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Nanozymes Decorated Metal-Organic Frameworks for Enhanced Photodynamic Therapy Yan Zhang, Faming Wang, Chaoqun Liu, Zhenzhen Wang, LiHua Kang, Yanyan Huang, Kai Dong, Jinsong Ren, and Xiaogang Qu ACS Nano, Just Accepted Manuscript • DOI: 10.1021/acsnano.7b07746 • Publication Date (Web): 31 Dec 2017 Downloaded from http://pubs.acs.org on December 31, 2017

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Nanozymes Decorated Metal-Organic Frameworks for Enhanced Photodynamic Therapy Yan Zhang,†,‡ Faming Wang,†,‡ Chaoqun Liu,†,‡ Zhenzhen Wang,†,‡ LiHua Kang,*,# Yanyan Huang,†,‡ Kai Dong,† Jinsong Ren,*,† and Xiaogang Qu*,† †

State Key Laboratory of Rare Earth Resource Utilization and Laboratory of Chemical Biology,

Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China #

Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061, PR China

‡

University of Chinese Academy of Sciences, Beijing 100039, PR China

ABSTRACT: Metal-organic frameworks (MOFs) have been used for photodynamic therapy (PDT) of cancers by integrating photosensitizers, which cause cytotoxic effects on cancer cells by converting tumor oxygen into reactive singlet oxygen (1O2). However, the PDT efficiency of MOFs is severely limited by tumor hypoxia. Herein, by decorating platinum nanozymes on photosensitizers integrated MOFs, we report a simple yet versatile strategy for enhanced photodynamic therapy. The platinum nanoparticles homogeneously immobilized on MOFs possess high stability and catalase-like activity. Thus, our nanoplatform can facilitate the

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formation of 1O2 in hypoxic tumor site via H2O2-activated evolvement of O2, which can cause more serious damage to cancer cells. Our finding highlights the composites of nanozymes and MOFs have the potential to serve as efficient agents for cancer therapy, which will open an avenue of nanozymes and MOFs toward biological applications.

KEYWORDS: metal-organic frameworks, nanozymes, singlet oxygen, photodynamic therapy, hypoxia Metal-organic frameworks (MOFs), crystalline porous hybrids constructed by bridging metalbased nodes (metal ions or clusters) with organic linkers (organic ligands), have emerged as a promising class of functional materials that sparked increasing interest in recent years.1,2 Particularly, the nanoscale MOFs with good biocompatibility, biodegradability and suitable size have been applied in biomedical field.3-7 More recently, photosensitizers integrated MOFs have been developed for photodynamic therapy (PDT).8-12 The stable crystalline structures of MOFs allow for integrating large amount of photosensitizers to generate highly cytotoxic reactive oxygen species (ROS), particularly singlet oxygen (1O2), under light, which contribute to the cytotoxic effects on cancer cells. Moreover, the well-isolated photosensitizers, facilitated intersystem crossing by heavy metal-based nodes and the facile diffusion pathway of MOFs enhance the 1O2 generation efficiency. Although promising, the therapeutic efficiency of PDT is severely limited by tumor hypoxia.13-15 Hypoxia is common in most solid tumors, as the oxygen supply is reduced by uncontrolled proliferation of cancer cells. In addition, the consumption of O2 and the shut down effects of vascular mediated by PDT would further exacerbate hypoxia and in turn limit the PDT efficiency.16,17 To solve the problem, various strategies have been explored. For example, perfluorocarbon nanoparticles and red blood cells were used to transport oxygen into tumors.18,19 In addition, hyaluronidase have been explored to improve tumor oxygenation via


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normalizing tumor vasculatures and improving intratumoral blood flow.20 Furthermore, generating oxygen in situ inside the tumor with catalysts (catalase and MnO2) through the decomposition of intratumoral H2O2 have also been reported.21-24 However, the limited effects on reducing intratumoral hypoxia, the instability and easy inactivation of enzyme-based catalysts, the rapid consumption of MnO2, and the need of seeking specific carrier to load photosensitizers still restricted their applications.25,26 Hence, it is desired to develop intelligent therapeutic nanoagents that not only can integrate the advantage of MOFs to make full use of the photosensitizers, but also generate oxygen in a more efficient and facile way for better therapeutic outcomes of PDT. Encouraged by the outstanding catalytic performance of nature enzymes, a variety of synthetic structures have been engineered to mimic the functions and complexities of natural enzymes over the past few decades.27,28 Among them, nanozymes have attracted extensive research interest.29-33 For instance, carbon-based nanomaterials, metal nanoparticles and metallic nanocomposites have been discovered to possess enzyme mimetic properties and widely used for biomolecular detection, antibacterial applications, reactive oxygen species elimination and environmental monitoring, etc. Especially, platinum nanoparticles (Pt NPs), a kind of well known catalysts for a number of chemical reactions, have also been observed to have enzyme mimetic activities.34-39 For example, with the catalase- and superoxide dismutase-like properties, polyacrylic acid-protected Pt NPs could efficiently scavenge both H2O2 and superoxide anion.34 In addition, apoferritin-encapsulated Pt NPs have been reported to exhibit catalase- and peroxidase-like activities.35 Furthermore, citrate-capped Pt NPs showed multiple enzyme-mimic activities and good biocompatibility.36 Although great progress has been achieved in this field,


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the low stability and rapid clearance of unsupported small size NPs causes a serious decline in their performance during catalytic operation under physiological conditions.40,41 Herein, by decorating Pt nanozymes on photosensitizers integrated MOFs, we reported a simple yet versatile strategy for enhanced photodynamic therapy. The MOFs were able to hinder the aggregation of neighboring Pt nanoparticles and keep them stable, which made the Pt nanozymes possessed high stability and catalase-like activity. Thus, the nanoplatform could facilitate the formation of 1O2 in hypoxic tumor site via H2O2-activated evolvement of O2, which could be used for enhanced photodynamic therapy. In our approach, a kind of porphyrinic ZrMOF nanoparticles, PCN-224 (porous coordination network-224), were used. Then, Pt nanozymes were homogeneously decorated on PCN-224 via in-situ reduction. In addition, by taking advantage of coordination interaction, the surface of Pt decorated PCN-224 nanoconjugates was further coated with polyethylene glycol (PEG) (termed as PCN-224-Pt), which greatly improved the biocompatibility and physiological stability of the nanoconjugates. As excessive amounts of H2O2 were produced by malignant cancer cells and existed in the tumor microenvironment,42 PCN-224-Pt with high catalase-like activity were able to induce the decomposition of H2O2 for producing O2 at the hypoxic tumor site, which could facilitate the formation of cytotoxic 1O2 by PCN-224-Pt to kill cancer cells (Scheme 1). Taken together, the nanoplatform fabricated by us possessed high catalase-like activity, which enhanced the generation of ROS with the existence of H2O2 in hypoxia environment. In addition, by utilizing the advantages of MOF, such as, porosity, the tunable metal ions and organic ligands and controllable surface functionalities, it was possible to apply Pt decorated MOFs in other therapy treatments, such as chemotherapy, radiotherapy and sonodynamic therapy, the efficiency of which were also restricted by hypoxia.22,43-45 Thus, our nanosystems could also be used for other


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therapeutics and achieve enhanced therapy effect. Our finding highlights the composites of nanozymes and MOFs have the potential to serve as efficient agents for cancer therapy, which will open an avenue of nanozymes and MOFs toward biological applications. RESULTS AND DISCUSSION To substantiate our design, the PCN-224 nanoparticles were synthesized firstly. Scanning electron microscopy (SEM) (Figure 1A) and transmission electron microscopy (TEM) images (Figure 1B) of the resulting purple product revealed that the nanoparticles with an average diameter of about 90 nm. For in situ formation of Pt nanoparticles (Pt NPs), H2PtCl6 were then mixed with PCN-224 nanoparticles for 1 h. After that, highly dispersed Pt NPs could be formed on the surface of PCN-224 by in situ reduction of platinum chloride ions with NaBH4. The TEM image showed that the structure of PCN-224 was well maintained and the formed Pt NPs of approximately 2 nm (Figure 1C) were uniformly dispersed on the surface of PCN-224. In addition, the lattice spacing of 0.224 nm was existed in the TEM images, corresponding to the (111) facet of Pt crystal.35 Meanwhile, the TEM elemental mappings (Figure 1D) indicated the distribution of Zr and Pt elements in the same particle, which also evidenced the decoration of Pt NPs on PCN-224. Finally, Pt decorated PCN-224 nanoconjugates were further coated with PEG (PCN-224-Pt) to enhance the solubility and biocompatibility, which were obtained through the coordination interaction of the Zr6 cluster available binding sites in PCN-224 and the carboxylate terminals of PEG. The X-ray diffraction (XRD) patterns of PCN-224-Pt (Figure 1E) showed excellent agreement with the theoretical powder pattern of PCN-224 at low angles of 2.5°-15° and Pt NPs at high angles of 30°-70°, which further confirmed that the products were composed of crystalline PCN-224 and Pt nanoparticles and no significant loss of crystallinity was observed for PCN-224 after Pt decoration.46,47 Besides, the energy-dispersive spectroscopy (EDS) pattern


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(Figure S1) and X-ray photon spectroscopy (XPS) (Figure S2) further verified the preparation of PCN-224-Pt, successfully. The content of Pt (15.1 wt%) in PCN-224-Pt was quantified by inductively coupled plasma mass spectrometry (ICP-MS). Moreover, the UV-Vis spectra (Figure 1F) of PCN-224 and PCN-224-Pt were tested, a major Soret peak and four Q-bands absorption were showed in both of them, revealing the photon absorption and electron-hole separation ability upon light irradiation on PCN-224 and PCN-224-Pt. Taking together, all results proved the fabrication of PCN-224-Pt nanocomposites. After successful fabrication of the PCN-224-Pt nanocomposites, we then investigated their properties. Firstly, the catalase-like activity of PCN-224-Pt was verified. As hydrogen peroxide could be decomposed by catalase to generate oxygen, the gas bubbles were formed in the tubes containing catalase and H2O2. Similarly, the tubes containing PCN-224-Pt and H2O2 also produced gas bubbles (Figure S3). A series of control experiments were further conducted and no gas bubbles were shown. It proved that it was PCN-224-Pt that had catalase-like activity. Then, the detailed concentrations of H2O2 in different reaction conditions were estimated according to the absorbance at 240 nm (Figure S4). As shown in Figure 2A, the concentration of H2O2 was decreased along with the reaction time in the sample containing PCN-224-Pt. In contrast, there were negligible changes in the one containing PCN-224 (Figure 2B). As pH had an important influence on the catalytic capacity of nanozymes, the catalase-like activities of PCN-224-Pt were further tested at pH 6.5, which was the characteristic pH value of tumor microenvironment resulted from the exuberant metabolism of cancer cells. As shown in Figure S5, PCN-224-Pt also showed high catalytic activity at pH 6.5. All these results indicated that PCN-224-Pt possessed catalase-like property at pH 7.4 and pH 6.5 for inducing the decomposition of H2O2 to produce O2 (Figure S6). The characteristic of PCN-224-Pt showed


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great potential for modulating the hypoxic tumor environment and inducing enhanced PDT by decomposing intratumoral H2O2 to produce O2. Then, we investigated the ROS generation ability of PCN-224-Pt. 2’,7’-Dichlorofluorescein (DCFH) was employed as a fluorescent probe to evaluate the production of ROS.48 Under light irradiation, we found that PCN-224-Pt induced the generation of certain amount of ROS, which showed the similar capacity of PCN-224 (Figure 2C). As the generated ROS in the experiment were almost 1O2, a kind of classical 1O2 probe molecules 1,3-diphenylisobenzofuran (DPBF) were also used for the detection.49 Upon 1O2 oxidation, the intensity of the characteristic absorption of DPBF at around 426 nm would decrease. In addition, the 1O2 generation ability of PCN-224 and PCN-224-Pt in a H2O2 solution was further investigated. The experiment were conducted in the presence of 100 µM H2O2, a concentration relevant to the tumor environment, and measured by DPBF probe. The results further proved the 1O2 production ability of PCN-224Pt, which was similar to the one of PCN-224 (Figure S7). Afterwards, the ROS production ability of PCN-224-Pt and PCN-224 were further tested in hypoxic condition. As shown in Figure 2D, the quantity of 1O2 generated by PCN-224-Pt without H2O2 was nearly the same with PCN-224 in the presence or absence of H2O2. Nevertheless, after addition of H2O2, remarkable enhanced amount of 1O2 was generated by PCN-224-Pt. The results indicated that, with the assistance of catalase-like activity, PCN-224-Pt could efficiently produce 1O2 in hypoxic condition with the presence of H2O2. In addition, the experiments were also conducted at pH 6.5 and consistent results were obtained (Figure S8). The above results also indicated that the Pt decorated on PCN-224 fabricated by us did not show obvious 1O2 scavenging capacity. Therefore, it was possible to significantly improve the PDT efficiency of PCN-224-Pt inside the hypoxic tumor environment with the existence of H2O2.


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In vitro experiments were further conducted to determine the effectiveness of our nanoconjugates to serve as agents for PDT. Firstly, the cellular uptake efficiency of PCN-224-Pt was evaluated by flow cytometry after incubation with cells for 4 h. Although tetrakis (4carboxyphenyl) porphyrin (TCPP), the organic linkers of PCN-224-Pt, showed strong fluorescence emissions at 642 nm when excited at 420 nm, the fluorescence intensity of TCPP in PCN-224-Pt dropped significantly due to the enhanced intersystem crossing after the coordination of the porphyrin ligands to the heavy metal cluster secondary building units (Figure S9).50 So fluorescein isothiocyanate (FITC) labeled PCN-224-Pt (FITC-PCN-224-Pt) were used for the experiment. As observed in Figure S10, a large shift was observed for HeLa cells treated with FITC-PCN-224-Pt and the shift distance was related to the amount of added materials. It was indicated that FITC-PCN-224-Pt was internalized in HeLa cells effectively. Then, the methyl thiazolyl tetrazolium (MTT) assay was used to evaluate the biocompatibility of PCN224-Pt. In the absence of light, PCN-224-Pt showed no obvious toxicity to normal cells (RAW264.7) and the tumor cells (HeLa and 4T1) at tested concentrations for 24 h (Figure 3A). The results reflected that the PCN-224-Pt showed negligible cytotoxicity. All above experiment showed that PCN-224-Pt could entered into HeLa cells effectively with good biocompatibility. Then, the generation of 1O2 in tumor cells were also studied by fluorescence microscopy using 2’,7’-dichlorofluorescein diacetate (DCFH-DA) as ROS sensor, which could be rapidly oxidized by ROS to emit green fluorescence in cells.48 As shown in Figure 3B, HeLa cells in control group showed weak green fluorescence and the one treated with PCN-224-Pt in the absence of light. In contrast, cells treated with PCN-224-Pt under light irradiation showed much strong fluorescence, suggesting 1O2 generation in large amounts. Furthermore, the flow cytometry strategy also confirmed the effective light-activated ROS generation ability of PCN-224-Pt. All


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above results demonstrated that PCN-224-Pt would be an activator to sensitize the formation of 1

O2. Then, the PDT efficiency of PCN-224-Pt and PCN-224 by incubating with HeLa cells in either

oxygen-deficient or oxygen-sufficient conditions was examined. The viabilities of HeLa cells were measured by MTT assay after PCN-224 or PCN-224-Pt were exposed to light for certain time and further incubated for 24 h. As shown in Figure 3C, PCN-224-Pt exhibited much higher phototoxicity under irradiation of light than that of PCN-224 in the oxygen-deficient conditions. Furthermore, the phototoxicity increased along with the concentration of PCN-224-Pt. The experiment proved that the PDT efficiency of PCN-224-Pt would be significantly maintained inside the hypoxia environment with the intracellular level of H2O2 in cancer cells. Encouraged by the outstanding performance of PCN-224-Pt in vitro, we proceeded to evaluate the anticancer potentials in vivo. The therapy efficiency of PCN-224-Pt on tumor-bearing mice via intratumoural injection was evaluated. As we know, the hypoxic condition within the tumor microenvironment that can induce the expression of hypoxia-inducible factor (HIF)-1α, thereby up-regulating vascular endothelial growth factor (VEGF) secretion.51 To confirm that PCN-224Pt indeed had the ability to ameliorate hypoxia of the tumor, HIF-1α and VEGF staining assay was carried out on tumor slices extracted from mice 24 h post intratumoral injection of PCN224-Pt to evaluate hypoxic conditions. As shown in Figure 4A, the tumor tissues of the untreated group and PCN-224 injected group were displayed intense immunofluorescence of HIF-1α (green) and VEGF (red), indicating the hypoxic conditions in untreated and PCN-224 injected mice. In contrast, the tumors injected with PCN-224-Pt showed significantly weakened tumor hypoxia, as evidenced by the greatly decreased immonufluorescence intensity of HIF-1α and VEGF, which was due to the generation of O2 in tumor through decomposition of intracellular


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H2O2 that overcame the hypoxia by Pt NPs on PCN-224-Pt. Such enhanced oxygenation in tumor would be conducive to decreasing the hypoxia-associated photodynamic resistance during PDT in vivo. Afterwards, the efficacy of PCN-224-Pt for PDT of cancer was investigated with the H22 tumor-bearing mice model. The mice bearing subcutaneous H22 tumors were divided into six groups and received various treatments, respectively. The tumor sizes were recorded and the changes of which were used to assess the PDT effects. While the tumors of mice injected with PCN-224 after light irradiation were suppressed, tumor growth was completely inhibited with the injection of PCN-224-Pt after irradiation treatment (Figure 4B-D). We speculated that it was the hypoxia-induced PDT resistance effect that limited the therapy effect of PCN-224. In other words, the enhanced PDT effect of tumors injected with PCN-224-Pt was due to the decoration of Pt NPs on PCN-224, which owned the catalase-like activity to supply O2 through decomposing intratumoral H2O2. In addition, no significant therapeutic effect was observed for PCN-224 or PCN-224-Pt without light irradiation, which further indicated that PCN-224-Pt and PCN-224 had little dark toxicity. Hematoxylin and eosin (H&E) staining and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining assay were also performed to assess the treatment efficacy on the tumors. Tumor tissues of different groups were collected 24 h after the corresponding treatments. Microscopy images of H&E and TUNEL stained tumor slices revealed that most serious damages to tumor cells were triggered by the treatment of PCN-224-Pt-mediated PDT under light (Figure 5). Taken together, all results proved the good efficacy of PCN-224-Pt for cancer PDT. With the excellent in vivo tumor therapy performance of PCN-224-Pt nanoconjugates, detailed toxicity in vivo were further investigated. The body weight of tumor-bearing mice in various groups was recorded and no


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significant change was observed during the treatment in all test groups (Figure S11). Furthermore, H&E staining with the major organ tissues of mice after PCN-224-Pt-mediated PDT treatment was performed. No abnormalities were observed compared with normal mice (Figure S12). These results evidenced that, at our tested dose, PCN-224-Pt nanoconjugates did not cause noticeably toxicity to mice. After the study of intratumoral injection, we examined the efficacy of PCN-224-Pt by intravenous injection. As the high affinity of Zr(IV) to phosphate ions restricted the usage of PCN-224 in cancer therapy via intravenous injection, the degradation rate of our PCN-224-Pt in PBS and serum should be studied. Through measuring the release amount of TCPP ligands in the supernatant, we evaluated the degradation degree of PCN-224 and PCN-224-Pt in PBS and serum after various incubation times. As the results shown (Figure S13), PCN-224 nanoparticles were not stable in PBS buffers, which rapidly released TCPP ligands in both 5 mM and 10 mM PBS. In contrast, due to the strong covalent interaction between Pt nanoparticles and PCN-224, the stability of the nanocomposites in PBS were greatly improved. Besides, as the concentration of phosphate in blood was lower than 5 mM,52 it was possible to apply PCN-224-Pt in biomedical applications via intravenous injection. In addition, because the dynamic diameter of PCN-224-Pt was about 160.1 nm (Figure S14), which had the advantage of prolonged retention in the circulation, the biodistribution of PCN-224-Pt was then investigated after intravenous injection into the H22 tumor-bearing mice. The major tissues and tumor were collected from the mice after administration for various time points and the content of Zr was determined by inductively coupled plasma mass spectrometer. As shown in Figure S15, most of PCN-224-Pt are retained in liver, spleen and lung because of the strong phagocytosis in reticuloendothelial system (RES) organs. However, there is still a few parts of PCN-224-Pt accumulated in tumor


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due to the enhanced permeability and retention (EPR) effect. In addition, the relative amounts of PCN-22-Pt within tumor reached the maximum at 24 h post injection. All these results indicated that it was possible to apply PCN-224-Pt in cancer therapy through intravenous injection. Due to the instability of PCN-224 in solutions containing phosphate and intratumoral injection were chosen in most articles, PCN-224 were not used as a therapy agent through intravenous injection in our experiments.50,53 Firstly, the ability of PCN-224-Pt to ameliorate hypoxia inside the tumor after intravenous injection was evaluated. As shown in Figure 6A, PCN-224-Pt reduced the degree of hypoxia in tumor after 24 h post injection. Then, the mice bearing subcutaneous H22 tumors were divided into four groups, including the saline control group and the PCN-224-Pt groups with and without laser irradiation. The tumor volumes as a function of time were monitored after respective treatments. The groups of mice injected with PCN-224-Pt after light irradiation showed obvious tumor suppressive effect, while no reduction was found in that of the other groups (Figure 6B-D). Furthermore, microscopy images of H&E and TUNEL stained tumor slices, which were from the tumor tissues collected 24 h post respective treatments, showed that PCN-224–Pt with light irradiation caused serious damages to tumor cells (Figure S16). In addition, the body weight of tumor-bearing mice showed no significant change in all test groups (Figure S17). Moreover, H&E images of the major organ tissues of mice in PCN-224-Pt with light irradiation group after treatment revealed no noticeable tissue damage in all of the organ structures (Figure S18), demonstrating the favorable biocompatibility of our nanocomposites. The above results indicated that our PCN-224-Pt nanocomposites showed good performance for in vivo photodynamic therapy via intratumoral and intravenous injection. CONCLUSIONS


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In summary, we developed a versatile nanoplatform for enhanced photodynamic therapy by decorating Pt nanozymes on photosensitizers integrated MOFs. The Pt nanozymes decorated on MOFs possessed high catalase-like activity and stability that could produce O2 to facilitate the formation of cytotoxic 1O2 at the hypoxic tumor site. Thus, the PCN-224-Pt nanoconjugates showed much enhanced PDT efficiency via H2O2-activated evolvement of O2 and light-irradiated formation of 1O2. All the experiments results proved the therapy efficacy of PCN-224-Pt. This nanozyme-MOF hybrid system provide a way to improve the efficiency of photodynamic therapy and promote the application of nanozymes and MOFs in modern oncology. MATERIALS AND METHODS Chemicals. Zirconyl chloride octahydrate (ZrClO2•8H2O), benzoic acid and fluorescein isothiocyanate isomer I (FITC) were purchased from Sigma. Tetrakis (4-carboxyphenyl) porphyrin (TCPP) was obtained from TCI (Shanghai) Industrial Development Co. Chloroplatinic acid (H2PtCl6) were obtained from Sinopharm Chemical Reagent Co. (Shanghai, China). Sodium borohydride (NaBH4) was obtained from Alfa Aesar. HOOC-PEG-COOH (Mw=1k), H2O2 and all other reagents were of analytical reagent grade, and used as received. Ultrapure water (18.2 MΩ; Millpore Co., USA) was used in all experiments and to prepare all buffers. Instruments. Transmission electron microscope images were recorded using an FEI TECNAI G2 20 high-resolution transmission electron microscope operating at 200 kV. The morphology and composition of the as-prepared samples were tested using a field emission scanning electron microscope (FESEM, S4800, Hitachi) equipped with an energy-dispersive X-ray spectrum. A JASCO V-550 UV/vis spectrometer was used for determining the UV–vis spectroscopy. An Olympus BX-51 optical equipped with a CCD camera was used for capturing fluorescence images. X-ray photoelectron Spectroscopy (XPS) spectra were analyzed by Thermo Fisher


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Scientific ESCALAB 250Xi Spectrometer Electron Spectroscopy (America). ICP-MS measurements were performed on a Thermo Scientific X series Ⅱ inductively coupled plasma mass spectrometer. The flow cytometry data was obtained by BD LSRFortessaTM Cell Analyzer. Synthesis of PCN-224 nanoparticles. ZrOCl2•8H2O solution (10 mL, 15 mg mL-1 in N,Ndimethylformamide (DMF)), TCPP solution (20 mL, 2.5 mg mL-1 in DMF), and benzoic acid solution (20 mL, 70 mg mL-1 in DMF) were added to round bottom flask and reacted at 90 °C for 5 h under stirring. The product was collected by centrifugation and washed with DMF for 3 times. Synthesis of PCN-224-Pt. H2PtCl6 (19.31 mM, 1 mL) was stirred with PCN-224 nanoparticles (2.5 mg mL−1) for 1 h in 20 mL water system. After that, 2 mL NaBH4 (4 mg mL-1) was added under drastic agitation for further 3 h to obtain Pt decorated PCN-224 nanoparticles. Finally, the mixture was centrifuged and washed with water for three times. The precipitate was then redispersed in water. For PEGylation, 1 mL Pt decorated PCN-224 nanoparticles (1 mg mL-1) were mixed with 50 µL HOOC-PEG-COOH (5 mg mL-1) under stirring at room temperature for 30 min. The obtained PCN-224-Pt were centrifuged and redispersed in water for further use. The amount of PCN-224-Pt and PCN-224 used in all the experiment were convert to the amount of TCPP in used nanoparticles. The catalase-like activity of PCN-224-Pt. The catalase-like activity of PCN-224-Pt was assayed by observing the generation of oxygen through the catalytic decomposition of hydrogen peroxide, firstly. The tubes containing 1) catalase (10 µg mL-1) + H2O2 (20 mM), 2) PCN-224-Pt (50 µg mL-1) + H2O2 (20 mM), 3) PCN-224 (50 µg mL-1) + H2O2 (20 mM), 4) H2O2 (20 mM), respectively, were reacted at 37 °С for 30 min and the photos were obtained.


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Then, the detailed concentrations of H2O2 in different reaction conditions were estimated. The calibration curve of absorbance and the concentration of H2O2 (0-30 mM) were recorded by monitoring the absorbance at 240 nm with different concentration of H2O2. Besides, the H2O2 decomposition experiment were carried out by adding PCN-224-Pt or PCN-224 (100 µg mL-1) in Tris buffer (25 mM) containing H2O2 (20 mM) at 37 °С. After a period of time, the mixtures were centrifuged and the UV-Vis spectra of the remaining H2O2 was recorded. The ROS generation ability of PCN-224-Pt. Firstly, DCFH, which was converted from DCFH-DA was employed as a probe for ROS measurement. 2 mL of 0.01 M NaOH was added in 0.5 mL of DCFH-DA in DMSO to chemically hydrolyze DCFH-DA to DCFH with in the dark for 30 min at room temperature. Then, 10 mL of the Tris buffer (25 mM, pH 7.2) was added to stop the reaction. The stock solution of DCFH was kept on ice in the dark before use. For a typical test, the PCN-224-Pt or PCN-224 nanoparticles (50 µg mL-1) were mixed with the stock solution of DCFH (10 µM). Then, the mixture was irradiated by 638 nm light at the power density of 1 W cm-2 for 5 min. Immediately after the irradiation, the solutions were centrifuged and the fluorescence of the supernatants were measured for the estimation of the produced ROS. Then, the DPBF was also used for the detection of ROS. In a typical process, 5 µL of a DPBF/DMSO solution (10 mM) was added to 1 mL Tris buffer containing PCN-224-Pt or PCN224 nanoparticles (10 µg mL-1) with or without H2O2 (100 µM). And then the mixture was irradiated under a 638 nm laser for various time periods. The characteristic UV-vis absorption spectrum of the DPBF was measured to determine the generation of ROS. For hypoxic conditions, the mixture of DPBF and nanoparticles in Tris buffer was ventilated with N2 for 30 min and the mixture was sealed up immediately after the addition of H2O2. Then the mixture was kept for 10 min at 37 °С before exposed to 638 nm irradiation at a power density


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of 1 W cm−2 for certain time. The characteristic UV-vis absorption spectrum of the DPBF was measured to determine the generation of ROS. Cell Culture. HeLa, 4T1 and RAW264.7 cells were cultured at 37 °С under 5% CO2 in air with regular growth medium consisting of high glucose DMEM. The cell growth media were supplemented with 10% heat-inactivated FBS, 100 U mL-1 penicillin, and 100 mg mL-1 streptomycin. The media was changed every two days, and the cells were digested by trypsin and resuspended in fresh complete medium before plating. Analysis of the cellular uptake efficiency by flow cytometry. FITC labeled PCN-224-Pt (FITC-PCN-224-Pt) was synthesized firstly. PCN-224-Pt nanoparticles (2 mg mL-1) were dissolved in MES buffer (0.1 M, pH 6.0), and activated by EDC (2 mg mL-1) and NHS (2 mg mL-1) for 12 hours. Then ethylenediamine (1 µL per mg PCN-224) was added to the mixture at room temperature with continuous stirring for 12 h. The obtained PCN-224-Pt-NH2 nanoparticles was collected by centrifugation and washed with water for three times. Then, PCN-224-Pt-NH2 nanoparticles (1 mg mL-1, 200 µL) in DMF was reacted with FITC (1 mg mL-1, 20 µL) at 4 °С in dark over light. Then, flow cytometric analysis was performed to detect the cellular uptake efficiency. HeLa cells were seeded in a 6-well plate and maintained for 24 h. Then the cells were incubated with PBS and FITC-PCN-224-Pt, respectively, for 4 h at 37 °С. After that, the cells were washed several times with PBS and analyzed by flow cytometry. Cytotoxicity Assays. Cells were seeded in 96-well plates for 24 h incubation. After that, PCN224-Pt, at the indicated concentrations, was added to the cell culture medium and incubated with cells for 24 h. Finally, MTT solution (BBI), an indicator to probe the viability of cells, was added to each well and measured by standard MTT assay.


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In vitro photodynamic therapy. For photodynamic therapy, HeLa cells were seeded in 96-well plates. Then, PCN-224-Pt or PCN-224 at various concentrations were added to the plates and incubated with cells for 4 h. Then, the plates were placed in a transparent box, ventilated with air (N2 for hypoxia condition) in advance, for 30 min and then irradiated with 638 nm laser at a power density of 1 W cm−2 for 10 min. After that, cells were placed in cell culture box and further incubated for 24 h. The quantitative evaluation of the photodynamic cytotoxicity was performed by MTT assay as described above. To confirm the ROS generation in cells, experimants were studied by fluorescence microscopy and flow cytometry analysis. For fluorescence microscopy, HeLa cells were seeded into 12 mm sterile cover slips in a 24-well plate and maintained for 24 h. Then the cells were incubated with certain materials and received certain treatments. Afterwards, DCFH-DA was added to incubate together with cells and imaged. For flow cytometry analysis, the experiments were conducted nearly the same with the above operation except that HeLa cells were seeded in 6-well plate. Finally, the cells were washed several times with PBS and analyzed by flow cytometry. Quantitative analysis the degradation rate of PCN-224 and PCN-224-Pt. The

TCPP

standard solutions were prepared in the mixture of H2O/DMF (v:v = 1:1). The UV-vis absorbance spectra of TCPP standard solutions at concentrations of 0.1, 0.5, 1, 2.5 and 5 µM were recorded and the calibration curve of absorbance at 418 nm and the concentration of TCPP was plotted. The TCPP content of PCN-224 and PCN-224-Pt stock solutions were analyzed after digested with negligible amount of 1 M NaOH. To analyze the degradation rate, PCN-224 and PCN-224-Pt at the same concentrations were dispersed in PBS buffer solutions (serum) with various incubation times. Then, the supernatant was collected and diluted with H2O/DMF (v:v=


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1:1) mixture (diluted with water when in serum). The absorbance at 418 nm was utilized to determine the concentration of TCPP. Animal Experiments. Healthy female Kunming mice (20-25 g) were purchased from the Laboratory Animal Center of Jilin University (Changchun, China) and handing procedures were according to the guidelines of the Regional Ethics Committee for Animal Experiments. Tumor Models. Hepatoma 22 (H22) tumor bearing mice were chose as the animal model to assess the antitumor effect. H22 cells were harvested from the peritonea cavity of mice 5-7 days after inoculation. Then, the cells of 2 × 105 cells were suspended in saline (about 50 µL) and subcutaneously injected into the oxter region of mice. In vivo photodynamic therapy. For studying the therapy efficiency via intratumoral injection, when the tumor volumes were about 100 mm3, tumor bearing mice were divided into six groups (n = 6 mice/group) randomly for different formulations: (1) saline alone; (2) saline + light; (3) PCN-224; (4) PCN-224-Pt; (5) PCN-224 + light; (6) PCN-224-Pt + light. The solution of PCN224 or PCN-224-Pt (200 µL, 2 mg mL−1) was intratumorally injected into mice and then irradiated by the 638 nm laser (1 W cm-2) for 8 min. For studying the therapy efficiency via intravenous injection, tumor bearing mice were divided into four groups (n = 6 mice/group) randomly for different formulations: (1) saline alone; (2) saline + light; (3) PCN-224-Pt and (4) PCN-224-Pt + light. The solution of PCN-224-Pt (500 µL, 1 mg mL−1) was intravenously injected into mice and then irradiated by the 638 nm laser (1 W cm-2) for 8 min. The tumor dimensions (length and width) and body weight were measured every other day after the treatment. The mice were sacrificed after 2 weeks post-treatment, and the tumors were collected and taken photos.


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Histology. For histology, the tumor tissues (n=2) in each group were harvested from mice 24 h after the first time treatment. The tumor tissues were dissected to make paraffin section for further hematoxylin and eosin (H&E) staining and terminal deoxynucleotidyl transferasemediated dUTP-biotin nick end labeling (TUNEL) staining assay. Images of TUNEL staining assay were obtained under magnification of 20 and that of H&E were obtained under magnification of 40. After the two weeks’ treatment, the mice were sacrificed. The major organs of health mice and the one of PCN-224-Pt + light group were dissected to make paraffin section for further H&E staining. In vivo overcoming hypoxia study. For studying the hypoxia alleviation efficiency via intratumoral injection, tumor bearing mice were randomly divided into three groups (n = 2 mice/group): (1) saline alone; (2) PCN-224; (3) PCN-224-Pt. The solution of PCN-224 or PCN224-Pt (200 µL, 2 mg mL−1) was intratumorally injected into mice. For studying the hypoxia alleviation efficiency via intravenous injection, tumor bearing mice were randomly divided into two groups (n = 2 mice/group): (1) saline alone and (2) PCN-224-Pt. The solution of PCN-224Pt (500 µL, 1 mg mL−1) was intravenously injected into mice. Twenty-four hours after the injection, mice were sacrificed and their tumors were collected. The tumor tissues were dissected to make paraffin section for further HIF-1α and VEGF immunofluorescence staining.


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Scheme 1. Schematic illustration of (A) the preparation process of PCN-224-Pt and (B) the use of PCN-224-Pt for enhanced photodynamic therapy.


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Figure 1. A) SEM image of PCN-224. B) TEM image of PCN-224. C) TEM image of Pt decorated PCN-224 nanoparticles. D) Dark-field TEM image of Pt decorated PCN-224 nanoparticles, and corresponding TEM elemental mappings of the Zr-L edge and Pt-L edge signals. E) XRD patterns of PCN-224-Pt. F) UV-vis absorption spectra of PCN-224 and PCN224-Pt.


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Figure 2. The UV-vis spectra of remainder H2O2 were recorded after reaction with A) PCN-224Pt and B) PCN-224 for different times in pH 7.4. C) Fluorescence spectra of DCFH incubated with PCN-224 or PCN-224-Pt in the presence or absence of light irradiation for 5 min. D) Photodegradation rates of DPBF incubated with PCN-224 or PCN-224-Pt in the presence or absence of H2O2 under light irradiation in N2 atmosphere at pH 7.4. A0 is the initial absorbance of the probe.


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Figure 3. A) Cytotoxicity studies by MTT assay for HeLa, RAW264.7, and 4T1 cells after incubation with various concentrations of PCN-224-Pt for 24 h. B) Fluorescence images and flow cytometry analysis of ROS generation in HeLa cells treated with different agents, as detected with DCFH-DA. C) In vitro PDT treatment of HeLa cells by PCN-224 and PCN-224-Pt under light irradiation in hypoxia or normoxia conditions.


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Figure 4. Photodynamic therapy of PCN-224-Pt by intratumoral injection in a subcutaneous tumour model. A) HIF-1α and VEGF staining of tumor tissues collected from mice in different groups. B) Photographs of the H22 tumor-bearing mice before treatment and on day 14 after the various treatments. C) Representative photographs of the tumor dissection. D) Relative tumor volume after various treatments indicated. Asterisks indicate significant differences (*P< 0.05, **P< 0.01, ***P< 0.001).


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Figure 5. Micrographs of TUNEL stained (A) and H&E stained (B) tumor slices 24 h after the first treatment in different groups via intratumoral injection.


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Figure 6. Photodynamic therapy of PCN-224-Pt by intravenous injection in a subcutaneous tumour model. A) HIF-1α and VEGF staining of tumor tissues collected from mice in different groups. B) Photographs of the H22 tumor-bearing mice before treatment and on day 14 after the various treatments. C) Representative photographs of the tumor dissection. D) Relative tumor volume after various treatments indicated. Asterisks indicate significant differences (*P< 0.05, **P< 0.01, ***P< 0.001).

ASSOCIATED CONTENT


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Supporting Information. Supplementary materials contains thirteen supplementary figures. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] *E-mail: [email protected] *E-mail: [email protected] ACKNOWLEDGMENT Financial support was provided by the National Basic Research Program of China (Grants 2012CB720602) and the National Natural Science Foundation of China (Grants 21210002, 21431007, 21533008, 81502277, 21601175, 21673223). REFERENCES 1.

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44. Chen, J.; Luo, H.; Liu, Y.; Zhang, W.; Li, H.; Luo, T.; Zhang, K.; Zhao, Y.; Liu, J. Oxygen-Self-Produced Nanoplatform for Relieving Hypoxia and Breaking Resistance to Sonodynamic Treatment of Pancreatic Cancer. ACS Nano 2017, DOI: 10.1021/acsnano.7b08225. 45. Tian, H.; Luo, Z.; Liu, L.; Zheng, M.; Chen, Z.; Ma, A.; Liang, R.; Han, Z.; Lu, C.; Cai, L. Cancer Cell Membrane-Biomimetic Oxygen Nanocarrier for Breaking Hypoxia-Induced Chemoresistance. Adv. Funct. Mater. 2017, 27, 1703197. 46. Bai, L.; Zhang, S.; Chen, Q.; Gao, C. Synthesis of Ultrasmall Platinum Nanoparticles on Polymer Nanoshells for Size-Dependent Catalytic Oxidation Reactions. ACS Appl. Mater. Inter. 2017, 9, 9710-9717. 47. Feng, D.; Chung, W. C.; Wei, Z.; Gu, Z. Y.; Jiang, H. L.; Chen, Y. P.; Darensbourg, D. J.; Zhou, H. C. Construction of Ultrastable Porphyrin Zr Metal-Organic Frameworks through Linker Elimination. J. Am. Chem. Soc. 2013, 135, 17105-17110. 48. Lin, L. S.; Cong, Z. X.; Li, J.; Ke, K. M.; Guo, S. S.; Yang, H. H.; Chen, G. N. GraphiticPhase C3N4 Nanosheets as Efficient Photosensitizers and pH-Responsive Drug Nanocarriers for Cancer Imaging and Therapy. J. Mater. Chem. B 2014, 2, 1031-1037. 49. Li, X. S.; Ke, M. R.; Huang, W.; Ye, C. H.; Huang, J. D. A pH-Responsive Layered Double Hydroxide (LDH)-Phthalocyanine Nanohybrid for Efficient Photodynamic Therapy. Chem. Eur. J. 2015, 21, 3310-3317. 50. Lu, K.; He, C.; Lin, W. A Chlorin-Based Nanoscale Metal-Organic Framework for Photodynamic Therapy of Colon Cancers. J. Am. Chem. Soc. 2015, 137, 7600-7603.


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51. Dahmani, F. Z.; Xiao, Y.; Zhang, J.; Yu, Y.; Zhou, J.; Yao, J. Multifunctional Polymeric Nanosystems for Dual-Targeted Combinatorial Chemo/Antiangiogenesis Therapy of Tumors. Adv. Healthcare Mater. 2016, 5, 1447-1461. 52. Cheng, W. L.; Sue, J. W.; Chen, W. C.; Chang, J. L.; Zen, J. M. Activated Nickel Platform for Electrochemical Sensing of Phosphate. Anal. Chem. 2010, 82, 1157-1161. 53. Yang, J.; Chen, X.; Li, Y.; Zhuang, Q.; Liu, P.; Gu, J. Zr-Based MOFs Shielded with Phospholipid Bilayers: Improved Biostability and Cell Uptake for Biological Applications. Chem. Mater. 2017, 29, 4580-4589. Table of Contents figure


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