Zheng, J. J.; Chen, B.; Wu, A. G. Nanoscale 2013, 5, 2107. (386) Huang, P.; Li, Z. M.; Lin, J.; Yang, D. P.; Gao, G.; Xu, C.; Bao, L.; Zhang, C. L.; Wang, K.; Song, H.; Hu, H. Y.; Cui, D. X. Biomaterials 2011, 32, 3447.

(387) Li, Z.; Wang, C.; Cheng, L.; Gong, H.; Yin, S.; Gong, Q.; Li, Y.; Liu, Z. Biomaterials 2013, 34, 9160. (388) Klostranec, J. M.; Chan, W. C. W. Adv. Mater. 2006, 18, 1953. (389) Biju, V.; Mundayoor, S.; Omkumar, R. V.; Anas, A.; Ishikawa, M. Biotechnol. Adv. 2010, 28, 199. (390) Zrazhevskiy, P.; Sena, M.; Gao, X. Chem. Soc. Rev. 2010, 39, 4326. (391) Probst, C. E.; Zrazhevskiy, P.; Bagalkot, V.; Gao, X. Adv. Drug Delivery Rev. 2013, 65, 703. (392) Juzenas, P.; Chen, W.; Sun, Y. P.; Coelho, M. A. N.; Generalov, R.; Generalova, N.; Christensen, I. L. Adv. Drug Delivery Rev. 2008, 60, 1600. (393) Anas, A.; Akita, H.; Harashima, H.; Itoh, T.; Ishikawa, M.; Biju, V. J. Phys. Chem. B 2008, 112, 10005. (394) Chen, J. Y.; Lee, Y. M.; Zhao, D.; Mak, N. K.; Wong, R. N. S.; Chan, W. H.; Cheung, N. H. Photochem. Photobiol. 2010, 86, 431. (395) Juzenas, P.; Generalov, R.; Juzeniene, A.; Moan, J. J. Biomed. Nanotechnol. 2008, 4, 450. (396) Tsay, J. M.; Trzoss, M.; Shi, L. X.; Kong, X. X.; Selke, M.; Jung, M. E.; Weiss, S. J. Am. Chem. Soc. 2007, 129, 6865. (397) Chen, Z. Y.; Ma, L. J.; Liu, Y.; Chen, C. Y. Theranostics 2012, 2, 238. (398) Sharma, S. K.; Chiang, L. Y.; Hamblin, M. R. Nanomedicine (London, U. K.) 2011, 6, 1813. (399) Mroz, P.; Tegos, G. P.; Gali, H.; Wharton, T.; Sarna, T.; Hamblin, M. R. Photochem. Photobiol. Sci. 2007, 6, 1139. (400) Tokuyama, H.; Yamago, S.; Nakamura, E.; Shiraki, T.; Sugiura, Y. J. Am. Chem. Soc. 1993, 115, 7918. (401) Burlaka, A. P.; Sidorik, Y. P.; Prylutska, S. V.; Matyshevska, O. P.; Golub, O. A.; Prylutskyy, Y. L.; Scharff, P. Exp. Oncol. 2004, 26, 326. (402) Yang, X. L.; Fan, C. H.; Zhu, H. S. Toxicol. In Vitro 2002, 16, 41. (403) Tabata, Y.; Murakami, Y.; Ikada, Y. Jpn. J. Cancer Res. 1997, 88, 1108. (404) Liu, J.; Ohta, S.; Sonoda, A.; Yamada, M.; Yamamoto, M.; Nitta, N.; Murata, K.; Tabata, Y. J. Controlled Release 2007, 117, 104. (405) Mroz, P.; Xia, Y.; Asanuma, D.; Konopko, A.; Zhiyentayev, T.; Huang, Y. Y.; Sharma, S. K.; Dai, T.; Khan, U. J.; Wharton, T.; Hamblin, M. R. Nanomedicine (London, U. K.) 2011, 7, 965. (406) Zhu, Z.; Tang, Z. W.; Phillips, J. A.; Yang, R. H.; Wang, H.; Tan, W. H. J. Am. Chem. Soc. 2008, 130, 10856. (407) Lee, D. J.; Park, S. Y.; Oh, Y. T.; Oh, N. M.; Oh, K. T.; Youn, Y. S.; Lee, E. S. Macromol. Res. 2011, 19, 848. (408) Shiraki, T.; Dawn, A.; Thi, N. L. L.; Tsuchiya, Y.; Tamaru, S.; Shinkai, S. Chem. Commun. 2011, 47, 7065. (409) Erbas, S.; Gorgulu, A.; Kocakusakogullari, M.; Akkaya, E. U. Chem. Commun. 2009, 4956. (410) Dong, H. Q.; Zhao, Z. L.; Wen, H. Y.; Li, Y. Y.; Guo, F. F.; Shen, A. J.; Frank, P.; Lin, C.; Shi, D. L. Sci. China: Chem. 2010, 53, 2265. (411) Huang, P.; Xu, C.; Lin, J.; Wang, C.; Wang, X. S.; Zhang, C. L.; Zhou, X. J.; Guo, S. W.; Cui, D. X. Theranostics 2011, 1, 240. (412) Zhou, L.; Wang, W.; Tang, J.; Zhou, J. H.; Jiang, H. J.; Shen, J. Chem.Eur. J. 2011, 17, 12084. (413) Li, F.; Park, S.; Ling, D.; Park, W.; Han, J. Y.; Na, K.; Char, K. J. Mater. Chem. B 2013, 1, 1678. (414) Huang, P.; Lin, J.; Wang, X. S.; Wang, Z.; Zhang, C. L.; He, M.; Wang, K.; Chen, F.; Li, Z. M.; Shen, G. X.; Cui, D. X.; Chen, X. Y. Adv. Mater. 2012, 24, 5104. (415) Markovic, Z. M.; Ristic, B. Z.; Arsikin, K. M.; Klisic, D. G.; Harhaji-Trajkovic, L. M.; Todorovic-Markovic, B. M.; Kepic, D. P.; Kravic-Stevovic, T. K.; Jovanovic, S. P.; Milenkovic, M. M.; Milivojevic, D. D.; Bumbasirevic, V. Z.; Dramicanin, M. D.; Trajkovic, V. S. Biomaterials 2012, 33, 7084. (416) Gao, L.; Fei, J. B.; Zhao, J.; Li, H.; Cui, Y.; Li, J. B. ACS Nano 2012, 6, 8030. 10938


Chemical Reviews

Review

(417) Cheng, S. H.; Hsieh, C. C.; Chen, N. T.; Chu, C. H.; Huang, C. M.; Chou, P. T.; Tseng, F. G.; Yang, C. S.; Mou, C. Y.; Lo, L. W. Nano Today 2011, 6, 552. (418) Weissleder, R. Nat. Rev. Cancer 2002, 2, 11. (419) Chapman, D.; Thomlinson, W.; Johnston, R.; Washburn, D.; Pisano, E.; Gmür, N.; Zhong, Z.; Menk, R.; Arfelli, F.; Sayers, D. Phys. Med. Biol. 1997, 42, 2015. (420) Liu, Y. F.; Chen, W.; Wang, S. P.; Joly, A. G. Appl. Phys. Lett. 2008, 92, 043901. (421) Chen, W.; Zhang, J. J. Nanosci. Nanotechnol. 2006, 6, 1159. (422) Hsu, C. Y.; Chen, C. W.; Yu, H. P.; Lin, Y. F.; Lai, P. S. Biomaterials 2013, 34, 1204. (423) Zhou, J.; Liu, Z.; Li, F. Y. Chem. Soc. Rev. 2012, 41, 1323. (424) Wang, C.; Cheng, L.; Liu, Z. Theranostics 2013, 3, 317. (425) Wang, F.; Han, Y.; Lim, C. S.; Lu, Y.; Wang, J.; Xu, J.; Chen, H.; Zhang, C.; Hong, M.; Liu, X. Nature 2010, 463, 1061. (426) Gai, S.; Yang, P.; Li, C.; Wang, W.; Dai, Y.; Niu, N.; Lin, J. Adv. Funct. Mater. 2010, 20, 1166. (427) Chen, F.; Bu, W.; Zhang, S.; Liu, X.; Liu, J.; Xing, H.; Xiao, Q.; Zhou, L.; Peng, W.; Wang, L.; Shi, J. Adv. Funct. Mater. 2011, 21, 4285. (428) Zhang, F.; Braun, G. B.; Pallaoro, A.; Zhang, Y.; Shi, Y.; Cui, D.; Moskovits, M.; Zhao, D.; Stucky, G. D. Nano Lett. 2011, 12, 61. (429) Huang, P.; Li, Z.; Lin, J.; Yang, D.; Gao, G.; Xu, C.; Bao, L.; Zhang, C.; Wang, K.; Song, H.; Hu, H.; Cui, D. Biomaterials 2011, 32, 3447. (430) Idris, N. M.; Gnanasammandhan, M. K.; Zhang, J.; Ho, P. C.; Mahendran, R.; Zhang, Y. Nat. Med. 2012, 15, 1580. (431) Liu, K.; Liu, X.; Zeng, Q.; Zhang, Y.; Tu, L.; Liu, T.; Kong, X.; Wang, Y.; Cao, F.; Lambrechts, S. A.; Aalders, M. C.; Zhang, H. ACS Nano 2012, 6, 4054. (432) Park, S.; Hu, Y.; Hwang, J. O.; Lee, E. S.; Casabianca, L. B.; Cai, W.; Potts, J. R.; Ha, H. W.; Chen, S.; Oh, J.; Kim, S. O.; Kim, Y. H.; Ishii, Y.; Ruoff, R. S. Nat. Commun. 2012, 3, 638. (433) Cui, S. S.; Chen, H. Y.; Zhu, H. Y.; Tian, J. M.; Chi, X. M.; Qian, Z. Y.; Achilefu, S.; Gu, Y. Q. J. Mater. Chem. 2012, 22, 4861. (434) Wang, C.; Cheng, L.; Liu, Y. M.; Wang, X. J.; Ma, X. X.; Deng, Z. Y.; Li, Y. G.; Liu, Z. Adv. Funct. Mater. 2013, 23, 3077. (435) Cui, S. S.; Yin, D. Y.; Chen, Y. Q.; Di, Y. F.; Chen, H. Y.; Ma, Y. X.; Achilefu, S.; Gu, Y. Q. ACS Nano 2013, 7, 676. (436) Chen, Q.; Wang, C.; Cheng, L.; He, W.; Cheng, Z.; Liu, Z. Biomaterials 2014, 35, 2915. (437) Wang, F.; Deng, R. R.; Wang, J.; Wang, Q. X.; Han, Y.; Zhu, H. M.; Chen, X. Y.; Liu, X. G. Nat. Mater. 2011, 10, 968. (438) Wang, Y.-F.; Liu, G.-Y.; Sun, L.-D.; Xiao, J.-W.; Zhou, J.-C.; Yan, C.-H. ACS Nano 2013, 7, 7200. (439) Liu, Q.; Yin, B. R.; Yang, T. S.; Yang, Y. C.; Shen, Z.; Yao, P.; Li, F. Y. J. Am. Chem. Soc. 2013, 135, 5029. (440) Jalil, R. A.; Zhang, Y. Biomaterials 2008, 29, 4122. (441) Xiong, L. Q.; Yang, T. S.; Yang, Y.; Xu, C. J.; Li, F. Y. Biomaterials 2010, 31, 7078. (442) Cheng, L.; Yang, K.; Shao, M. W.; Lu, X. H.; Liu, Z. Nanomedicine (London, U. K.) 2011, 6, 1327. (443) Nahabedian, M. Y.; Cohen, R. A.; Contino, M. F.; Terem, T. M.; Wright, W. H.; Berns, M. W.; Wile, A. G. J. Natl. Cancer Inst. 1988, 80, 739. (444) Matthew Peterson, C.; Lu, J. M.; Sun, Y.; Anthony Peterson, C.; Shiah, J.-G.; Straight, R. C.; Kopeček, J. Cancer Res. 1996, 56, 3980. (445) Kopeček, J.; Kopečková, P.; Minko, T.; Lu, Z. R.; Peterson, C. M. J. Controlled Release 2001, 74, 147. (446) Conte, C.; Ungaro, F.; Maglio, G.; Tirino, P.; Siracusano, G.; Sciortino, M. T.; Leone, N.; Palma, G.; Barbieri, A.; Arra, C.; Mazzaglia, A.; Quaglia, F. J. Controlled Release 2013, 167, 40. (447) Shiah, J. G.; Sun, Y.; Kopečková, P.; Peterson, C. M.; Straight, R. C.; Kopeček, J. J. Controlled Release 2001, 74, 249. (448) Peng, C.-L.; Shieh, M.-J.; Tsai, M.-H.; Chang, C.-C.; Lai, P.-S. Biomaterials 2008, 29, 3599. (449) Khdair, A.; Di, C.; Patil, Y.; Ma, L.; Dou, Q. P.; Shekhar, M. P. V.; Panyam, J. J. Controlled Release 2010, 141, 137.

(450) Miao, W.; Shim, G.; Lee, S.; Lee, S.; Choe, Y. S.; Oh, Y.-K. Biomaterials 2013, 34, 3402. (451) Wang, T.; Zhang, L.; Su, Z.; Wang, C.; Liao, Y.; Fu, Q. ACS Appl. Mater. Interfaces 2011, 3, 2479. (452) Wang, C.; Sun, X.; Cheng, L.; Yin, S.; Yang, G.; Li, Y.; Liu, Z. Adv. Mater. 2014, 26, 4794. (453) Kuo, W.-S.; Chang, C.-N.; Chang, Y.-T.; Yang, M.-H.; Chien, Y.-H.; Chen, S.-J.; Yeh, C.-S. Angew. Chem., Int. Ed. 2010, 122, 2771. (454) Sahu, A.; Choi, W. I.; Lee, J. H.; Tae, G. Biomaterials 2013, 34, 6239. (455) Wang, Y.; Wang, H.; Liu, D.; Song, S.; Wang, X.; Zhang, H. Biomaterials 2013, 34, 7715. (456) Wang, J.; Zhu, G.; You, M.; Song, E.; Shukoor, M. I.; Zhang, K.; Altman, M. B.; Chen, Y.; Zhu, Z.; Huang, C. Z.; Tan, W. ACS Nano 2012, 6, 5070. (457) Jang, B.; Park, J.-Y.; Tung, C.-H.; Kim, I.-H.; Choi, Y. ACS Nano 2011, 5, 1086. (458) Zhang, M.; Murakami, T.; Ajima, K.; Tsuchida, K.; Sandanayaka, A. S. D.; Ito, O.; Iijima, S.; Yudasaka, M. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 14773. (459) Chen, R.; Zheng, X.; Qian, H.; Wang, X.; Wang, J.; Jiang, X. Biomater. Sci. 2013, 1, 285. (460) Wang, S.; Huang, P.; Nie, L.; Xing, R.; Liu, D.; Wang, Z.; Lin, J.; Chen, S.; Niu, G.; Lu, G.; Chen, X. Adv. Mater. 2013, 25, 3055. (461) Gao, L.; Fei, J.; Zhao, J.; Li, H.; Cui, Y.; Li, J. ACS Nano 2012, 6, 8030. (462) Peng, J.; Zhao, L.; Zhu, X.; Sun, Y.; Feng, W.; Gao, Y.; Wang, L.; Li, F. Biomaterials 2013, 34, 7905.

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