Multifunctional Theranostic Nanoplatform Based on Fe-mTa2O5@CuS

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Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

Multifunctional Theranostic Nanoplatform Based on FemTa2O5@CuS-ZnPc/PCM for Bimodal Imaging and Synergistically Enhanced Phototherapy Lili Feng,† Chuanqing Wang,† Chunxia Li,‡ Shili Gai,*,† Fei He,† Rumin Li,† Guanghui An,† Chongna Zhong,† Yunlu Dai,† Zailin Yang,† and Piaoping Yang*,† †

Key Laboratory of Superlight Materials and Surface Technology, Ministry of Education, College of Material Sciences and Chemical Engineering, Harbin Engineering University, Harbin 150001, P. R. China ‡ Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Zhejiang Normal University, Jinhua, Zhejiang 321004, P. R. China S Supporting Information *

ABSTRACT: Multifunctional nanotheranostic agent with high performance for tumor site-specific generation of singlet oxygen (1O2) as well as imaging-guidance is crucial to laser-mediated photodynamic therapy. Here, we introduced a versatile strategy to design a smart nanoplatform using phase change material (PCM) to encapsulate photosensitizer (zinc phthalocyanine, ZnPc) in copper sulfide loaded Fe-doped tantalum oxide (Fe-mTa2O5@CuS) nanoparticles. When irradiated by 808 nm laser, the PCM is melted due to the hyperthermia effect from CuS nanoparticles, inducing the release of ZnPc to produce toxic 1O2 triggered by 650 nm light with very low power density (5 mW/cm2). Then, the produced heat and toxic 1O2 can kill tumor cells in vitro and in vivo effectively. Furthermore, the special properties of Fe-mTa2O5 endow the nanoplatform with excellent computed tomography (CT) and T1-weighted magnetic resonance imaging (T1-MRI) performance for guiding and real-time monitoring of therapeutic effect. This work presents a feasible way to design smart nanoplatform for controllable generation of heat and 1O2, achieving CT/T1-MRI dual-modal imaging-guided phototherapy.

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INTRODUCTION Malignant tumor, as one of the most deadly and incompletely conquered diseases, has threatened human health seriously.1−3 The developments of versatile treatments with high therapeutic efficiencies and negligible side effects are of extreme importance in fighting against cancer.4−8 As a typical type of noninvasive treatment, phototherapy containing photodynamic therapy (PDT) and photothermal therapy (PTT) has aroused special attention owing to its unique advantages, such as low system toxicity, enhanced selectivity, specific tumor localization, and remote control.9−14 For PDT, the photosensitizer accumulates in the tumor site and produces singlet oxygen (1O2) when excited with specific laser in the presence of tissue oxygen, which is highly toxic to malignant tumor cells.15−18 PTT mainly applies photothermal agents to produce effective thermal effect to kill tumor cells via converting absorbed laser energy into heat.19−22 The concomitant use of PDT and PTT has been extensively evaluated and verified to be a feasible strategy on account of the synergistic effect.23−25 It is prominently demanded to design a multifunctional nanosystem with high performance, high stability, and good biocompatibility for imaging-guided phototherapy. However, the premature drug © XXXX American Chemical Society

leaking and harsh reaction condition limit the biomedical application of the nanosystems. As we know, sulfide copper (CuS) nanoparticles with strong near-infrared (NIR) absorption, low toxicity, high photostability, and negligible side effect have gained significant concern and have served as an ideal candidate for PTT.26−30 However, in previous literature, the synthesis of CuS nanoparticles usually requires toxic chemical ligands and a relatively high reflux temperature.31−34 Even worse, the produced CuS nanoparticles always possess irregular morphology and unsatisfactory photothermal performance. Accordingly, it is necessary to develop a simple, mild, and cost-effective method to synthesize and combine CuS nanoparticles functionalized nanotheranostic agents for PTT. Nowadays, phase change material (PCM, melting point: 39−40 °C, close to human body temperature) is a new kind of material for energy storage, and the thermal properties are key factors that determine its application areas and actual effects. As a newly emerging PCM, tetradecanol was usually utilized to seal Received: November 21, 2017

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DOI: 10.1021/acs.inorgchem.7b02959 Inorg. Chem. XXXX, XXX, XXX−XXX

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Figure 1. Preparation and characterization of Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles. (A) Schematic illustration of Fe-mTa2O5@CuS-ZnPc/ PCM synthetic procedure. TEM images of (B) mTa2O5, (C) Fe-mTa2O5@CuS, and (D) Fe-mTa2O5@CuS-ZnPc/PCM. (E) EDS spectrum of asprepared Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles. (F) DSC curves recorded from the PCM and Fe-mTa2O5@CuS-ZnPc/PCM sample. (G) TGA curves obtained for Fe-mTa2O5@CuS, Fe-mTa2O5@CuS/PCM, and Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles. The 10.32% weight loss corresponds to the evaporation of PCM and ZnPc.

provide nanosystems that concurrently fulfill the following: (1) serving as nanocarriers with high amount of drug loading to avoid premature drug leakage and realize thermoresponsive synergistic therapy; (2) being able to generate 1O2 in tumor site upon external laser stimuli to reduce systemic toxicity; (3) exhibiting multimodality imaging performance to implement imaging-guided phototherapy. In this research, a multifunctional nanosystem was rationally designed for enhanced tumor ablation by combined phototherapy. For the first time, biocompatible mesoporous Ta2O5 nanoparticles were prepared via a “surfactant template” strategy and have been developed as the nanocarrier that can intrinsically bond with metal iron ions (appointed as FemTa2O5) without additional molecular chelators. Then, ultrasmall CuS nanoparticles were conjugated onto the mesoporous channels of Fe-mTa2O5 via in situ growth method (denoted as Fe-mTa2O5@CuS). As it holds the 1O2 release channel, the mesoporous Fe-mTa2O5@CuS served as the ideal carrier for loading photosensitive drug zinc phthalocyanine (ZnPc) and was further covered by PCM, achieving higher payload capacity and an eventual thermoresponsive nanosystem (named as Fe-mTa2O5@CuS-ZnPc/PCM). The hyperthermia effect generated from the system upon 808 nm NIR laser irradiation is sufficient for PCM melting and effective release of ZnPc to produce toxic 1O2 excitation with mild 650 nm light. Moreover, the intrinsic features endow the sample with simultaneous CT and MRI imaging properties. Thus, such sample with all-in-one “smart” function could be employed as a multifunctional nanosystem to realize the above purposes synchronously.

nanocarrier for high amount of drug loading and acted as a thermoresponsive switch for better controlled drug release. However, there are few versatile strategies to integrate nanocarriers with anticancer drugs or photosensitizer agents for achieving desired therapeutic effect. Therefore, multifunctional nanocarriers that are able to specifically deliver therapeutic agent into the tumor site, avoid premature drug leakage, and release photosensitizer drugs in situ with a controlled switch are extremely desirable.35−38 To monitor in real time the phototherapy process, combining bioimaging and treatment into a single nanosystem is in development.39−42 Computed tomography (CT) is one of the most widely used imaging technologies in the medical field, which has aroused tremendous attention in diagnosis and surgical operation on account of its high temporal resolution.43−45 Nevertheless, poor sensitivity limits its proper distinction of soft tissue subtle changes. As another effective imaging technique, magnetic resonance imaging (MRI) has some different advantages, containing noninvasiveness, high contrast effect for soft-tissue, and high organization penetration capability.46−48 Consequently, CT combined MRI (CT/MRI) dual-modal imaging is considered as the most promising strategy in accurate cancer diagnosis, and it can further satisfy the medical research with the assistance of therapy.49−51 As we know, nanoparticles containing high-Z number elements (such as Bi, Gd, and Au) as CT imaging contrast agent not only exhibit good prospect for preoperative diagnosis but also provide real-time monitoring of the treatment process.52−59 Therefore, to achieve accurate diagnosis and highly effective treatment of malignant tumors, it is of great importance to B

DOI: 10.1021/acs.inorgchem.7b02959 Inorg. Chem. XXXX, XXX, XXX−XXX

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Figure 2. (A) The particle size distributions measured by DLS. (inset) The representative photograph of Fe-mTa2O5@CuS-ZnPc/PCM dispersed in aqueous solutions after incubation for 24 h. (B) Zeta potential of as-prepared samples at different steps. (C) N2 adsorption−desorption isotherms and the corresponding pore size distributions of Fe-mTa2O5 and Fe-mTa2O5@CuS. (D) UV−Vis absorption spectra of Fe-mTa2O5, ZnPc, FemTa2O5@CuS, and Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles aqueous solution. (E) ESR spectra of Fe-mTa2O5@CuS-ZnPc/PCM and FemTa2O5@CuS with both laser illumination and Fe-mTa2O5@CuS-ZnPc/PCM solutions upon only 650 nm laser irradiation. TEMP without laser irradiation was used as a control for comparison (from top to bottom). (F) UV−Vis absorption spectra of DPBF as a chemical probe for detecting the 1O2 generation from Fe-mTa2O5@CuS-ZnPc/PCM solutions upon laser irradiation (808 nm NIR laser for 5 min and then 650 nm light for different times (0, 2, 4, 6, 8, and 10 min) at the power densities of 0.5 W cm−2 and 5 mW cm−2, respectively).

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RESULTS AND DISCUSSION Synthesis and Characterization. In this work, multifunctional Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles as nanotheranostic agent were prepared via a smart synthetic strategy (Figure 1A), where Fe-doped mesoporous Ta2O5 (Fe-mTa2O5) nanoparticles served as the T1-weighted MRI/CT contrast agents and nanocarriers for loading treatment agents. And a simple surfactant template sol−gel method was adopted to prepare mTa2O5 nanoparticles. The average diameter of 20 ± 2 nm and spherical shape of mTa2O5 can be distinctly observed via transmission electron microscopy (TEM, Figure 1B). Because of the abundant tantalum hydroxyl groups (Ta−OH) on the surfaces and mesoporous channels of mTa 2 O 5 nanoparticles, the surfaces of mTa2O5 nanoparticles offer partly deprotonated tantalum hydroxyl groups (Ta−O−), which can serve as inherent oxygen donors to bond with metal ions.60−64 As displayed in Figure S1, the doped Fe3+ in Fe-mTa2O5 does not change the morphology and nanostructure of mTa2O5, but the colors of samples are changed from white to bright yellow. The energy-dispersive spectroscopy (EDS) spectrum of FemTa2O5 nanoparticles verifies the coexistence of Ta, O, and Fe elements, indicating the information on Fe3+ ion-doped mTa2O5 nanoparticles (Figure S2). X-ray diffraction (XRD) pattern shows the amorphous structure of Fe-mTa 2 O 5 nanoparticles (Figure S3). The as-obtained Fe-mTa2O5 nanoparticles were first modified with dopamine (DOPA), which could modify the surface with amino groups (Fe-mTa2O5− NH2). The ultrasmall CuS nanoparticles were then grown on the surface or the mesoporous channel of Fe-mTa2O5 through in situ growth method. Although CuS nanoparticles cannot be detected in Figure 1C due to their ultrasmall size, XRD of Fe-

mTa2O5@CuS sample shows the characteristic peaks of CuS, proving the successful functionalization of CuS nanoparticles (Figure S3). The large surface area and mesoporous pore structure of Fe-mTa2O5@CuS nanoparticles are facilitated to anchor ZnPc photosensitizer for imaging-guided PDT. And then the Fe-mTa2O5@CuS-ZnPc nanoparticles were sealed by PCM to avoid premature drug leakage gain higher photosensitizer loading amount, and they controlled production of 1 O2. In contrast to Fe-mTa2O5@CuS, the resulting FemTa2O5@CuS-ZnPc/PCM shows a significantly different surface (Figure 1D), and the corresponding colors of all synthetic steps are also recorded (Figure S1). The TEM image of CuS nanoparticles with uniform distribution was also presented in Figure S4. The EDS of the sample also verifies the existence of Cu and S elements compared with Fe-mTa2O5 nanoparticles, implying the CuS nanoparticles may successfully grow on the surface of Fe-mTa2O5 nanocarriers (Figure 1E). Furthermore, the differential scanning calorimetry (DSC) curves affirm that PCM is successfully coated on the surface of Fe-mTa2O5@CuS-ZnPc nanoparticles (Figure 1F).65 In Figure 1G, the thermogravimetric analysis (TGA) curves of different samples were performed, demonstrating the drug loading capacity of ∼10.32 wt % for ZnPc/PCM mixture. The weight percentage of ZnPc in Fe-mTa2O5@CuS-ZnPc/PCM was calculated to be 4.85%, which indicates a weight percentage of 5.47% for PCM. In addition, the loading capacity of ZnPc was also measured by UV−vis absorption spectrum (Figure S5), which is basically consistent with the results obtained from the TGA curve. In comparison with the sample diameter obtained from TEM, the dynamic light scattering (DLS) measurement of FeC

DOI: 10.1021/acs.inorgchem.7b02959 Inorg. Chem. XXXX, XXX, XXX−XXX

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Figure 3. Stability assessment: colloidal stability of Fe-mTa2O5@CuS-ZnPc/PCM dispersed in (A) H2O, (B) medium culture (10% fetal bovine serum), and (C) PBS (pH 7.4) vs incubation time. (D) Variation of size distribution of Fe-mTa2O5@CuS-ZnPc/PCM. (inset) digital photographs of Fe-mTa2O5@CuS-ZnPc/PCM dispersed in various solutions: (1) H2O, (2) PBS, (3) culture medium. Photostability of Fe-mTa2O5@CuS-ZnPc/ PCM: (E) Variation in UV−vis absorption spectra of the solution before and after laser irradiation (808 nm laser irradiation for 5 min at the power density of 0.5 W cm−2). (F) Size distribution. (inset) Digital photographs before and after laser irradiation. (G) Photothermal conversion curves for four cycles. (H) Relaxation time stability.

characteristic absorption peaks of C−O and O−H plane bending, respectively. The above characteristic peaks verify the existence of PCM in as-prepared nanoparticles.66 Besides, the benzene skeleton characteristic peaks at 1600−500 cm−1 affirm the presence of ZnPc. The aforementioned analysis exhibits that ZnPc and PCM coexist in the mesoporous Fe-mTa2O5@ CuS nanocarrier, suggesting the Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles were achieved as expected. X-ray photoelectron spectroscopy (XPS) survey spectrum of Fe-mTa2O5@CuSZnPc/PCM apparently demonstrates the characteristic peaks of Fe, Ta, O, Cu, S, and Zn; at the same time, the corresponding high-resolution spectra were also detected (Figure S6B−D). Two peaks corresponding to Ta (v) 4f7/2 and Ta (v) 4f5/2 were observed at 26.1 and 28.1 eV, respectively. Fe-mTa2O5 nanoparticles were composed of pentavalent tantalum. The UV−vis absorption spectra of Fe-mTa2O5, ZnPc, Fe-mTa2O5@ CuS, and Fe-mTa2O5@CuS-ZnPc/PCM were also measured. Especially, Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles exhibit pronounced absorbance at 650 and 808 nm compared with the Fe-mTa2O5@CuS aqueous solution owing to the combination of ZnPc (Figure 2D). This absorption characteristic is beneficial

mTa2O5@CuS-ZnPc/PCM nanoparticles exhibits a slight increase, which indicates the presence of individual nanoparticles and good dispersion in aqueous solution (Figure 2A). Zeta potential changes of each synthesis procedure further indicate the successful growth of CuS nanoparticles and introduction of ZnPc/PCM on Fe-mTa2O5 (Figure 2B). The well-defined mesoporous structure can still be maintained after CuS modification, which is confirmed by N2 absorption− desorption isotherms (Figure 2C). The Brunauer−Emmett− Teller (BET) surface areas of Fe-mTa2O5 and Fe-mTa2O5@ CuS are 503 and 461 m2 g−1, respectively. And the pore size of Fe-mTa2O5@CuS also decreased from 2.7 to 2.3 nm after CuS modification. All the results reveal the successful incorporation of CuS into the mesopores. Fourier transform infrared spectroscopy (FTIR) was utilized to examine the conformation of Fe-mTa2O5@CuS-ZnPc/PCM (Figure S6A). The vibration peak at 647 cm−1 indicates the Cu−S stretching modes of CuS nanoparticles. The sharp characteristic peak at 3630 cm−1 is attributed to the free O−H stretching vibration. The stretching vibration absorption of the intermolecular hydrogen bond O− H appears at 3298 cm−1. 1065 and 683 cm−1 are the D

DOI: 10.1021/acs.inorgchem.7b02959 Inorg. Chem. XXXX, XXX, XXX−XXX

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Figure 4. (A) Temperature change curves of Fe-mTa2O5@CuS-ZnPc/PCM solutions at varying Cu2+ concentrations (0−0.96 mM, 2 mL) under laser irradiation (808 nm, 0.5 W cm−2) as a function of the irradiation time. (B) Plot of the temperature increase (ΔT) over a period of 300 s vs Cu2+ concentration. (C) Infrared thermal images of deionized water, Fe-mTa2O5@CuS-ZnPc/PCM aqueous solution (Cu2+ concentration = 0.96 mM) irradiated with 808 nm laser, and Fe-mTa2O5@CuS-ZnPc/PCM illumination upon 650 nm light for 5 min at the power densities of 0.5 W cm−2 and 5 mW cm−2, respectively. (D) Temperature increase (ΔT) of Fe-mTa2O5@CuS-ZnPc/PCM irradiated with 808 nm laser; the laser was turned off after irradiation for 400 s. (E) Obtained time constant for heat transfer of this system (τs = 216.08 s) by applying linear time data vs −ln(θ) from the cooling stage.

CuS-ZnPc/PCM with only 650 nm light irradiation and FemTa2O5@CuS illuminated upon both 808 nm laser and 650 nm light, respectively (Figure S7). The characteristic absorption spectra of DPBF at 410 nm exhibit no significant change for FemTa2O5@CuS-ZnPc/PCM nanoparticles exposed to 650 nm light and Fe-mTa2O5@CuS illuminated upon both laser control groups, suggesting there is no generation of 1O2. Stability Assay of Fe-mTa2O5@CuS-ZnPc/PCM Nanoparticles. The colloidal stability of Fe-mTa2O5@CuS-ZnPc/ PCM nanoparticles was very important in biomedical application, which was investigated in detail after 7 d of cultivation in different solutions, including H2O, phosphatebuffered saline (PBS), and culture medium. The stability was evaluated via monitoring the changes in UV−vis absorption and size distribution, which served as the primary standard. The absorption curves of the resulting samples exhibit no significant change, and the dimension distribution remains stable at ∼36.2 nm (Figure 3A−D). Digital photographs show no significant aggregation phenomenon even after 7 d of storage in different solutions (inset in Figure 3D). In brief, these results reveal the excellent colloidal stability of the Fe-mTa2O5@CuS-ZnPc/ PCM in the physiological environment. Furthermore, the photostability of Fe-mTa2O5@CuS-ZnPc/PCM is of great concern for PTT and was thereby studied by comparing the size distribution, UV−vis absorption spectrum, temperature change, and relaxation time before and after 808 nm laser illumination for different storage times (Figure 3E−H). Before and after irradiation with 808 nm laser, strong NIR absorption

to achieve better PDT and PTT effect. Furthermore, electron spin resonance (ESR) spectrum was utilized to verify the corresponding mechanism of PDT process of Fe-mTa2O5@ CuS-ZnPc/PCM when exposed to combined 808 and 650 nm lasers (Figure 2E). The Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles exposed to 650 nm light and Fe-mTa2O5@CuS illuminated upon both lasers were set as control groups. The level of generated 1O2 was detected by 2,2,6,6-tetramethylpiperidine (TEMP), which can react with 1O2 to produce the nitroxide radical 2,2,6,6-tetramethyl-4-piperidone-N-oxyl (TEMPO). TEMPO possesses unpaired electrons in the NO groups as a paramagnetic substance. As shown, the ESR signal was separated into three lines with equal intensity due to the interaction between unpaired electronic spin and the nitrogen 14 N nucleus.67−69 The 1O2-induced characteristic signal peaks can be obviously observed in Fe-mTa2O5@CuS-ZnPc/PCM with both lasers treatment, indicating the generation of 1O2 in the course of experiment. The experimental results exhibit that no significant 1O2-induced characteristic ESR signal peaks can be observed for control groups. The 1,3-diphenylisobenzofuran (DPBF) as a typical chemical probe was adopted to further quantitatively analyze the production of 1O2. It can be observed that the characteristic absorption peak of DPBF at 410 nm decreases apparently in the presence of Fe-mTa2O5@CuSZnPc/PCM with the increase of illumination time (Figure 2F), suggesting the effective generation of 1O2 in the process of PDT. In addition, the characteristic absorption spectra of DPBF at 410 nm were also measured in the presence of Fe-mTa2O5@ E

DOI: 10.1021/acs.inorgchem.7b02959 Inorg. Chem. XXXX, XXX, XXX−XXX

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of 2′,7′-dichlorofluorescein diacetate (DCFH-DA) was utilized to evaluate the level of intracellular 1O2, because the nonfluorescence DCFH-DA can be converted into green fluorescent 2,7-dichlorofluorescein (DCF) when oxidized by 1 O2. Clearly, 808 and 650 nm combined lasers trigger the generation of intracellular 1O2 from Fe-mTa2O5@CuS-ZnPc/ PCM, as evidenced by strong intracellular green fluorescence. And the 1O2 generation process can be explained as follows: 808 nm laser irradiation induces the photothermal effect of CuS, and the produced heat melts the PCM, causing the rapid generation of 1O2 from ZnPc upon 650 nm laser irradiation. In addition, no green fluorescence signal can be detected when the HeLa cells are incubated with Fe-mTa2O5@CuS-ZnPc/PCM and illumination with 808 or 650 nm laser alone. By contrast, neither control group nor laser illumination only could display the intracellular fluorescence, as presented in Figure S9B. Integrated with the result of ESR test (Figure 2E), it can be inferred that Fe-mTa2O5@CuS-ZnPc/PCM as photosensitizers can produce 1O2 effectively upon both lasers irradiation, which can cause prominent toxic effect and achieve the goal of therapy. Prior to in vivo application, standard 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and hemolytic experiment were employed to confirm the biocompatibility of the resulting Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles. As exhibited in Figure 5A, no apparent cell toxicity can be detected after 24 and 48 h of incubation, and the relative cell survival rate is maintained up to 92% even if the concentration is as high as 800 μg mL−1. Similarly, the calculated ratio of hemolysis is less than 0.2% at the maximum experimental concentration of 500 μg mL−1, indicating that the Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles have good bio-

can be detected, and absorbance at 808 nm is almost identical via UV−vis absorption spectra for all the prepared nanoparticles; the hydrodynamic size of the nanoparticles remains ∼36.2 nm without aggregations. As presented in Figure 3G, FemTa2O5@CuS-ZnPc/PCM nanoparticles maintain relatively high photothermal conversion efficiency even after four cycles of laser illumination. In addition, the T1 relaxation times of the as-synthesized nanoparticles before and after exposure to NIR laser were evaluated. No significant relaxivity change was detected, indicating the excellent structural stability of FemTa2O5@CuS-ZnPc/PCM nanoparticles after laser irradiation. The above analysis suggests that Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles have outstanding stability, which exhibit potential application prospect in photothermal therapeutic. Photothermal Effect of Fe-mTa2O5@CuS-ZnPc/PCM. Inspired by the crucial absorption of the Fe-mTa2O5@CuSZnPc/PCM nanoparticles in the NIR region, we further studied their photothermal performance. The 808 nm NIR laser was adopted during the whole experiment process. As displayed in Figure 4A, the temperature of Fe-mTa2O5@CuS-ZnPc/PCM sample rises quickly after 5 min of irradiation at a power density of 0.5 W cm−2. The sample with 0.96 mM of Cu2+ exhibits the rapid temperature rise of 23.4 °C (Figure 4B), whereas no obvious temperature increase is observed in the control group of deionized water only. Furthermore, an infrared thermal imager was utilized to monitor the temperature change and further evaluate the photothermal effect of Fe-mTa2O5@CuSZnPc/PCM nanoparticle by 808 nm laser irradiation, of deionized water by 808 nm laser illumination, and of FemTa2O5@CuS-ZnPc/PCM irradiation by 650 nm light (5 mW cm−2). And the latter two groups served as control. Obviously, the temperature of Fe-mTa2O5@CuS-ZnPc/PCM irradiation upon 808 nm NIR laser for 5 min is increased by 25.2 °C (at a power density of 0.5 W cm−2), as exhibited in Figure 4C, while the temperature change of the control group only is ∼1.2 °C under the same experimental conditions. The corresponding temperature change curves were also presented in Figure S8. As a consequence, Fe-mTa2O5@CuS-ZnPc/PCM exhibits power density, illumination time, and sample concentration-dependent photothermal effect. On the basis of previous literature, the photothermal conversion efficiency of Fe-mTa2O5@CuSZnPc/PCM was investigated.70 With the extension of irradiation time, the temperature change of Fe-mTa2O5@ CuS-ZnPc/PCM nanoparticles was measured until the sample temperature reaches a relatively stable state, and then the laser was turned off. The linear time data versus ln(θ) from the cooling period was applied to evaluate the heat transfer effect of the resulted nanoparticles (Figure 4D,E). The photothermal conversion efficiency of Fe-mTa2O5@CuS-ZnPc/PCM is calculated to be 27.8%, suggesting prospect as potential candidate for PDT/PTT synergistic anticancer therapy. Cytotoxicity and Ablation Performance to Tumor Cells. The in vitro synergistic anticancer efficiency of FemTa2O5@CuS-ZnPc/PCM nanoparticles was investigated in detail. First of all, the resulting nanoparticles could efficiently enter the HeLa cells by observing the signal intensity of intracellular green fluorescence via confocal laser scanning microscopy (CLSM, Figure S9A), which is derived from fluorescein isothiocyanate (FITC)-decorated Fe-mTa2O5@ CuS-ZnPc/PCM nanoparticles. The green fluorescence signal intensity is elevated with the extension of incubation time. To further reveal the mechanism of Fe-mTa2O5@CuS-ZnPc/PCM as photosensitizer to kill malignant tumor cells, chemical probe

Figure 5. (A) Cytotoxicity of the Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles in L929 cells after 24 h of incubation. (B) Cell viability of HeLa cells incubated with Fe-mTa2O5@CuS-ZnPc/PCM at various concentrations (0−800 μg mL−1) irradiated with different kinds of laser. (C) Fluorescence images of HeLa cells costained with calcein AM (live cells, green) and propidium iodide (dead cells, red) after different treatments. All images share the same scale bar of 50 μm. F

DOI: 10.1021/acs.inorgchem.7b02959 Inorg. Chem. XXXX, XXX, XXX−XXX

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of 23.99 HU g L−1. The appealing CT enhancement ability of the resulting nanoparticles indicates the application prospect as contrast agent for clinical diagnosis and therapy. Encouraged by the excellent in vitro CT imaging performance, we further investigated in vivo CT imaging. The tumor-bearing mice were intravenously injected with Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles, and then imaging was taken at 24 h post injection. The remarkable contrast effect is observed in the tumor site with the signal value of 969.5 HU, which is markedly higher than 64.1 HU before injection (Figure 6B). As a consequence, the experimental results provide compelling evidence to demonstrate that Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles hold great promise as contrast agent for CT imaging in clinical treatment. Furthermore, MRI possesses high sensitivity to soft tissue, and an excellent spatial resolution has emerged in clinical application. Since Fe3+ is a paramagnetic ion, possesses a large number of unpaired electrons, and can serve as potential candidate for T1-weighted MRI by the interaction between protons of water molecules and electron spins of Fe3+, the magnetic property of as-prepared nanoparticles is concerned.71 In vivo T1-weighted MRI capability of Fe-mTa2O5@CuS-ZnPc/PCM with various concentrations was measured, which indicates the concentration-dependent brightening effect (Figure 6C). The longitudinal relaxivity (r1) of FemTa2O5@CuS-ZnPc/PCM is estimated to be 0.7075 mM−1 s−1, showing a good application prospect as T1-weighted MRI contrast agent. Then Fe-mTa2O5@CuS-ZnPc/PCM was utilized to study in vivo MRI effect. As provided in Figure 6D, the tumor site demonstrates remarkable enhanced signal intensity after intravenous injection of Fe-mTa2O5@CuSZnPc/PCM nanoparticles. The experimental results indicate the possibility of as-prepared nanoparticles as contrast agent for CT and MRI guided phototherapy. In Vivo Synergistic Therapeutic Performance. An infrared thermal imager was utilized to monitor and record the real-time thermal images by administrating Fe-mTa2O5@ CuS-ZnPc/PCM and saline into the tumor-bearing mice via intravenous injection and then illuminating with 808 nm NIR laser for 5 min (Figure 7A). It is found that the temperature of the tumor region is increased by 23.5 °C in the presence of FemTa2O5@CuS-ZnPc/PCM, which is much higher than that of 2.3 °C in the control group (saline + NIR laser, Figure 7B). The result can be attributed to the strong absorption of FemTa2O5@CuS-ZnPc/PCM nanoparticles at 808 nm and their high photothermal conversion efficiency. A direct proof to illustrate the synergistic therapeutic effect is the relative change curves of tumor volume, as displayed in Figure 7C. The tumorbearing mice injected with Fe-mTa2O5@CuS-ZnPc/PCM irradiation with 808 and 650 nm lasers (group 6) demonstrated an apparent regression on the fourth day due to the combined PTT and PDT effect, and almost complete ablation can be found after 10 d of treatment, while the tumors in the control groups injected with saline (group 1), laser illumination only (group 2), and Fe-mTa2O5@CuS-ZnPc/PCM alone (group 3) exhibit rapid tumor growth. The mice injected with FemTa2O5@CuS-ZnPc/PCM exposed to 650 nm laser treatment group exhibit no apparent tumor inhibition effect, implying ZnPc was encapsulated in the pore channel of Fe-mTa2O5@ CuS by PCM and cannot be leaked prematurely during the treatment process. For the tumor treated with Fe-mTa2O5@ CuS-ZnPc/PCM illumination with 808 nm NIR laser, a slight tumor growth inhibition in the first few days is found, but it continuously grows with the extension of treatment time,

compatibility and could serve as ideal nanomaterials for in vivo anticancer therapy (Figure S10). The in vitro phototherapy effect was evaluated on HeLa cells. As presented in Figure 5B, the relative viability of HeLa cells decreased dramatically as the sample concentration increase when irradiated by 808 and 650 nm NIR laser, whereas little cytotoxicity can be detected in the absence of laser illumination. In detail, ∼90% of the HeLa cells are killed by the photothermal effect of Fe-mTa2O5@CuSZnPc/PCM and the generated toxic 1O2 upon combined laser illumination at the concentration of 800 μg mL−1. For deeper insight of the synergistic anticancer therapy effect, HeLa cells stained with propidium iodide (dead cells, red) and calcein-AM (live cells, green) were performed with parallel treatments. As exhibited in Figure 5C, HeLa cells incubated with FemTa2O5@CuS-ZnPc/PCM irradiated with both 808 and 650 nm lasers demonstrate severe apoptosis in contrast to other control groups, indicating the combined hyperthermia and PDT ablation effect of Fe-mTa2O5@CuS-ZnPc/PCM in vitro. In Vitro and in Vivo Dual-Modal Imaging Performance. CT as a mature imaging tool has been widely applied in the field of clinical diagnostic and medical research. There have been many researches on different kinds of nanomaterials that are composed of high number elements, such as bismuth, gold, iodine, and lanthanides available for CT contrast agents.55−58 Ta, which is a nontoxic and biologically inert high-Z element with large X-ray absorption coefficient, has attracted extensive attention in clinical implantation. Thus, the possibility of asprepared nanoparticles as a contrast agent for CT imaging is further evaluated. Figure 6A provides the in vitro CT imaging effects and Hounsfield units (HU) values of Fe-mTa2O5@CuSZnPc/PCM in water with various concentrations, which display a prominent signal enhancement as the sample concentration increases. Fe-mTa2O5@CuS-ZnPc/PCM has a high HU value

Figure 6. (A) In vitro CT images and HU value of Fe-mTa2O5@CuSZnPc/PCM aqueous solutions as a function of the Ta concentration. (B) In vivo CT imaging in tumor-bearing mice before and after intravenous injection of Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles. (C) In vitro MRI images of Fe-mTa2O5@CuS-ZnPc/PCM at varying Fe3+ concentrations ranging from 0 to 10 mM in H2O, and plots of 1/ T1 vs Fe3+ concentration. (D) In vivo T1-weighted MRI in tumorbearing mice before (bottom) and after (top) intravenous injection of Fe-mTa2O5@CuS-ZnPc/PCM. G

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Figure 7. (A) Thermal imaging of U14 tumor-bearing mice before and after intravenous injection with saline (bottom) and Fe-mTa2O5@CuSZnPc/PCM (top) followed by 808 nm laser irradiation for 5 min. (B) Corresponding temperature change curves at tumor sites. (C) Relative tumor growth curves and (D) changes in body weight of the mice treated with different conditions. (E) Average tumor weight and (F) H&E stained slices of tumor tissues collected from different groups after treatment (including control (1), laser only (2), Fe-mTa2O5@CuS-ZnPc/PCM only (3), FemTa2O5@CuS-ZnPc/PCM plus 650 nm (4) or 808 nm (5) laser illumination, and Fe-mTa2O5@CuS-ZnPc/PCM plus 650 and 808 nm laser irradiation (6)). Error bars indicate standard deviations (***p < 0.001, **p < 0.01, or *p < 0.05, by the student’s post-test). All images share the same scale bar of 50 μm.

necrosis of karyolysis could be observed for the tissue section of the control group. As intended, the respective tumor tissue structure of tumor-bearing mice injected with Fe-mTa2O5@ CuS-ZnPc/PCM upon both laser irradiations is seriously destroyed, suggesting the combined PTT and PDT is thorough and highly efficient. Main organs containing heart, liver, spleen, lung, and kidney of the tumor-bearing mice from various treated groups were collected after 14 d of treatment and sliced for H&E staining analysis. The H&E staining result indicates no noticeable histopathological abnormalities and negligible toxic side effects of as-prepared Fe-mTa2O5@CuS-ZnPc/PCM mediated synergistic therapy (Figure S12). Toxicology examination and analysis of Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles were performed by in vivo blood biochemistry test, blood routine analysis, and H&E staining. The tumorbearing mice were injected with Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles at the dosage of 25 mg kg−1. As exhibited in Figure S13A−D, no noticeable difference was observed on the levels of these functional indicators via the blood biochemistry test, suggesting the excellent hepatic and kidney safety of the

verifying that the tumor growth cannot be effectively inhibited through a single PTT modality. This result indicates that the heat (∼49 °C) produced via Fe-mTa2O5@CuS-ZnPc/PCM upon 808 nm NIR laser illumination is sufficient to melt PCM and enhanced the generation of 1O2 excitation with 650 nm laser for effective tumor ablation. Furthermore, the body weight of the tumor-bearing mice maintains stability in the course of treatment, confirming that the resulting nanoparticles have excellent biocompatibility and low toxic side effect (Figure 7D). The representative photographs of tumor excised from tumorbearing mice after 14 d of treatment and corresponding tumor weights are provided in Figure S11 and Figure 7E, respectively. As shown, Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles induce significant photodamage to the tumor upon both laser irradiations, and complete tumor ablation without any regrowth was realized during the 14 d of treatment, especially in comparison with the other control groups. Hematoxylin and eosin (H&E) staining was further provided to analyze and evaluate the synergistic therapeutic efficacy of Fe-mTa2O5@ CuS-ZnPc/PCM nanoparticles. In Figure 7F, no apparent H

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cetyl trimethylammonium bromide (CTAB) and 3 mL of anhydrous ethanol were added into deionized water with appropriate ratio; the transparent solution was achieved after a few minutes of ultrasound. And then, 5 mL of anhydrous ethanol including 100 μL of talum ethoxide was placed into the above solution dropwise with stirring. After 1 h of reaction, the mTa2O5 was obtained via centrifugation and washed with ethanol. After that, the as-synthesized sample was dispersed into FeCl3·6H2O aqueous solution. After ultrasonication for several minutes, the as-obtained homogeneous mixture was heated to 40 °C for 1 h. The Fe-mTa2O5 sample was acquired via centrifugation and rinsed with water several times. Preparation of Fe-mTa2O5@CuS Nanoparticles. First, dopamine (0.4 g) was placed into the as-prepared Fe-mTa2O5 nanoparticles aqueous solution, and 1 mM of CuCl2·2H2O was added simultaneously, which was stirred continuously at room temperature for 12 h. Then, sodium citrate (Na3Cit) and Na2S were added and reacted according to a previous report.26 The resulting Fe-mTa2O5@ CuS nanoparticles were obtained after they were centrifuged and washed three times. Loading of ZnPc and PCM. For the loading of ZnPc into FemTa2O5@CuS nanoparticles, 0.5 g of Fe-mTa2O5@CuS was dispersed in deionized water containing N-hydroxysuccinimide (NHS) (1 mL, 2 mg mL−1), 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDC) (1 mL, 6 mg mL−1), ZnPc (0.5 mg mL−1 with dimethyl sulfoxide (DMSO)), and 0.15 g of tetradecanol. Under magnetic stirring at 40 °C for 12 h, the mixture was centrifuged, and the supernatant was kept for measuring the loading efficiency of ZnPc, followed by several ethanol washes to remove the free PCM and ZnPc. The resulting Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles were obtained. Characterization. TEM and EDS were recorded on an FEI Tecnai T20 microscope. FTIR spectra were performed by an AVATAR 360 FTIR spectrophotometer. The UV−vis absorbance spectra of the samples were obtained using UV-1601 spectrophotometer. ESR spectrum of the sample was acquired by Bruker EMX1598 spectrometer. The DSC and TGA measurements were performed using TA Instruments under nitrogen protection. XRD patterns were achieved on a TTR-III diffractometer within the range from 10° to 80° with a scanning rate of 15° min−1. N2 adsorption/desorption isotherms were gained on a Tristar II 3020 instrument. Pore size distribution was calculated by the Barrett−Joyner−Halenda (BJH) method. The DLS and zeta potential were measured via a zetasizer instrument. All tests were performed at room temperature. Singlet Oxygen Detection. DPBF served as a chemical probe to detect the relative production of 1O2 via measuring the UV−vis absorption spectrum. Typically, DPBF ethanol solution (2 mL, 10 mmol L−1) was placed into 2 mL of Fe-mTa2O5@CuS-ZnPc/PCM samples in ethanol solution (400 μg mL−1). The solution was kept in dark and illuminated by 808 nm NIR laser for 5 min and then 650 nm light for different times (0, 2, 4, 6, 8, and 10 min) at the power densities of 0.5 W cm−2 and 5 mW cm−2, respectively. After irradiation, the mixture was centrifuged, and supernatant was collected for further testing. The comparison experiment was performed under the same conditions. Cytotoxicity Evaluation of Fe-mTa2O 5@CuS-ZnPc/PCM Nanoparticles. For the cytotoxicity study, HeLa cells were placed into 96-well plate incubation overnight. These HeLa cells were treated with Fe-mTa2O5@CuS-ZnPc/PCM at different concentrations (0, 12.5, 25, 50, 100, 200, 400, and 800 μg mL−1) for 6 h and then irradiated with 808 (0.5 W cm−2) and 650 nm (5 mW cm−2) laser light alternately. For comparison, the cells treated with Fe-mTa2O5@CuSZnPc/PCM illumination with a single laser (808 or 650 nm laser for 30 min with the same power density as mentioned above) were also performed. Simultaneously, the temperature was monitored via infrared thermal imager. Cell viability was determined via a standard MTT assay. In addition, the survival circumstance of cells was also detected via Calcein AM/propidium iodide marked. After incubation, the monolayer HeLa cells were obtained and treated with FemTa2O5@CuS-ZnPc/PCM for 6 h, then illuminated with different

mice injected with Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles. Simultaneously, standard blood parameters were measured and presented in Figure S13E−L; as expected, all of these markers are in the normal range, and no significant abnormal phenomenon was detected compared with the control group, showing an excellent blood compatibility. To further evaluate the potential tissue damage and in vivo toxicity induced by Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles, H&E staining analysis was provided (Figure S13M). In contrast to the control group, the tissue sections of major organs were also collected from tumor-bearing mice treated with Fe-mTa2O5@ CuS-ZnPc/PCM. No apparent cell necrosis can be noticed in the major organs after 14 d of treatment. It can be illustrated that the versatile Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles have an excellent biocompatibility for living mice, which plays a crucial role in in vivo biomedical applications. The blood circulation and biodistribution behavior of FemTa2O5@CuS-ZnPc/PCM nanoparticles were studied; the blood samples and tissues were achieved at various time points from the tumor-bearing mice injected intravenously with FemTa2O5@CuS-ZnPc/PCM. The Ta5+ levels in the blood samples were detected via inductively coupled plasma mass spectrometry (ICP-MS). As demonstrated in Figure S14A, both a two-compartment model and a long blood circulation half-life during the second phase (∼7.68 h) were obtained. The long circulation time of Fe-mTa2O5@CuS-ZnPc/PCM in the blood is beneficial for effective tumor accumulation, which was calculated to be ∼6.9% ID g−1 (percent of injected dose per gram tissue) at 24 h post injection (Figure S14B). Such efficient tumor accumulation behavior of Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles can be assigned to the enhanced permeability and retention effect.

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CONCLUSIONS In summary, we presented a new kind of Fe-mTa2O5@CuSZnPc/PCM multifunctional therapeutic nanosystem for enhanced synergistic phototherapy. Fe-mTa2O5 nanoparticles have been served as ideal nanocarriers to grow CuS nanoparticles with good photothermal effect and load photosensitizer ZnPc, then sealed by PCM. PCM plays the role of thermal switch, avoiding premature leakage of photosensitizer. The nanosystem exhibited the ability of thermoresponsive release, which provides 1O2 generation performance (from photosensitizer ZnPc) as well as a strong NIR photothermal conversion capability (from CuS nanoparticles) with good stability. Importantly, the intrinsic properties of Fe-mTa2O5 nanoparticles allowed them to act as both CT/T1-MRI contrast agents. The in vivo antitumor therapeutic effect was implemented via the synergistic phototherapy. The nanoparticles with excellent photostability and biocompatibility have favorable development foreground for further clinical theranostic application. Furthermore, this nanosystem should be also applicable to deliver other drugs and opens a new prospect for the development of multifunctional nanomedical therapeutic system.

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EXPERIMENTAL SECTION

Reagents and Materials. All of the chemicals used in this paper were purchased from Sigma-Aldrich except tantalum ethoxide, which was purchased from Alfa. Chemicals were used as received without further purification. Preparation of Fe3+-Doped Mesoporous Tantalum Oxide Nanoparticles (Fe-mTa2O5 Nanoparticles). Typically, 0.25 g of I

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nm light for 5 min with the power density of 0.5 W cm−2 and 5 mW cm−2, respectively (group 6). Similarly, groups 4 and 5 were only irradiated with a single laser (650 nm laser or 808 nm NIR light). Group 3 only injected nanoparticles without laser irradiation. Group 2 was only excited with 808 and 650 nm laser alternatively. Finally, Group 1 was injected with saline set as control. Tumor sizes and body weight were monitored and recorded every 2 d for two weeks. The digital caliper was utilized to measure the length and width of the tumors. The tumor volume was calculated according to the following formula: V = (width2 × length)/2. Histological Staining. After two weeks, mice were dissected with tumors and other major organs collected from different treatment groups for further analysis. The tissue sections were stained with H&E following the typical procedure. All sections were imaged via CLSM. In Vivo Blood Circulation Behavior and Biodistribution Analysis. The U14 tumor-bearing mice (n = 3) were intravenously injected with Fe-mTa2O5@CuS-ZnPc/PCM (10 mg kg−1). Then, the blood samples, major organs, and tumors were collected at various time points, followed by weighing and dissolution in chloroazotic acid (HCl/HNO3 = 1:3). The Ta5+ content of the samples was quantified using ICP-MS.

kinds of lasers. Finally, the live and dead cells were observed via imaging. In Vitro Biocompatibility of Fe-mTa2O5@CuS-ZnPc/PCM. This test was conducted to determine the biocompatibility of asprepared sample, which behaved similarly to cytotoxicity tests. The only difference was that L929 cells were utilized to evaluate the biocompatibility. Cellular Uptake Observation of Fe-mTa2O5@CuS-ZnPc/PCM. To investigate the cellular uptake of the as-prepared nanoparticles, the nanoparticles modified with FITC were synthesized. First, FITC (2 mg mL−1) and 250 μL of (3-aminopropyl)triethoxysilane (APTES) were dissolved in ethanol with magnetic stirring in the dark for 12 h, and APTES-FITC was obtained. Then, 10 μL of this solution was added to the final nanoparticles with rigorous stirring for 12 h shielded from light; FITC-labeled Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles were achieved via centrifugation. HeLa cells were placed into a 6-well culture plate and incubated overnight. The cells were incubated with FITC-modified Fe-mTa2O5@CuS-ZnPc/PCM (1 mL, 400 μg mL−1) at various intervals (1 and 3 h). Then the cells were rinsed with PBS and stained with 4′,6-diamidino-2-phenylindole (DAPI; 10 μg mL−1) to label nucleus. At last, the samples were irradiated with 405 nm for nuclei and 528 nm for fluorescence of FITC, respectively. The cells were observed via CLSM. Singlet Oxygen Production in Cells. 2′,7′-Dichlorofluorescein diacetate (DCFH-DA) served as a chemical probe to monitor the generation of intracellular 1O2. Simply, HeLa cells were incubated with Fe-mTa2O5@CuS-ZnPc/PCM (1 mL, 400 μg mL−1) for 3 h in a CO2 incubator, followed by illumination upon 808 nm laser for 5 min and then 650 nm light for 5 min alternatively. Then, the cells were treated with DCFH-DA (10 μM) for 20 min in the dark, and the generation of 1 O2 was observed via fluorescence imaging. Red Blood Cells Oxidative Hemolysis. The Fe-mTa2O5@CuSZnPc/PCM nanoparticle-triggered hemolysis was investigated. Blood cells suspension (0.3 mL) was treated with 1.2 mL of Fe-mTa2O5@ CuS-ZnPc/PCM phosphate buffer solution with various concentrations (15.63, 31.25, 62.5, 125, and 500 μg mL−1), deionized water, and PBS regarded as a positive and negative control, respectively. The content of hemolysis was calculated by measuring the absorbance via UV−vis spectrometer. Infrared Thermal Imaging. Mice bearing U14 tumors treated with saline and Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles (200 μL, 400 μg mL−1) were excited with the 808 nm NIR light for 5 min with the power density of 0.5 W cm−2, and simultaneously they were observed and imaged by an infrared thermal camera. In Vitro and in Vivo CT Imaging. The CT imaging effect of FemTa2O5@CuS-ZnPc/PCM nanoparticles was obtained via a CT scanner. The samples were dispersed in saline with various concentrations for in vitro experiments. The signal intensity was recorded. In vivo CT imaging was performed via injected FemTa2O5@CuS-ZnPc/PCM nanoparticles (200 μL, 400 μg mL−1) into the tumor-bearing mice intravenously. The signal intensity was detected before and after 24 h of injection. In Vitro and in Vivo T1-Weighted Magnetic Resonance Imaging. Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles were dispersed in deionized water with various Fe3+ concentrations. T1 signal values versus repetition time (RT) were measured with a 3 T MR scanner. Finally, the r1 relaxation value was calculated via the fitted curve of 1/T 1 relaxation time (s −1 ) as a function of Fe 3+ concentrations. For in vivo MRI, tumor-bearing mice were intravenously injected with Fe-mTa2O5@CuS-ZnPc/PCM (200 μL, 400 μg mL−1). The in vivo MRI was performed at 24 h postinjection. Animal Experiments. Female Kunming mice (18−22 g) were achieved from Harbin Veterinary Research Institute. The tumors were established by subcutaneous injection of mouse U14 cervical cancer cell line at left armpit. When the average tumor size reached 80 mm3, the tumor-bearing mice were separated into six groups (n = 5). The Fe-mTa2O5@CuS-ZnPc/PCM nanoparticles (200 μL, 400 μg mL−1) were injected into the tumor-bearing mice intravenously from 3 to 6 groups. After postinjection for 24 h, the tumor sites were repeatedly illuminated with 808 nm NIR laser for 5 min and then exposed to 650

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.7b02959. TEM and EDS images of Fe-mTa2O5 nanoparticles; XRD patterns of Fe-mTa2O5 and Fe-mTa2O5@CuS nanoparticles; TEM image of CuS nanoparticles; the standard curve for ZnPc solution and absorption spectrum of ZnPc; FTIR spectra and XPS survey spectrum of the final sample; UV−vis absorption spectra of DPBF for detecting the 1O2 generated from different samples upon laser irradiation; temperature change curves of different samples irradiation upon laser; CLSM images of HeLa cells after incubation with FemTa2O5CuS-ZnPc/PCM for different times; hemolytic experiment of the resulting nanoparticles; the photographs of excised tumor tissues and mice from different groups (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. (S.G.) *E-mail: [email protected]. (P.-P.Y.) ORCID

Piaoping Yang: 0000-0002-9555-1803 Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the National Natural Science Foundation of China (NSFC 51772059, 51472058, and 51602072), the Natural Science Foundation of Heilongjiang Province (B2015020), the Special Innovation Talents of Harbin Science and Technology (2016RAXXJ005), a General Financial Grant from the China Postdoctoral Science Foundation (2015M581430), Ph.D. Student Research and Innovation J

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Y. Activatable Singlet Oxygen Generation from Lipid Hydroperoxide Nanoparticles for Cancer Therapy. Angew. Chem., Int. Ed. 2017, 56, 6492−6496. (17) Zeng, S. J.; Yi, Z. G.; Lu, W.; Qian, C.; Wang, H. B.; Rao, L.; Zeng, T. M.; Liu, H. R.; Liu, H. J.; Fei, B.; Hao, J. H. Simultaneous Realization of Phase/Size Manipulation, Upconversion Luminescence Enhancement, and Blood Vessel Imaging in Multifunctional Nanoprobes through Transition Metal Mn2+ Doping. Adv. Funct. Mater. 2014, 24, 4051−4059. (18) Idris, N. M.; Gnanasammandhan, M. K.; Zhang, J.; Ho, P. C.; Mahendran, R.; Zhang, Y. In Vivo Photodynamic Therapy Using Upconversion Nanoparticles as Remote-Controlled Nanotransducers. Nat. Med. 2012, 18, 1580−1587. (19) Dong, W. J.; Li, Y. S.; Niu, D. C.; Ma, Z.; Gu, J. L.; Chen, Y.; Zhao, W. R.; Liu, X. H.; Liu, C. S.; Shi, J. L. Facile Synthesis of Monodisperse Superparamagnetic Fe3O4 Core@Hybrid@Au Shell Nanocomposite for Bimodal Imaging and Photothermal Therapy. Adv. Mater. 2011, 23, 5392−5398. (20) Huang, P.; Lin, J.; Li, W. W.; Rong, P. F.; Wang, Z.; Wang, S. J.; Wang, X. P.; Sun, X. L.; Aronova, M.; Niu, G.; Leapman, R. D.; Nie, Z. H.; Chen, X. Y. Biodegradable Gold Nanovesicles with an Ultrastrong Plasmonic Coupling Effect for Photoacoustic Imaging and Photothermal Therapy. Angew. Chem., Int. Ed. 2013, 52, 13958−13964. (21) Tian, Q. W.; Hu, J. Q.; Zhu, Y. H.; Zou, R. J.; Chen, Z. G.; Yang, S. P.; Li, R. W.; Su, Q. Q.; Han, Y.; Liu, X. G. Sub-10 nm Fe3O4@ Cu2‑XS Core-Shell Nanoparticles for Dual-Modal Imaging and Photothermal Therapy. J. Am. Chem. Soc. 2013, 135, 8571−8577. (22) He, J. J.; Zheng, W.; Ligmajer, F. L.; Chan, C. F.; Bao, Z. Y.; Wong, K. L.; Chen, X. Y.; Hao, J. H.; Dai, J. Y.; Yu, S. F.; Lei, D. Y. Plasmonic Enhancement and Polarization Dependence of Nonlinear Upconversion Emissions from Single Gold Nanorod@SiO 2@ CaF2:Yb3+,Er3+ Hybrid Core-Shell-Satellite Nanostructures. Light: Sci. Appl. 2016, 6, e16217. (23) Chen, Z. W.; Li, Z. H.; Wang, J. S.; Ju, E. G.; Zhou, L.; Ren, J. S.; Qu, X. G. A Multi-Synergistic Platform for Sequential IrradiationActivated High-Performance Apoptotic Cancer Therapy. Adv. Funct. Mater. 2014, 24, 522−529. (24) Yin, M. L.; Li, Z. H.; Ju, E. G.; Wang, Z. Z.; Dong, K.; Ren, J. S.; Qu, X. G. Multifunctional Upconverting Nanoparticles for NearInfrared Triggered and Synergistic Antibacterial Resistance Therapy. Chem. Commun. 2014, 50, 10488−10490. (25) Feng, L. L.; He, F.; Liu, B.; Yang, G. X.; Gai, S. L.; Yang, P. P.; Li, C. X.; Dai, Y. L.; Lv, R. C.; Lin, J. G-C3N4 Coated Upconversion Nanoparticles for 808 nm Near-Infrared Light Triggered Phototherapy and Multiple Imaging. Chem. Mater. 2016, 28, 7935−7946. (26) Lv, R. C.; Yang, P. P.; Hu, B.; Xu, J. T.; Shang, W. T.; Tian, J. In Situ Growth Strategy to Integrate Up-Conversion Nanoparticles with Ultrasmall CuS for Photothermal Theranostics. ACS Nano 2017, 11, 1064−1072. (27) Dong, K.; Liu, Z.; Li, Z. H.; Ren, J. S.; Qu, X. G. Hydrophobic Anticancer Drug Delivery by a 980 nm Laser-Driven Photothermal Vehicle for Efficient Synergistic Therapy of Cancer Cells in Vivo. Adv. Mater. 2013, 25, 4452−4458. (28) Liu, Z.; Liu, X. J.; Du, Y. D.; Ren, J. S.; Qu, X. G. Using Plasmonic Copper Sulfide Nanocrystals as Smart Light-Driven Sterilants. ACS Nano 2015, 9, 10335−10346. (29) Guo, L. R.; Yan, D. D.; Yang, D. F.; Li, Y. J.; Wang, X. D.; Zalewski, O.; Yan, B. F.; Lu, W. Combinatorial Photothermal and Immuno Cancer Therapy Using Chitosan-Coated Hollow Copper Sulfide Nanoparticles. ACS Nano 2014, 8, 5670−5681. (30) Li, Y.; Lu, W.; Huang, Q.; Li, C.; Chen, W. Copper Sulfide Nanoparticles for Photothermal Ablation of Tumor Cells. Nanomedicine 2010, 5, 1161−1171. (31) Ding, K.; Zeng, J.; Jing, L.; Qiao, R.; Jiao, M.; Li, Z.; Gao, M.; Liu, C. Aqueous Synthesis of PEGylated Copper Sulfide Nanoparticles for Photoacoustic Imaging of Tumors. Nanoscale 2015, 7, 11075− 11081. (32) Zha, Z.; Zhang, S.; Deng, Z.; Li, Y.; Li, C.; Dai, Z. EnzymeResponsive Copper Sulphide Nanoparticles for Combined Photo-

Fund of the Fundamental Research Funds for the Central Universities (HEUGIP201711), the Fundamental Research funds for the Central Universities, and Research Fund for Key Laboratory of the Ministry of Education for Advanced Catalysis Materials are greatly acknowledged.

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REFERENCES

(1) Fan, L.; Strasser-Weippl, K.; Li, J.-J.; St Louis, J.; Finkelstein, D. M.; Yu, K.-D.; Chen, W.-Q.; Shao, Z.-M.; Goss, P. E. Breast Cancer in China. Lancet Oncol. 2014, 15, 279−289. (2) Koboldt, D. C.; et al. Comprehensive Molecular Portraits of Human Breast Tumours. Nature 2012, 490, 61−70. (3) Roberts, K. G.; et al. Genetic Alterations Activating Kinase and Cytokine Receptor Signaling in High-Risk Acute Lymphoblastic Leukemia. Cancer Cell 2012, 22, 153−166. (4) Del Mastro, L. y.; et al. Fluorouracil and Dose-Dense Chemotherapy in Adjuvant Treatment of Patients with Early-Stage Breast Cancer: An Open-Label, 2 × 2 Factorial, Randomised Phase 3 Trial. Lancet 2015, 385, 1863−1872. (5) Farokhzad, O. C.; Langer, R. Nanomedicine: Developing Smarter Therapeutic and Diagnostic Modalities. Adv. Drug Delivery Rev. 2006, 58, 1456−1459. (6) Law, W. C.; Yong, K. T.; Roy, I.; Xu, G.; Ding, H.; Bergey, E. J.; Zeng, H.; Prasad, P. N. Optically and Magnetically Doped Organically Modified Silica Nanoparticles as Efficient Magnetically Guided Biomarkers for Two-Photon Imaging of Live Cancer Cells. J. Phys. Chem. C 2008, 112, 7972−7977. (7) Lee, J. E.; Lee, N.; Kim, H.; Kim, J.; Choi, S. H.; Kim, J. H.; Kim, T.; Song, I. C.; Park, S. P.; Moon, W. K.; Hyeon, T. Uniform Mesoporous Dye-Doped Silica Nanoparticles Decorated with Multiple Magnetite Nanocrystals for Simultaneous Enhanced Magnetic Resonance Imaging, Fluorescence Imaging, and Drug Delivery. J. Am. Chem. Soc. 2010, 132, 552−557. (8) Chen, G. Y.; Roy, I.; Yang, C. H.; Prasad, P. N. Nanochemistry and Nanomedicine for Nanoparticle-Based Diagnostics and Therapy. Chem. Rev. 2016, 116, 2826−2885. (9) Cheng, L.; Shen, S.; Shi, S.; Yi, Y.; Wang, X.; Song, G.; Yang, K.; Liu, G.; Barnhart, T. E.; Cai, W.; Liu, Z. FeSe2-Decorated Bi2Se3 Nanosheets Fabricated Via Cation Exchange for Chelator-Free Cu-64Labeling and Multimodal Image-Guided Photothermal-Radiation Therapy. Adv. Funct. Mater. 2016, 26, 2185−2197. (10) Fan, W.; Shen, B.; Bu, W.; Chen, F.; He, Q.; Zhao, K.; Zhang, S.; Zhou, L.; Peng, W.; Xiao, Q.; Ni, D.; Liu, J.; Shi, J. A Smart Upconversion-Based Mesoporous Silica Nanotheranostic System for Synergetic Chemo-/Radio-/Photodynamic Therapy and Simultaneous MR/UCL Imaging. Biomaterials 2014, 35, 8992−9002. (11) Feng, L. Z.; Tao, D. L.; Dong, Z. L.; Chen, Q.; Chao, Y.; Liu, Z.; Chen, M. W. Near-Infrared Light Activation of Quenched Liposomal Ce6 for Synergistic Cancer Phototherapy with Effective Skin Protection. Biomaterials 2017, 127, 13−24. (12) Wang, G. H.; Zhang, F.; Tian, R.; Zhang, L. W.; Fu, G. F.; Yang, L. L.; Zhu, L. Nanotubes-Embedded Indocyanine Green-Hyaluronic Acid Nanoparticles for Photoacoustic-Imaging-Guided Phototherapy. ACS Appl. Mater. Interfaces 2016, 8, 5608−5617. (13) Xie, L. S.; Wang, G. H.; Zhou, H.; Zhang, F.; Guo, Z. D.; Liu, C.; Zhang, X. Z.; Zhu, L. Functional Long Circulating Single Walled Carbon Nanotubes for Fluorescent/Photoacoustic Imaging-Guided Enhanced Phototherapy. Biomaterials 2016, 103, 219−228. (14) Guo, M.; Mao, H. J.; Li, Y. L.; Zhu, A. J.; He, H.; Yang, H.; Wang, Y. Y.; Tian, X.; Ge, C. C.; Peng, Q. L.; Wang, X. Y.; Yang, X. L.; Chen, X. Y.; Liu, G.; Chen, H. B. Dual Imaging-Guided Photothermal/ Photodynamic Therapy Using Micelles. Biomaterials 2014, 35, 4656− 4666. (15) Zhou, Z. J.; Song, J. B.; Nie, L. M.; Chen, X. Y. Reactive Oxygen Species Generating Systems Meeting Challenges of Photodynamic Cancer Therapy. Chem. Soc. Rev. 2016, 45, 6597−6626. (16) Zhou, Z. J.; Song, J. B.; Tian, R.; Yang, Z.; Yu, G. C.; Lin, L. S.; Zhang, G. F.; Fan, W. P.; Zhang, F. W.; Niu, G.; Nie, L. M.; Chen, X. K

DOI: 10.1021/acs.inorgchem.7b02959 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry acoustic Imaging, Tumor-Selective Chemotherapy and Photothermal Therapy. Chem. Commun. 2013, 49, 3455−3457. (33) Chen, F.; Hong, H.; Goel, S.; Graves, S. A.; Orbay, H.; Ehlerding, E. B.; Shi, S.; Theuer, C. P.; Nickles, R. J.; Cai, W. In Vivo Tumor Vasculature Targeting of CuS@ MSN Based Theranostic Nanomedicine. ACS Nano 2015, 9, 3926−3934. (34) Zhang, C.; Fu, Y. Y.; Zhang, X. J.; Yu, C. S.; Zhao, Y.; Sun, S. K. BSA-Directed Synthesis of CuS Nanoparticles as A Biocompatible Photothermal Agent for Tumor Ablation In Vivo. Dalton Trans. 2015, 44, 13112−13118. (35) He, Q.; Shi, J. Mesoporous Silica Nanoparticle Based Nano Drug Delivery Systems: Synthesis, Controlled Drug Release and Delivery, Pharmacokinetics and Biocompatibility. J. Mater. Chem. 2011, 21, 5845−5855. (36) Luo, G.; Chen, W.; Jia, H.; Sun, Y.; Cheng, H.; Zhuo, R.; Zhang, X. An Indicator-Guided Photo-Controlled Drug Delivery System Based on Mesoporous Silica/Gold Nanocomposites. Nano Res. 2015, 8, 1893−1905. (37) Vakrat-Haglili, Y.; Weiner, L.; Brumfeld, V.; Brandis, A.; Salomon, Y.; McIlroy, B.; Wilson, B. C.; Pawlak, A.; Rozanowska, M.; Sarna, T.; Scherz, A. The Microenvironment Effect on the Generation of Reactive Oxygen Species by Pd-Bacteriopheophorbide. J. Am. Chem. Soc. 2005, 127, 6487−6497. (38) Lucky, S. S.; Muhammad Idris, N.; Li, Z. Q.; Huang, K.; Soo, K. C.; Zhang, Y. Titania Coated Upconversion Nanoparticles for NearInfrared Light Triggered Photodynamic Therapy. ACS Nano 2015, 9, 191−205. (39) Yang, K.; Hu, L. L.; Ma, X. X.; Ye, S. Q.; Cheng, L.; Shi, X. Z.; Li, C. H.; Li, Y. G.; Liu, Z. Multimodal Imaging Guided Photothermal Therapy Using Functionalized Graphene Nanosheets Anchored with Magnetic Nanoparticles. Adv. Mater. 2012, 24, 1868−1872. (40) Cheng, L.; Liu, J. J.; Gu, X.; Gong, H.; Shi, X. Z.; Liu, T.; Wang, C.; Wang, X. Y.; Liu, G.; Xing, H. Y.; Bu, W. B.; Sun, B. Q.; Liu, Z. PEGylated WS2 Nanosheets as a Multifunctional Theranostic Agent for in Vivo Dual-Modal CT/Photoacoustic Imaging Guided Photothermal Therapy. Adv. Mater. 2014, 26, 1886−1893. (41) Song, X. J.; Gong, H.; Yin, S. N.; Cheng, L.; Wang, C.; Li, Z. W.; Li, Y. G.; Wang, X. Y.; Liu, G.; Liu, Z. Ultra-Small Iron Oxide Doped Polypyrrole Nanoparticles for in Vivo Multimodal Imaging Guided Photothermal Therapy. Adv. Funct. Mater. 2014, 24, 1194−1201. (42) Ai, X. Z.; Ho, C. J. H.; Aw, J.; Attia, A. B. E.; Mu, J.; Wang, Y.; Wang, X. Y.; Wang, Y.; Liu, X. G.; Chen, H. B.; Gao, M. Y.; Chen, X. Y.; Yeow, E. K. L.; Liu, G.; Olivo, M.; Xing, B. G. In Vivo Covalent Cross-Linking of Photon-Converted Rare-Earth Nanostructures for Tumour Localization and Theranostics. Nat. Commun. 2016, 7, 10432. (43) Lu, S.; Tu, D. T.; Hu, P.; Xu, J.; Li, R. F.; Wang, M.; Chen, Z.; Huang, M. D.; Chen, X. Y. Multifunctional Nano-Bioprobes Based on Rattle-Structured Upconverting Luminescent Nanoparticles. Angew. Chem., Int. Ed. 2015, 54, 7915−7919. (44) Lei, P. P.; Zhang, P.; Yao, S.; Song, S. Y.; Dong, L. L.; Xu, X.; Liu, X. L.; Du, K. M.; Feng, J.; Zhang, H. J. Optimization of Bi3+ in Upconversion Nanoparticles Induced Simultaneous Enhancement of Near-Infrared Optical and X-Ray Computed Tomography Imaging Capability. ACS Appl. Mater. Interfaces 2016, 8, 27490−27497. (45) Lei, P. P.; Zhang, P.; Yuan, Q. H.; Wang, Z.; Dong, L. L.; Song, S. Y.; Xu, X.; Liu, X. L.; Feng, J.; Zhang, H. J. Yb3+/Er3+-Codoped Bi2O3 Nanospheres: Probe for Upconversion Luminescence Imaging and Binary Contrast Agent for Computed Tomography Imaging. ACS Appl. Mater. Interfaces 2015, 7, 26346−26354. (46) Ju, Q.; Tu, D. T.; Liu, Y. S.; Li, R. F.; Zhu, H. M.; Chen, J. C.; Chen, Z.; Huang, M. D.; Chen, X. Y. Amine-Functionalized Lanthanide-Doped KGdF 4 Nanocrystals as Potential Optical/ Magnetic Multimodal Bioprobes. J. Am. Chem. Soc. 2012, 134, 1323−1330. (47) Zheng, X. Y.; Wang, Y. J.; Sun, L. D.; Chen, N. X.; Li, L. D.; Shi, S.; Malaisamy, S.; Yan, C. H. TbF3 Nanoparticles as Dual-Mode Contrast Agents for Ultrahigh Field Magnetic Resonance Imaging and X-Ray Computed Tomography. Nano Res. 2016, 9, 1135−1147.

(48) Wang, L. Y.; Bao, J.; Wang, L.; Zhang, F.; Li, Y. D. One-Pot Synthesis and Bioapplication of Amine-Functionalized Magnetite Nanoparticles and Hollow Nanospheres. Chem. - Eur. J. 2006, 12, 6341−6347. (49) Dai, Y.; Xiao, H.; Liu, J.; Yuan, Q.; Ma, P. a.; Yang, D.; Li, C.; Cheng, Z.; Hou, Z.; Yang, P.; Lin, J. In Vivo Multimodality Imaging and Cancer Therapy by Near-Infrared Light-Triggered Trans-Platinum Pro-Drug-Conjugated Upconverison Nanoparticles. J. Am. Chem. Soc. 2013, 135, 18920−18929. (50) Chalela, J. A.; Kidwell, C. S.; Nentwich, L. M.; Luby, M.; Butman, J. A.; Demchuk, A. M.; Hill, M. D.; Patronas, N.; Latour, L.; Warach, S. Magnetic Resonance Imaging and Computed Tomography in Emergency Assessment of Patients with Suspected Acute Stroke: A Prospective Comparison. Lancet 2007, 369, 293−298. (51) Popovtzer, R.; Agrawal, A.; Kotov, N. A.; Popovtzer, A.; Balter, J.; Carey, T. E.; Kopelman, R. Targeted Gold Nanoparticles Enable Molecular CT Imaging of Cancer. Nano Lett. 2008, 8, 4593−4596. (52) Bao, J.; Chen, W.; Liu, T. T.; Zhu, Y. L.; Jin, P. Y.; Wang, L. Y.; Liu, J. F.; Wei, Y. G.; Li, Y. D. Bifunctional Au-Fe3O4 Nanopartides for Protein Separation. ACS Nano 2007, 1, 293−298. (53) Dou, Y.; Guo, Y.; Li, X.; Li, X.; Wang, S.; Wang, L.; Lv, G.; Zhang, X.; Wang, H.; Gong, X.; Chang, J. Size-Tuning Ionization to Optimize Gold Nanoparticles for Simultaneous Enhanced CT Imaging and Radiotherapy. ACS Nano 2016, 10, 2536−2548. (54) Liu, J.-N.; Bu, W.-B.; Shi, J.-L. Silica Coated Upconversion Nanoparticles: A Versatile Platform for the Development of Efficient Theranostics. Acc. Chem. Res. 2015, 48, 1797−1805. (55) Song, G.; Liang, C.; Gong, H.; Li, M.; Zheng, X.; Cheng, L.; Yang, K.; Jiang, X.; Liu, Z. Core-Shell MnSe@Bi2Se3 Fabricated Via a Cation Exchange Method as Novel Nanotheranostics for Multimodal Imaging and Synergistic Thermoradiotherapy. Adv. Mater. 2015, 27, 6110−6117. (56) Yong, Y.; Cheng, X.; Bao, T.; Zu, M.; Yan, L.; Yin, W.; Ge, C.; Wang, D.; Gu, Z.; Zhao, Y. Tungsten Sulfide Quantum Dots as Multifunctional Nanotheranostics for in Vivo Dual-Modal ImageGuided Photothermal/Radiotherapy Synergistic Therapy. ACS Nano 2015, 9, 12451−12463. (57) Oh, M. H.; Lee, N.; Kim, H.; Park, S. P.; Piao, Y.; Lee, J.; Jun, S. W.; Moon, W. K.; Choi, S. H.; Hyeon, T. Large-Scale Synthesis of Bioinert Tantalum Oxide Nanoparticles for X-Ray Computed Tomography Imaging and Bimodal Image-Guided Sentinel Lymph Node Mapping. J. Am. Chem. Soc. 2011, 133, 5508−5515. (58) Song, G.; Chen, Y.; Liang, C.; Yi, X.; Liu, J.; Sun, X.; Shen, S.; Yang, K.; Liu, Z. Catalase-Loaded TaOx Nanoshells as BioNanoreactors Combining High-Z Element and Enzyme Delivery for Enhancing Radiotherapy. Adv. Mater. 2016, 28, 7143−7149. (59) Liu, X.; Lee, C.; Law, W. C.; Zhu, D. W.; Liu, M. X.; Jeon, M.; Kim, J.; Prasad, P. N.; Kim, C.; Swihart, M. T. Au-Cu2‑XSe Heterodimer Nanoparticles with Broad Localized Surface Plasmon Resonance as Contrast Agents for Deep Tissue Imaging. Nano Lett. 2013, 13, 6298−6298. (60) Chen, F.; Goel, S.; Valdovinos, H. F.; Luo, H.; Hernandez, R.; Barnhart, T. E.; Cai, W. In Vivo Integrity and Biological Fate of Chelator-Free Zirconium-89-Labeled Mesoporous Silica Nanoparticles. ACS Nano 2015, 9, 7950−7959. (61) Chen, Y.; Chen, H.; Zhang, S.; Chen, F.; Sun, S.; He, Q.; Ma, M.; Wang, X.; Wu, H.; Zhang, L.; Zhang, L.; Shi, J. Structure-Property Relationships in Manganese Oxide-Nnesoporous Silica Nanoparticles Used for T1-Weighted MRI and Simultaneous Anti-Cancer Drug Delivery. Biomaterials 2012, 33, 2388−2398. (62) Liu, T.; Wu, G.; Cheng, J.; Lu, Q.; Yao, Y.; Liu, Z.; Zhu, D.; Zhou, J.; Xu, J.; Zhu, J.; He, D. Multifunctional Lymph-Targeted Platform Based on Mn@mSiO(2) Nanocomposites: Combining PFOB for Dual-Mode Imaging and Dox for Cancer Diagnose and Treatment. Nano Res. 2016, 9, 473−489. (63) Kim, S. M.; Im, G. H.; Lee, D.-G.; Lee, J. H.; Lee, W. J.; Lee, I. S. Mn2+-Doped Silica Nanoparticles for Hepatocyte-Targeted Detection of Liver Cancer in T1-Weighted MRI. Biomaterials 2013, 34, 8941− 8948. L

DOI: 10.1021/acs.inorgchem.7b02959 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry (64) Chen, Y.; Yin, Q.; Ji, X.; Zhang, S.; Chen, H.; Zheng, Y.; Sun, Y.; Qu, H.; Wang, Z.; Li, Y.; Wang, X.; Zhang, K.; Zhang, L.; Shi, J. Manganese Oxide-Based Multifunctionalized Mesoporous Silica Nanoparticles for PH-Responsive MRI, Ultrasonography and Circumvention of MDR in Cancer Cells. Biomaterials 2012, 33, 7126−7137. (65) Shen, S.; Zhu, C.; Huo, D.; Yang, M.; Xue, J.; Xia, Y. A Hybrid Nanomaterial for the Controlled Generation of Free Radicals and Oxidative Destruction of Hypoxic Cancer Cells. Angew. Chem., Int. Ed. 2017, 56, 8801−8804. (66) Long, D.; Liu, T. L.; Tan, L. F.; Shi, H. T.; Liang, P.; Tang, S. S.; Wu, Q.; Yu, J.; Dou, J. P.; Meng, X. W. Multisynergistic Platform for Tumor Therapy by Mild Microwave Irradiation-Activated Chemotherapy and Enhanced Ablation. ACS Nano 2016, 10, 9516−9528. (67) Huang, P.; Qian, X. Q.; Chen, Y.; Yu, L. D.; Lin, H.; Wang, L. Y.; Zhu, Y. F.; Shi, J. L. Metalloporphyrin-Encapsulated Biodegradable Nanosystems for Highly Efficient Magnetic Resonance ImagingGuided Sonodynamic Cancer Therapy. J. Am. Chem. Soc. 2017, 139, 1275−1284. (68) He, W.; Liu, Y.; Wamer, W. G.; Yin, J.-J. Electron Spin Resonance Spectroscopy for the Study of Nanomaterial-Mediated Generation of Reactive Oxygen Species. J. Food. Drug. Anal. 2014, 22, 49−63. (69) He, W.; Kim, H.-K.; Wamer, W. G.; Melka, D.; Callahan, J. H.; Yin, J.-J. Photogenerated Charge Carriers and Reactive Oxygen Species in ZnO/Au Hybrid Nanostructures with Enhanced Photocatalytic and Antibacterial Activity. J. Am. Chem. Soc. 2014, 136, 750−757. (70) Liu, Y.; Ai, K.; Liu, J.; Deng, M.; He, Y.; Lu, L. DopamineMelanin Colloidal Nanospheres: An Efficient Near-Infrared Photothermal Therapeutic Agent for in Vivo Cancer Therapy. Adv. Mater. 2013, 25, 1353−1359. (71) Kim, B. H.; Lee, N.; Kim, H.; An, K.; Park, Y. I.; Choi, Y.; Shin, K.; Lee, Y.; Kwon, S. G.; Na, H. B.; Park, J.-G.; Ahn, T.-Y.; Kim, Y.-W.; Moon, W. K.; Choi, S. H.; Hyeon, T. Large-Scale Synthesis of Uniform and Extremely Small-Sized Iron Oxide Nanoparticles for HighResolution T1 Magnetic Resonance Imaging Contrast Agents. J. Am. Chem. Soc. 2011, 133, 12624−12631.

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DOI: 10.1021/acs.inorgchem.7b02959 Inorg. Chem. XXXX, XXX, XXX−XXX