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Cite This: Acc. Chem. Res. 2017, 50, 2529-2538

Design and Functionalization of the NIR-Responsive Photothermal Semiconductor Nanomaterials for Cancer Theranostics Xiaojuan Huang,† Wenlong Zhang,† Guoqiang Guan,† Guosheng Song,‡ Rujia Zou,*,† and Junqing Hu*,† †

State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, China ‡ Department of Radiology, School of Medicine, Stanford University, Stanford, California 94305, United States CONSPECTUS: Despite the development of medical technology, cancer still remains a great threat to the survival of people all over the world. Photothermal therapy (PTT) is a minimally invasive method for selective photothermal ablation of cancer cells without damages to normal cells. Recently, copper chalcogenide semiconductors have emerged as a promising photothermal agent attributed to strong absorbance in the near-infrared (NIR) region and high photothermal conversion efficiency. An earlier study witnessed a rapid increase in their development for cancer therapy, including CuS, Cu2−xSe and CuTe nanocrystals. However, a barrier is that the minimum laser power intensity for effective PTT is still significantly higher than the conservative limit for human skin exposure. Improving the photothermal conversion efficiency and reducing the laser power density has become a direction for the development of PTT. Furthermore, in an effort to improve the therapeutic efficacy, many multimode therapeutic nanostuctures have been formulated by integrating the photothermal agents with antitumor drugs, photosensitizers, or radiosensitizers, resulting in a synergistic effect. Various functional materials also have been absorbed, attached, encapsulated, or coated on the photothermal nanostructures, including fluorescence, computed tomography, magnetic resonance imaging, realizing cancer diagnosis, tumor location, site-specific therapy, and evaluation of therapeutic responses via incorporation of diagnosis and treatment. In this Account, we present an overview of the NIR-responsive photothermal semiconductor nanomaterials for cancer theranostics with a focus on their design and functionalization based on our own work. Our group has developed a series of chalcogenides with greatly improved NIR photoabsorption as photothermal agents, allowing laser exposure within regulatory limits. We also investigated the photothermal bioapplications of hypotoxic oxides including WO3−x, MoO3−x, and RuO2, expanding their applications into a new field of photothermal materials. Furthermore, considering a much more enhanced therapeutic effect of multifunctional nanoagents, our group elaborately designed many nanocomposites, such as core−shell nanoparticles of Fe3O4@Cu2−xS and Cu9S5@mSiO2, based on the integration of photothermal agents with contrast agents or other anticancer medicines, achieving cancer theranostic and synergistic treatment. Ternary compound nanocrystals were also prepared with synthetic simplicity for multimodal imaging-guided therapy for cancer. This Account summarizes our past work, including the design and concept, synthesis, and characterization for in vitro and in vivo applications. Then, we analyzed the tendencies of the NIR-responsive photothermal semiconductor nanomaterials for clinical applications, highlighting their prospects and challenges. We believe that the photothermal technology from the NIR-responsive photothermal semiconductor nanomaterials would promote cancer theranostics to result in giant strides forward in the future.

1. INTRODUCTION Cancer is a serious disease that challenges the survival of people across the world. As indicated by the American Cancer Society, there are 1,688,780 new cancer cases and 600,920 cancer deaths projected to occur in the United States only in 2017, and it is estimated that the number of new cancer cases increase approximately 70% within the next two decades from 14 million in 2012 worldwide.1,2 Therefore, cancer treatment lies at the forefront of all human concern. Traditional methods for cancer treatment mainly include chemotherapy, radiotherapy (RT), and surgery. However, these treatments have high potential for collateral damages to healthy cells and tissues because of their nonspecificity and excessive radiation. © 2017 American Chemical Society

Furthermore, multidrug resistance and cancer metastasis of patients during the treatment period are hard to avoid. As a result, the final therapeutic effects are not sufficient. Exploring an alternative or supplementary approach with both precise tumor localization and effective destruction is imperative. Photothermal therapy (PTT), as a method of physiotherapy, has obtained immense popularity. It is where a photothermal agent is employed to absorb light-energy and then transform it to heat at the tumor site, thereby killing cancer cells via hyperthermia (40−45 °C) or thermal ablation (>45 °C),3 Received: June 12, 2017 Published: October 3, 2017 2529

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Figure 1. Our progress in the NIR-responsive photothermal semiconductor nanomaterials for cancer theranostics.

Adapted with permission from ref 14. Copyright 2011, Wiley.

Figure 2. (a) Schematic representation of a CuS superstructure. (b) Absorption spectra of the aqueous dispersions of CuS superstructures and comparable CuS nanoplates (building blocks). Inset photograph shows the CuS superstructures dispersed in water after 1 week. (c) Temperature elevation of the aqueous dispersions containing CuS superstructures and their building blocks, respectively. (d) Temperature elevation of the CuS superstructures dispersion coated with chicken skin. Inset: photograph of the measuring facility.

nanomaterials,9,10 organic dyes and polymers,11,12 and semiconductor nanomaterials.3,13,14 Among them, NIR-responsive semiconductor photothermal nanomaterials of metal oxides15,16 and chalcogenides,3,17,18 as a new type of photothermal agent, have made tremendous progress in recent years and show promising prospects dedicated to their unique features. First, the semiconductor photothermal nanomaterials hold facile synthesis and extremely low cost. Literature reports that the price of making 1 mol of CuS is US $330, and 1 mol of Au costs US $52,200.3 Second, they are not vulnerable to photobleaching and photodegradation like organic nanomaterials. Furthermore, because

which possesses advantages of high selectivity, minimal invasiveness, and no systemic effects. The effectiveness of PTT relies heavily on the photothermal agent. Primarily, ideal photothermal agents for PTT should have strong optical absorption, especially in the near-infrared (NIR) region (700− 1300 nm),4,5 due to the fact that water and blood cells have little absorption to NIR light, allowing deep tissue penetration of light to stimulate the optical-sensitive nanoparticles and minimize the damage in the surrounding healthy tissue.6 So far, a wide range of NIR-responsive photothermal agents have been explored covering noble metal nanostructures,7,8 carbon-based 2530

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Adapted with permission from ref 25. Copyright 2011, American Chemical Society.

Figure 3. (a) TEM image of the synthesized Cu9S5 NCs. (b) Absorption spectrum (red line) and molar extinction coefficient (blue line) of the Cu9S5 dispersion (40 ppm). An inset photograph shows the Cu9S5 NCs in water after 1 week. (c) Photothermal effect of the Cu9S5 dispersion with the laser (980 nm, 0.51 W/cm2) on for 10 min and then off. (d) Representative H&E-stained histological images of ex vivo tumor sections treated with Cu9S5 NCs and laser irradiation.

chalcogenides (Cu2−xX) prove to be an owner for LSPR, where the increased free carriers in Cu2−xX undergo a resonant interaction with the oscillating electromagnetic field of driving light.19 Taking Cu2−xS for instance, the carrier concentration reaches ∼1021 cm−3, corresponding to an LSPR frequency in the NIR region.20 That is to say, Cu2−xS demonstrates a strong NIR absorption from an optical standpoint, resulting in its emergence as a promising photothermal agent the same as Cu2−xSe and Cu2−xTe. An earlier study witnessed a rapid increase in their development for cancer therapy, including CuS,3 Cu2−xSe,13 and CuTe nanocrystals (NCs).21 They possess simple synthesis, low cost, and hypotoxicity. However, it is a barrier that the minimum laser power intensity used in these research studies for an efficient PTT effect (12 W/cm2, 808 nm laser) is still significantly higher than the conservative limit (∼0.33 W/cm2) for human skin exposure.22 To improve the photothermal conversion efficiency (PCE) and reduce the laser power density has become a direction for the development of PTT. On the basis of previous works, our group takes enormous effort to study the properties and applications of chalcogenides. We successfully developed CuS flower-like superstructures by a facile hydrothermal method14 in which the special flower-like structure composed of flakes makes it serve as excellent lasercavity mirrors, greatly improving the light-absorption ability in the NIR region as well as the photothermal effect.23,24 As shown in Figure 2b, the absorbance of our CuS superstructures at 980 nm shows a 2-fold promotion compared to CuS hexagonal nanoplates. With a 980 nm laser chosen as an excitation source, the temperature of the superstructure

of the localized surface plasmon resonance (LSPR) in substoichiometric compounds, these photothermal semiconductor nanomaterials exhibit fine-tune absorption spectrum and large extinction coefficients in the NIR region. During the past several years, enormous efforts have been devoted to the photothermal performance and biomedical applications of the NIR-responsive photothermal semiconductor nanomaterials by our group, and some accomplishments have been achieved. We investigated the photothermal performance of various chalcogenides, including copper sulfides, bismuth sulfide, and tin sulfide, originally developed W18O49 and MoO3−x as PTT agents, and designed a variety of multifunctional nanoplatforms for cancer theranostics, like the Cu2−xS@SiO2 and Fe3O4@Cu2−xS core−shell nanocomposites, and ternary Cu3BiS3 nanocrystals, as shown in Figure 1. Therefore, in this Account we present a simple overview of the NIR-responsive photothermal semiconductor nanomaterials for cancer theranostics with a focus on their design and functionalization from three sections according to our own work, aiming to briefly demonstrate our design and concept, summarize some of our past works, and analyze tendencies regarding the NIR-responsive photothermal semiconductor nanomaterials for clinical applications.

2. CHALCOGENIDES Chalcogenides, as a typical class of semiconductor nanomaterials, draw significant attention for their applications in printed electronics, photovoltaic semiconductors, and solar cells in terms of their optical and electrical properties. Recently, ascribed to the copper vacancies, substoichiometric copper 2531

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Adapted with permission from ref 15. Copyright 2013, Wiley.

Figure 4. (a, b) TEM images of W18O49 nanowires. (c) Cell viabilities estimated by MTT tests versus W18O49 concentrations. (d) Temperature plots within the irradiated tumor area in two mice injected with saline and PBS solution of W18O49 (2 g/L), respectively. Inset shows the corresponding full-body thermographic image of mice (left: W18O49, right: saline) at 180 s. (e) H&E-stained histological images of the corresponding ex vivo tumor sections after irradiation (980 nm, 0.72 W/cm2) for 10 min.

dispersion increased from ∼25 to ∼42 °C within 5 min, whereas the nanoplate dispersion showed a maximum temperature of ∼36 °C under the same conditions. Moreover, a low power density of 0.51 W/cm2 could stimulate a temperature increment of 10.7 °C in 5 min of the aqueous dispersion covered with a layer of chicken skin (thickness: ∼1 mm) as a biosimulation environment and demonstrate efficient photothermal ablation on tumors in vivo. The unique CuS flower-like superstructures exhibited a greatly improved photothermal efficiency, allowing an efficient PTT effect with a laser exposure below the regulatory limit (0.726 W/cm2 for 980 nm laser).22 Although, there remains the problem that the CuS superstructures with relatively large size (∼1 μm) are unfavorable to be eliminated from living bodies. Serious underlying long-term toxicity and even vessel barrage could perhaps result. To solve this problem, our group again prepared smaller Cu9S5 plate-like NCs via a themolysis approach followed by surface modification.25 They were maintained with a small size of ∼70 nm × 13 nm, escaping from the drawbacks of large size, and are more suitable for biological applications. Furthermore, because of the LSPR property induced by copper deficiency, a dispersion of Cu9S5 (40 ppm) exhibited a large molar extinction coefficient of 1.2 × 109 cm−1 M−1 at 980 nm; the PCE reached as high as 25.7%, ensuring their application as an effective photothermal agent. In animal experiments, after the treatment with Cu9S5 and laser irradiation, tumors presented severe damage, including abundant karyorrhectic debris and considerable regions of karyolysis, as distinguished from hematoxylin and eosin (H&E)-stained images in Figure 3. Later, some other chalcogenide semiconductor nanomaterials were also successively constructed within our group, such as the

Cu7.2S4 NCs,26 Cu7S4 hollow structures,27 SnS nanosheets,28 and Bi2S3 nanoflowers.29 Especially, the Cu7.2S4 NCs promote the PCE up to 56.7% irradiated by a 980 nm laser, noticeably higher than the previously reported photothermal nanomaterials, including Au nanorods (21%), Cu9S5 NCs (25.7%), and Cu2−xSe NCs (22%). Dual effect of the 3-dimensional flowerlike structure and lower band gap (Eg = 0.79 eV) also endows the Bi2S3 nanoflowers with a much more elevated photothermal performance compared with that of the Bi2S3 nanobelts.29

3. OXIDES Ensuring the safety of the photothermal nanomaterials is of great importance to their continued march toward clinical practice. Because of the impact of the crystalline phase, size, shape, surface-coating, and surface charge of the nanoparticles on their toxicity, our group has tried to apply the hydrophilic modification, SiO2-coating, and size-adjustment to improve the biosafety of the photothermal semiconductor nanomaterials. However, the toxicity of the chalcogenides as therapeutic agents still remains an issue. Researchers have proven that dysfunction in organisms can be induced by sulfide via an inhibition of cytochrome C oxidase and interference with almost 20 enzymes.30 From another aspect, chalcogenides are likely to release toxic metallic ion due to the relatively weaker chemical bonds between metallic ion and chalcogen (for example, D0Cu−S = 285 kJ/mol, D0Cu−O = 343 kJ/mol, 298 K).31,32 Therefore, we focused our attention on the stable and hypotoxic oxides. In 2013, our group prepared PEGylated W18O49 ultrafine nanowires (thickness of ∼0.9 nm, width of ∼4 nm, and lengths of ∼50 nm, as shown in Figure 4a and b) by a facile solvothermal pathway and studied their photothermal performance.15 Furthermore, they manifest a pretty low toxicity as 2532

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Adapted with permission from ref 16. Copyright 2016, Wiley.

Figure 5. (a) Time-dependent biodistribution of molybdenum in female Balb/c mice after intravenous injection of MoOx-PEG. (b) Molybdenum in urine and feces collected at various time points after injection. (c) Ultrasound and photoacoustic (PA) imaging of the tumor and muscle at 0.5 and 24 h postinjection. (d) Relative PA signal intensities.

oxidation process. Thus, it is possible that MoOx nanosheets accessing organisms could degrade under normal physiological pH. Furthermore, just as predictably, the biodistribution of Mo shown in Figure 5a and b articulate that the nanomaterial retention in major organs and tissues decreases quickly over time and becomes extremely low, even in the liver and spleen. It ensured that the MoOx-PEG would not be retained for a long time in normal tissues and showed no further long-term toxicity to mice. On the other hand, the MoOx-PEG accumulating in tumor regions through the EPR effect were stable because of the acidic and lower oxygen level’s microenvironment (Figure 5c) and remained at a high level even 24 h postinjection. In this way, the MoOx-PEG nanosheets got in-suit PTT for tumors and efficiently degraded in vivo. Hydrous RuO2 (RuOx(OH)y) NCs were also studied by our group.37 They displayed good biocompatibility, photostability, low cytotoxicity, and high PCE (54.8%) due to the mixed valence of Ru3+/Ru4+. Moreover, cancer cells incubated with RuO2 could be efficiently thermally killed upon 808 nm laser irradiation. These results illustrate that RuO2 can be a novel photothermal agent for bioapplications as well.

anticipated. With 1 mg/mL of W18O49 solution administration, cell viability (>90%) was almost twice that of the CuS-treated cells (50%). In addition, the unusual oxygen deficiency reinvests the nanowires with LSPR character as well, thereby affording an increasing photoabsorption at a wavelength range from 510 to 1100 nm. Consequently, under 980 nm laser irradiation, the tumor region of the W18O49-treated mice showed a significant thermal signal, and its temperature increased to ∼50 °C rapidly, thus resulting in a hyperthermia-toxicity on cancer cells (Figure 4). This was the first report on the photothermal bioapplication of oxides, expanding their applications into a new field of photothermal treatment. In our other work, self-assembled WO3−x hierarchical nanostructures were developed as photothermal agents.33 A 915 nm laser was selected as the laser source for treatment; it avoids a negative influence on normal tissues induced by the strong photoabsorption of water at 980 nm and increases the tissue penetration depth compared with the 808 nm laser, which is meaningful for the PTT of cancer. At the same time, we also investigated the photothermal performance of molybdenum oxide. The hydrophilic MoO3−x nanoribbons were synthesized by a simple hydrothermal route.34 They were found to exhibit good photothermal performance similar to that of WO3−x and could effectively kill osteosarcoma U2OS cells through a photothermal conversion effect.34 However, it is worth noting that the oxidation reaction may dissatisfy the stability of the substoichiometric MoO3−x. When exposed to air, the prior absorption peak of MoO3−x would disappear, and the blue nanosheets gradually transform to white nanotubes.35 Some research studies have been done to improve its photostability, for example, using an ultrathin carbon layer coating (C/MoO2).36 On the contrary, taking advantage of the instability, we put this work forward to design and synthesize MoOx-PEG nanosheets with a pH-dependent degradation property.16 The MoOx holds a constitutional formula of Hx(MoVx)(MoVI1−x)Ox, which is prone to be oxidized to soluble MoVIO42− in the presence of oxygen in alkali environments, whereas conditions of neutral and acid are not beneficial to or even stop the

4. MULTIFUNCTIONAL NANOPLATFORMS 4.1. Synergistic Therapy

NIR-responsive photothermal semiconductors have been demonstrated to be a promising nanomedicine in oncotherapy. However, the therapeutic effect is less than satisfactory in light of limitations generally found in each treatment approach. In attempts to improve the treatment performance, the PTT agents can be integrated with antitumor drugs, photosensitizers, and radiosensitizers. In this way, preloaded drugs, reactive oxygen species, and radioactivity could be released or generated in a controllable manner once exposed to a correspondingly appropriate extrinsic stimulus, thus leading to a synergistic therapeutic effect. Namely, apart from a combination of multimode treatments, the generated heat from PTT improves vessel permeability, blood circulation, and oxygen supply within tumors, favoring proceeding of drug-release, PDT, and RT. Furthermore, the enhanced hypoxic microenvironment led by 2533

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Adapted with permission from ref 38. Copyright 2013, Wiley.

Figure 6. (a) Schematic illustration of the Cu9S5@mSiO2−PEG core−shell nanocomposites as a multifunctional nanoplatform for cancer treatment. (b) Cell viability rate of the free DOX, Cu9S5@mSiO2−PEG, and DOX-loaded Cu9S5@mSiO2−PEG nanocomposites incubated with Hep3B cells as a function of concentration. Cells were either exposed to 980 nm laser (0.72 W/cm2) for 3 min or not. (c) Photograph of tumors and (d) mean tumor weights from four groups. (e) Representative photographs of mice on the 10th day. (f) Mean body weights of the mice after treatment.

effect for cells and nude mice bearing tumor model. It showed that the DOX-loaded Cu9S5@mSiO2−PEG nanocomposite could effectively kill cells in vitro and inhibit tumor growth under the NIR laser irradiation, and more importantly, the associated synergistic inhibition effect was the most remarkable. Moreover, the body-weight plots in Figure 6f indicated that all the mice’s weights were kept a normal level during the treatment period, further certifying the low toxicity of Cu9S5@ mSiO2 and its relevant treatment. Subsequently, various multifunctional DOX-loading nanocomposites such as CuS@mSiO2−PEG39 and Cu2−xSe@ mSiO2−PEG40 have been synthesized. SN38 and Ce6 were also effectively loaded on the graphene analogues of MoOx− PEG nanosheets, realizing synergistic therapy of photothermal, photodynamic, and chemotherapy for cancer.16 The folic acidconjugated hollow mSiO2/CuS nanocomposites41 were devel-

PDT or RT endows the tumors with an increased heatsensitivity for PTT. Our group has integrated the photothermal agent with antitumor drug to rationally design the DOX-loaded Cu9S5@ mSiO2 (mesoporous silica) core−shell nanocomposites for the first time by a thermal decomposition approach and coating process.38 On one hand, SiO2 protects the core materials from the external environment and renders them hydrophilic, biocompatible, and chemically stable. On the other hand, the mesoporous shell with advantages of large specific surface volume and numerous pores makes it possible for drug or targeting delivery by loading functional molecules. Moreover, the drug delivery nanosystems show a pH-responsive release properties. At pH 4.8, the drug exhibited relatively higher release compared to that at pH 7.4, which is conducive to drug accumulation in an acidic tumor microenvironment rather than the neutral normal tissues. Figure 6 briefly exhibits the PTT 2534

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980 nm laser irradiation. This illustrated that the magnetic property of the Fe3O4@Cu2−xS core−shell nanocomposites not only renders them to serve as a diagnostic reagent but also makes them available for a targetable PTT effect. Then, considering the commonly complicated synthetic processes and low productivities of nanotheranostics based on composites, we continued to construct the simple ternary Cu3BiS3 NCs as theranostic nanoplatforms.44 Because of the unusual defects as Cu2−xS and the large X-ray attenuation coefficient of bismuth (Bi: 5.74, I: 1.94 cm2/g at 100 keV), the concise Cu3BiS3 NCs exhibit strong NIR absorption and CT properties. Panels c and e in Figure 8 demonstrate the in vitro

oped to compensate for the limitation of passive targeting and acquire the actively targetable therapeutic effect. 4.2. Diagnosis and Treatment

From another perspective, theranostics based on the combination of photothermal nanomaterials and contrast agents is fascinating as their applications for cancer diagnosis, tumor location, site-specific therapy, and evaluation of therapeutic responses. It tends toward the movement of cancer therapy and has important clinical significance. On account of the noninvasion, high spatial resolution, and deep tissue penetration of magnetic resonance (MR) imaging, our group designed a theranostic nanostructure in which spherical-shaped Fe3O4 NCs were encapsulated into Cu2−xS thin shells forming ultrathin ( 1

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