Cancer-Cell-Activated Photodynamic Therapy Assisted by Cu(II

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Cancer-Cell-Activated Photodynamic Therapy Assisted by Cu(II)-Based Metal−Organic Framework Yuanbo Wang,†,∥ Wenbo Wu,†,∥ Jingjing Liu,† Purnima Naresh Manghnani,† Fang Hu,† Dou Ma,‡ Cathleen Teh,§ Bo Wang,‡ and Bin Liu*,† Downloaded via BUFFALO STATE on July 17, 2019 at 11:57:41 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

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Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585, Singapore ‡ School of Chemistry and Chemical Engineering, Beijing Institute of Technology, 5 South Zhongguancun Street, Beijing 100081, P. R. China § Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore S Supporting Information *

ABSTRACT: Activation of photosensitizers (PSs) in targeted lesion and minimization of reactive oxygen species (ROS) depletion by endogenous antioxidants constitute promising approaches to perform highly effective image-guided photodynamic therapy (PDT) with minimal non-specific phototoxicity. Traditional strategies to fabricate controllable PS platforms rely on molecular design, which requires specific modification of each PS before PDT. Therefore, construction of a general tumor-responsive PDT platform with minimum ROS loss from endogenous antioxidant, typically glutathione (GSH), is highly desirable. Herein, MOF-199, a Cu(II) carboxylate-based metal−organic framework (MOF), is selected to serve as an inert carrier to load PSs with prohibited photosensitization during delivery. After cellular uptake, Cu (II) in the MOFs effectively scavenges endogenous GSH, concomitantly induces decomposition of MOF-199 to release the encapsulated PSs, and recovers their ROS generation. In vitro and in vivo experiments demonstrate highly effective cancer cell ablation and anticancer PDT with diminished normal cell phototoxicity. This strategy is generally applicable to PSs with both aggregation-induced emission and aggregation-caused quenching to implement activatable and enhanced image-guided PDT. KEYWORDS: activatable photodynamic therapy, photosensitizers, aggregation-induced emission, metal−organic frameworks, glutathione

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mechanisms to quench photosensitization have been proved effective in producing activatable PSs. However, all these strategies are only limited to certain types of PSs, which also requires specific modification on each PS molecule before they can be used for activatable PDT. The other challenge faced by PSs is that ROS generated inside tumor cells could be depleted by endogenous antioxidants, typically glutathione (GSH), an important antioxidant and the most abundant thiol in vivo, with an upregulated concentration ranging from 1 to 10 mM.29−31 In this regard, the therapeutic effects brought by PSs are highly compromised.32−34 To address this issue, several research

hotodynamic therapy (PDT) represents a promising treatment approach to oncotherapy.1,2 It mainly relies on reactive oxygen species (ROS), including peroxides, superoxide, singlet oxygen (1O2), etc., generated under light irradiation to perform cell ablation for therapy.3−6 The rapid development in image-guided PDT3,7,8 drives researchers to look for photosensitizers (PSs) with efficient ROS generation and bright far-red (FR)/near infrared (NIR) emission for optimized treatment effect.9−17 One of the challenges faced by most PSs is their unwanted uptake by skin and healthy tissue, which brings in non-targeted phototoxicity.18,19 Therefore, target-specific and activatable PSs in the aimed lesions are in high demand to provide PDT with good selectivity and minimal side effects.10,20,21 At present, different strategies, such as the design of selfquenching PSs,22−25 utilization of Förster resonance energy transfer, and photoinduced electron transfer (PET)26−28 © 2019 American Chemical Society

Received: March 1, 2019 Accepted: June 13, 2019 Published: June 13, 2019 6879

DOI: 10.1021/acsnano.9b01665 ACS Nano 2019, 13, 6879−6890

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Cite This: ACS Nano 2019, 13, 6879−6890

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Figure 1. (A) Synthetic scheme to PS@MOF-199 and F127-coated PS@MOF-199 (PS@MOF-199 NPs). (B) Quench and trigger of photosensitization originated from PS@MOF-199 NPs in the tumor microenvironment. Process I: MOF-199 reacts with GSH to collapse the framework. Process II: Light illumination to produce ROS.

groups have utilized enzyme,35 MnO2 nanosystems,36 and metal complex nanomaterials37,38 to intracellularly decrease GSH levels and thus realize effective ROS-based tumor regression. Therefore, integration of activatable PS with effective GSH consumption in one PDT platform is of great interest, which has not been reported so far. Metal−organic frameworks (MOFs) are porous complexes which have been widely employed in biosensing, gas storage, gas separation, and catalysis.39−49 Nanoscale MOFs have been designed as exquisite PDT carriers through the incorporation of versatile PSs as ligands or linkers in MOFs.50 These works take advantage of the structural diversity and high specific surface area of MOFs to achieve effective delivery of PSs for PDT. They require specific designs and syntheses of the corresponding PSs before they could be used to fabricate the corresponding MOFs. Since MOFs possess porous structure, if PSs are loaded into the pores or defects of MOFs, they could be isolated from O2 to quench the ROS production, and meanwhile, specific design and synthesis of PS ligands or linkers could be circumvented. Given that redox-active metal ions such as manganese(IV) and copper(II) tend to oxidize GSH and decrease the intracellular GSH level,36,51 we believe that MOFs with redox-active metal ions would favor effective consumption of GSH. Upon reaction with GSH inside cancer cells, dissociation of MOFs will occur, and the released PSs will be in contact with the cellular O2 to generate ROS for PDT. Therefore, we hypothesize that loading PSs in MOFs containing redox-active metal ions could be a general strategy for realizing activatable photosensitization with inhibited intracellular GSH, facilitating cancer-cell-specific PDT with enhanced efficacy. To demonstrate the generality of this design concept, we synthesized a PS of 2-(4-(diphenylamino)phenyl)anthracene9,10-dione (TPAAQ) with aggregation-induced emission (AIE).52 We also selected chlorin e6 (Ce6, a commercial photosensitizer with aggregation-caused quenching (ACQ)) and loaded each of them into MOF-199 (HKUST-1), a Cu(II) carboxylate MOF [Cu3(TMA)2]n (where TMA is benzene-

1,3,5-tricarboxylate), to yield PS@MOF-199. F-127 was subsequently used to encapsulate PS@MOF-199 to yield PS@MOF-199 nanoparticles (PS@MOF-199 NPs). Both in vitro and in vivo experiments demonstrate that by administrating PS@MOF-199 NPs, activatable photosensitization with decreased endogenous GSH levels has been achieved, which endows PDT with enhanced therapeutic effects and minimal non-specific phototoxicity. With bright FR/NIR emission from Ce6 and TPAAQ in cancer cells, cancer-cell-specific imageguided PDT is demonstrated.

RESULTS AND DISCUSSION Design Principle and Operation Mechanism. To simultaneously achieve cancer-cell-specific activation of PSs and significant GSH reduction, we selected and constructed MOFs with the following properties. First, the pore size and the window size of the MOFs need to be large enough to load general PSs. Second, the MOFs need to possess a GSHreactive component with high content to efficiently consume cellular GSH, rendering the corresponding nanoplatform effective in cancer treatment. Third, nanoscale MOFs are in demand to facilitate nanoparticle accumulation at the tumor site. Based on these considerations, we selected defective MOF-199, copper-based MOF with the highly porous feature, nanoscale pore size, and window size.53 Notably, Cu (II), as metal centers in MOF-199, could serve as the PS-activating switch and GSH-scavenging reagent, to activate PSs and deplete GSH. In addition, Cu (II) MOFs have shown good biocompatibility with the facile synthetic approach.38,54,55 All these merits make defective MOF-199 an ideal carrier for PSs. To demonstrate the general applicability of the MOFincorporated nanoplatform, a commercial PS, Ce6, and the synthesized PS, TPAAQ, were chosen to be loaded in MOF199 via physical adsorption to yield PS@MOF-199. To increase dispersity and biocompatibility of PS@MOF-199, F127 was used to encapsulate PS@MOF-199 through thin-film dispersion method to yield PS@MOF-199 NPs (Figure 1A). As indicated in Figure 1B, since 1O2 is generated from oxygen 6880


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Figure 2. (A) UV−vis absorption and PL spectra of TPAAQ in THF/water (1/99, v/v), λex = 470 nm). (B) PL spectra of TPAAQ in solvent with different THF-water ratios. The inset shows photographs of TPAAQ in different solvents, and 90% indicates THF:H2O = 1:9; 10% indicates THF:H2O = 9:1. (C) Different PS-induced decomposition rates of ABDA under white light (100 mW cm−2, 400−700 nm) irradiation in THF/water (1/99, v/v). A0 and A are the absorbance of ABDA at 378 nm before and after irradiation, respectively. [PS] = 10 μg mL−1, and [ABDA] = 20 μg mL−1. (D) PXRD patterns of MOF-199, Ce6@MOF-199, TPAAQ@MOF-199, PBS (1× , 24 h), GSH (1 mM, 40 min) treated Ce6@MOF-199, and TPAAQ@MOF-199. (E) Loading kinetics of Ce6 and TPAAQ into MOF-199. (F) Titration of GSH treated with MOF-199, Ce6@MOF-199, and TPAAQ@MOF-199, respectively, measured via HPLC. Concentrations of MOF-199 in each of three groups include 0, 80, 160, 240, 320, 400, 480, 560, 640, 720, and 800 μg mL−1. TEM images of (G) MOF-199 NPs, (H) Ce6@MOF199 NPs, and (I) TPAAQ@MOF-199 NPs.

synthesize TPAAQ with a small energy gap between S1 and T1 (ΔEST = 0.25 eV). The synthetic route is shown in Scheme S1. TPAAQ has an absorption peak at 470 nm with an emission maximum at 655 nm in THF/water (1/99, v/v), as shown in Figure 2A. TPAAQ is almost non-emissive in THF and becomes emissive after introducing over 80% water into THF, revealing that TPAAQ exhibits AIE characteristics (Figure 2B). On the contrary, in Figure S1, Ce6 is highly emissive in DMSO, but the fluorescence is gradually decreased after a certain amount of water is introduced to DMSO, revealing the ACQ feature of Ce6. By adopting 9,10anthracenediyl-bis(methylene)dimalonic acid (ABDA) (20 μg mL−1) as a 1O2 indicator, under white light irradiation (400− 700 nm, 100 mW cm−2), the average ABDA degradation rates induced by PSs were calculated (Figure 2C). Specifically, the ABDA degradation rate induced by TPAAQ was around 4 μg min−1, over five times higher than that (0.7 μg min−1) induced by ICG, the most popular PS with NIR emission, and 33% higher than that (3 μg min−1) sensitized by Ce6, one of the most efficient PSs reported so far. As shown in Figure S2, the photostability of TPAAQ is better than that of ICG and Ce6. Defective MOF-199 was synthesized under room temperature through a modified method.55 In Figures 2D and S3, powder X-ray diffraction (PXRD) data show the highly

under the catalysis of PSs, which is closely related to the contacted oxygen,2,8 MOF-199 in the PS@MOF-199 NPs can block photosensitization of PSs owing to the isolation of oxygen when the NPs are outside cancer cells. Once the PS@ MOF-199 NPs are internalized in tumor sites through enhanced permeation and retention (EPR) effect and enter cancer cells via endocytosis, MOF-199 is decomposed by GSH, and the loaded TPAAQ or Ce6 is released to meet O2, leading to activated photosensitization for PDT under light irradiation. Meanwhile, the Cu(II) in MOF-199 could effectively consume GSH to ensure that the PS-generated ROS can be fully utilized for PDT. Together with the FR/NIR emission from Ce6 and TPAAQ after release, image-guided PDT with enhanced therapeutic effects and minimal non-specific phototoxicity is achieved. Characterization of PSs, MOF-199, and PS@MOF-199. Once PSs are loaded in MOF-199, traditional PSs, such as Ce6, tend to suffer from ACQ, responsible for quenched fluorescence and mitigated 1O2 generation in the aggregate state.56,57 Therefore, PSs with AIE characteristics58,59 are in demand to show bright fluorescence and effective 1O 2 production in aggregate states.60−63 To design AIE PSs with FR/NIR emission, we selected triphenylamine as an electron donor and anthraquinone as an electron acceptor64 to 6881


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Figure 3. Different reagent-induced decomposition rates of ABDA under white light (100 mW cm−2, 400−700 nm) irradiation on (A) TPAAQ and (B) Ce6 in THF/water (1/99, v/v). A0 and A are the absorbances of ABDA at 378 nm before and after irradiation, respectively. [PSs] = 5 μg mL−1, [MOF-199] = 800 μg mL−1, and [ABDA] = 20 μg mL−1; control indicates the photodegradation rates of ABDA (C) N2 adsorption and desorption isotherms of MOF-199, Ce6@MOF-199, and TPAAQ@MOF-199 at 77 K. (D) Pore size distribution of MOF199, Ce6@MOF-199, and TPAAQ@MOF-199. (E) O2 adsorption and desorption isotherms of MOF-199, Ce6@MOF-199, and TPAAQ@ MOF-199 at room temperature. (F) Release profile of PSs originally loaded in MOF-199 upon GSH treatment, measured via HPLC. Before GSH treatment, [PS] = 5 μg mL−1 and [MOF-199] = 800 μg mL−1 in PS@MOF-199.

Ce6 or TPAAQ was then loaded in MOF-199 to yield Ce6@MOF-199 or TPAAQ@MOF-199. Because of the AIE property of TPAAQ, TPAAQ-loaded MOF-199 is highly emissive (Figure S8), which makes TPAAQ@MOF-199 promising for monitoring the delivery process. However, after Ce6 is loaded in MOF-199, the emission of Ce6 is almost completely quenched due to its inherent ACQ property. After GSH decomposes MOF-199, the encapsulated Ce6 is released to regain bright fluorescence. Such a fluorescence turn-on feature endows the Ce6@MOF-199 with real-time in situ monitoring of Ce6 release. F-127 encapsulation was subsequently performed to improve in vivo dispersity and biocompatibility of PS@MOF-199 to yield PS@MOF-199 NPs, which exhibit good dispersity in water with sizes around 150 nm under TEM (Figure 2H,I). Activation and Inhibition of Photosensitization. Before applying Ce6@MOF-199 NPs or TPAAQ@MOF-199 NPs for cancer cell ablation, we examined the 1O2 generation for Ce6, TPAAQ, Ce6@MOF-199, and TPAAQ@MOF-199 via ABDA (20 μg mL−1) in the absence and presence of GSH (Figure 3A,B). When Ce6 and TPAAQ were treated with 10 mM GSH, the photodegradation rates of ABDA significantly dropped from 2 μg mL−1 min−1 and 1.75 μg mL−1 min−1, respectively, to lower than 0.3 μg mL−1 min−1, compared with those induced by TPAAQ and Ce6 without GSH treatment. It demonstrates that 1O2 generation efficiency of TPAAQ is higher than that of Ce6, and more importantly, GSH could significantly scavenge ROS generated by PSs, hindering PDT. Meanwhile, when TPAAQ and Ce6 were encapsulated inside MOF-199, the photodegradation rates of ABDA induced by TPAAQ@MOF-199 and Ce6@MOF-199 were suppressed to below 0.35 μg mL−1 min−1, indicating that MOF-199

crystalline nature of as-synthesized MOF-199 with acceptable stability in PBS, FBS, and low pH medium, and the characteristic diffraction peaks match well with those of simulated MOF-199. To study the PS-loading capacity of MOF-199, the kinetics for TPAAQ and Ce6 loading were studied via UV−vis absorption spectra (Figure S4). The maximum loading contents for TPAAQ and Ce6 in MOF-199 reached 58 and 49 wt % within 8 h, respectively (Figure 2E), which are further supported by thermogravimetric analysis (TGA) (Figure S5). Besides, TGA also showed that copper nodes in the MOF-199 we synthesized could coordinate 30− 60% weight percent water molecules, as indicated in Figure S5. For GSH depletion assessment, 10 mM GSH, the upper limit of GSH levels in vivo,29−31 was used to treat different concentrations of MOF-199. As shown in Figure 2F, 160, 400, and 640 μg mL−1 MOF-199 could deplete around 1.2, 4.8, and 9 mM of GSH, and 800 μg mL−1 MOF-199 is able to scavenge almost 10 mM GSH. The robust GSH-depletion ability of MOF-199 should be due to its relatively high copper content (around 32%), compared with other copper MOFs.38,65,66 In addition, under transmission electron microscopy (TEM), as indicated in Figure 2G, the average size of the synthesized MOF-199 is around 120 nm with highly crystalline morphology and narrow size distribution, which is favorable for tumor accumulation and cellular uptake. After GSH treatment, MOF-199 is decomposed into pieces (Figure S6) and loses its crystallinity (Figure 2D), and the hydrodynamic radius of the MOF-199 drops to around 70 nm, which is confirmed by dynamic light scattering (DLS) (Figure S7). The notable PS-loading capacity, effective GSH scavenging, and nanoscale size render MOF-199 a promising GSHdepleting nanocarrier for different PSs. 6882


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control groups, and all the four kinds of NPs possessed similar sizes (Figures 2H,I and S14) and surface charges (Figure S15). To explore the fluorescence on and off mechanism, HepG2 cells were first treated with Ce6@MOF-199 NPs or TPAAQ@ MOF-199 NPs and then transferred into NP-free medium to observe fluorescence change inside the cells. In Figure S16A, HepG2 cells treated with Ce6@MOF-199 NPs for 8 h showed dim fluorescence with successful NP endocytosis. However, after these cells were further soaked into NP-free medium for 2 h, the fluorescence inside the cells was turned on, which indicates that the loaded Ce6 was released within 2 h via MOF-199 decomposition in the presence of GSH. On the contrary, the HepG2 cells treated by TPAAQ@MOF-199 NPs for 8 h showed bright fluorescence and further treatment of these cells in fresh medium for 2 h did not obviously affect the fluorescence. In Figure 4A, after HepG2 cells were soaked in Ce6@MOF-199 NPs or TPAAQ@MOF-199 NPs for 10 h, bright red fluorescence was observed, comparable to that of the cells treated with Ce6 NPs or TPAAQ NPs (Figure S18A).

encapsulation can successfully inhibit the PS photosensitization.67 Moreover, when Ce6@MOF-199 and TPAAQ@MOF199 were soaked with 10 mM GSH, the resulting ABDA bleaching rates increased to similar values as those caused by Ce6 and TPAAQ without GSH treatment, respectively. The ROS generation difference between PS@MOF-199 with and without 10 mM GSH treatment indicates that the activation of ROS generation in PS@MOF-199 is highly dependent on GSH. In the presence of 10 mM GSH, the much higher 1O2 generation efficiency for TPAAQ@MOF-199 and Ce6@MOF199 relative to that for TPAAQ and Ce6 without MOF encapsulation clearly indicates that PS@MOF-199 is promising for PDT. To explore the proposed 1O2 off-on mechanism in PS@ MOF-199, we first examined the specific surface area and pore size of the synthesized MOF-199 with and without PS loading. As shown in Figure 3C, the capacity of the MOF-199 for nitrogen adsorption at 77 K decreases greatly after the MOF199 encapsulated Ce6 and TPAAQ. Defective MOF-199 has a specific surface area of 1694.5 m2 g−1, which is significantly dropped to 215.2 m2 g−1 and 180.3 m2 g−1 for Ce6@MOF-199 and TPAAQ@MOF-199, respectively. At the same time, the pore volume of Ce6@MOF-199 and TPAAQ@MOF-199 was, respectively, reduced by 69% and 78%, as compared to that of MOF-199, without much variation on pore size distribution before and after loading (Figure 3D). The pore distributions in as-synthesized MOF-199, Ce6@MOF-199, and TPAAQ@ MOF-199 vary from around 0.7 to 2.5 nm, much broader than that in perfect MOF-199,23 indicating the defective nature of as-synthesized MOF-199. Moreover, the adsorbed volumes of oxygen in Ce6@MOF-199 and TPAAQ@MOF-199 also greatly decreased, compared with that in pristine MOF-199 (Figure 3E), which indicates that the loaded PSs in MOF-199 are isolated from O2 to yield inhibited 1O2 generation efficiency. We then studied the PS release profile of GSHtreated PS@MOF-199. As shown in Figure 3F, upon exposure to 5 mM GSH, half of the PSs are released; with 10 mM GSH, almost all the PSs are released, which is consistent with the results shown in Figure 3A,B. On the contrary, when Ce6@ MOF-199 and TPAAQ@MOF-199 were immersed in low-pH medium (Figure S9), compared with those in GSH solution, the PSs were barely released within 40 min, which indicates that the release of PSs is mainly redox driven other than acid driven. As shown in both TEM images and DLS results (Figures S10 and S11), for Ce6@MOF-199 and TPAAQ@ MOF-199 after MOF-199 dissociation, the collapse of MOF199 backbones is clearly visualized to yield fragments with reduced sizes. Besides, GSH titration with PS@MOF-199 (Figure 2F) indicates the robust GSH-depletion capability of PS@MOF-199. PS@MOF-199 NPs possess almost the same properties and mechanisms in the activation and quenching of photosensitization (Figure S12). In Vitro Activation and Enhancement of Cell Ablation of PS@MOF-199 NPs. Ce6@MOF-199-NP and TPAAQ@ MOF-199-NP treated HepG2 cells and NIH-3T3 cells were visualized under confocal laser scanning microscopy (CLSM) to assess cellular internalization. The mass ratio of the concentration of MOF-199 containing 60 wt % water to the concentration of TPAAQ or Ce6 is maintained to be 10, and the concentrations of Ce6@MOF-199 NPs or TPAAQ@ MOF-199 NPs are based on Ce6 or TPAAQ, respectively, for all the in vitro and in vivo experiments. HepG2 and NIH-3T3 cells were also incubated with Ce6 NPs and TPAAQ NPs as

Figure 4. Confocal imaging of (A) HepG2 cancer cells and (B) NIH-3T3 cells upon incubation with Ce6 NPs, Ce6@MOF-199 NPs, TPAAQ NPs, and TPAAQ@MOF-199 NPs for 10 h. In these NPs, the PS concentration is 10 μg mL−1. White arrows show the Ce6@MOF-199 NPs uptake inside 3T3 cells, and the enlarged image with white arrows is shown in Figure S13. 6883


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Figure 5. Viability of HepG2 (A) and NIH-3T3 cells (B) upon incubation with Ce6 NPs, Ce6@MOF-199 NPs, TPAAQ NPs, and TPAAQ@ MOF-199 NPs under white light or dark. Illumination intensity, time, and wavelength are 100 mW cm−2, 5 min, and 400−700 nm, respectively. n = 4 per group, *p < 0.05, **p < 0.01, ***p < 0.001.

MOF-199 NPs under dark and upon white light irradiation (100 mW cm−2, 400−700 nm). For HepG2 cells, as shown in Figure 5A, MOF-199 alone showed only slight cytotoxicity, while Ce6 and TPAAQ NPs efficiently ablated the cells with an IC50 of around 10 μg mL−1 based on PSs. However, the IC50 values of Ce6@MOF-199 NPs and TPAAQ@MOF-199 NPs for HepG2 cells were significantly reduced to 3.5 and 2 μg mL−1 based on PSs, respectively. The >80% HepG2 cell viability in the dark indicates that the tested NPs possess acceptable toxicity. On the other hand, in Figure 5B, both Ce6 and TPAAQ NPs showed high phototoxicity to 3T3 cells as a result of non-specific cellular uptake. However, under the same experimental conditions, Ce6@MOF-199 NPs and TPAAQ@ MOF-199 NPs showed significantly reduced phototoxicity. It could be attributed to scarce endogenous GSH in 3T3 cells and effective isolation of oxygen from PSs inside MOF-199, since uptake quantities of Ce6@MOF-199 NPs and TPAAQ@ MOF-199 NPs are similar between HepG2 cells and 3T3 cells (Figures 4, S16, and S18). No obvious dark toxicity was observed for 3T3 normal cells. Therefore, both Ce6@MOF199 NPs and TPAAQ@MOF-199 NPs show good selectivity between HepG2 and 3T3 cells, demonstrating that MOF-199 platform is effective in addressing the challenges faced by traditional PSs in terms of selectivity and therapeutic efficiency. To understand how the cellular GSH level is modulated in these processes, GSH-based detection kit was used for cell staining. Monochlorobimane inside the kit is essentially nonfluorescent until conjugation with glutathione. The glutathione conjugate of monochlorobimane has absorption and emission maxima at 394 and 490 nm, respectively. HepG2 cells

These results indicate the strong cell imaging ability of PSloaded MOF-199 NPs. On the other hand, as 3T3 cells are normal cells, they have low concentrations of cellular GSH as compared to that of cancer cells, such as HepG2 cells.29−31 The GSH levels were quantified using 5,5′-dithio-bis(2-nitrobenzoic acid), which reveals that GSH concentrations are 5.6 ± 2 μg per million 3T3 cells and 65.2 ± 7 μg per million HepG2 cells (Figure S19). This agrees with the trend of previous reports.29−31 As shown in Figure S16B, Ce6@MOF-199 NP-treated cells were not emissive even after the NP treatment for 8 h, followed by further incubation in fresh medium for 2 h. This is due to the absence of Ce6 release from MOF-199 as a result of low GSH concentrations in normal cell lines. On the other hand, TPAAQ@MOF-199 NPs lightened up the cells under all of the tested conditions. Therefore, in Figures 4B and S18B, although the endocytosis of Ce6@MOF-199 NPs was completed in the 3T3 normal cells, only dim fluorescence was found in the cells, as a result of both low concentration of intracellular GSH and the ACQ effect of Ce6 in MOF-199. On the contrary, TPAAQ@MOF-199 NPs showed bright red fluorescence in normal cells. Figures 4 and S16 reveal that Ce6@MOF-199 NPs are only able to show red fluorescence after releasing Ce6 from MOF-199 by GSH, while TPAAQ@MOF-199 NPs are always fluorescence-on in cells regardless of GSH levels. To quantitatively evaluate in vitro cancer cell ablation efficacy and cytotoxicity for PS@MOF-199 NPs, methylthiazolyldiphenyltetrazolium bromide (MTT) assay was conducted after HepG2 cells and 3T3 cells were incubated with different concentrations of MOF-199 NPs, PS NPs, and PS@ 6884


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Figure 6. (A) Confocal imaging of HepG2 cancer cells upon incubation with PS NPs (10 μg mL−1) and PS@MOF-199 NPs (10 μg mL−1); further treatment with Glutathione Cell-Based Detection Kit. Confocal imaging of (B) HepG2 cancer cells and (C) 3T3 cells upon incubation with PS NPs (10 μg mL−1) and PS@MOF-199 NPs (10 μg mL−1); further treatment with 20 μM DCFDA for 30 min.

could escalate ROS levels in the cytoplasm. As a result of both factors, after Ce6@MOF-199 NPs and TPAAQ@MOF-199 NPs were used to treat HepG2 cells, the generated ROS levels in the cytoplasm were further boosted, compared with those afforded by Ce6 NPs and TPAAQ NPs. The depletion of GSH by MOF-199 before light illumination indeed protects the ROS generated by PSs from being consumed by endogenous GSH; the elevated ROS levels inside cancer cells then boost the cancer cell ablation efficiency. As shown in Figures 6C and S20C, for 3T3 cells, PSs with and without MOF-199 encapsulation showed an obvious difference in ROS generation, due to the low concentration of GSH in 3T3 cells. With the encapsulation of MOF-199, the ROS generation of PSs exposed to light was successfully prohibited due to their isolation from oxygen. The difference in GHS level between cancerous and normal cells allows the selective release of PSs in GSH-upregulated cells for ROS production to specifically kill cancer cells. Enhanced PDT of PS@MOF-199 NPs. The high efficacy of PS@MOF-199 NPs in killing cancer cells motivated us to

pretreated with Ce6 NPs and TPAAQ NPs possessed declined GSH levels under light irradiation, compared with those in pristine HepG2 cells as the control (Figures 6A and S20A), illustrating the consumption of GSH by the ROS generated by PSs. After the cells were pretreated by Ce6@MOF-199 NPs and TPAAQ@MOF-199 NPs, after light illumination, the GSH levels were further reduced, because of the extra consumption of GSH by MOF-199. Apart from the assessment of endogenous GSH levels, the intracellular ROS levels were also assessed using 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA), a ROS indicator. For HepG2 cells, without light illumination, MOF-199 itself could induce the almost same amount of ROS, comparable to those generated by Ce6 and TPAAQ NPs under light (Figures 6B and Figure S20B). This is the result of unbalanced intracellular ROS and GSH amount,68 and the reduction in GSH levels tends to escalate intracellular ROS production.38 Similarly, in Figure S21, when HepG2 cells were treated with L-buthionine-sulfoximine (BSO), a GSH reducer, intracellular ROS levels were also enhanced, which demonstrates that reduction in GSH levels 6885


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Figure 7. Confocal images of EGFP-krasV12 zebrafish larva of 7 dpf before and after their liver tumors were intravenously injected with (A) Ce6 NPs, Ce6@MOF-199 NPs, TPAAQ NPs, and TPAAQ@MOF-199 NPs (B) without treatment, before, and after light treatment and injected intravenously with MOF-199 NPs. (C) The relative tumor volume changes in each group (*p < 0.05, ***p < 0.001), studied over time span of 24 h after individual treatment. [PSs] = 100 μg mL−1. Injection volume = 20 nL. Red fluorescence is emitted from the NPs in blood vessels and liver tumors, and green fluorescence indicates GFP-positive liver tumors.

To examine in vivo PS release and PDT efficacy of PS@ MOF-199 NPs, zebrafish larvae were injected with Ce6 NPs, Ce6@MOF-199 NPs, TPAAQ NPs, TPAAQ@MOF-199 NPs, and MOF-199 NPs (groups 1, 2, 3, 4, and 7), respectively, at 7 dpf, that is, 0 day post-injection (dpi).71,73 The tumor size was recorded, exposed to white light at 1 dpi (8 dpf), and detected under CLSM to check tumor volume change for therapeutic effects at 2 dpi (9 dpf). Zebrafish larvae in group 5 without light illumination and zebrafish larvae in group 6 with white light illumination at 8 dpf were imaged for tumor size at 8 dpf and 9 dpf. Three-dimensional (3D) projections of the liver tumor with GFP and FR/NIR fluorescence channels enabled by Ce6 and TPAAQ are shown in Figure 7A,B. In Figure 7A, effective uptake of NPs by tumor could be visualized in all larvae treated with Ce6 NPs, Ce6@MOF-199 NPs, TPAAQ NPs, and TPAAQ@MOF-199 NPs in groups 1−4, from 0 dpi to 1 dpi. Obvious volume shrinkage of the liver tumor was observed in these groups from 1 dpi to 2 dpi after light administration, which shows an effective imaged-guided anticancer therapeutic effect. On the contrary, the groups without treatment or only with light treatment and MOF-199 NPs treatment showed tumor increase in volume in Figure 7B. Intriguingly, in group 2, for Ce6@MOF-199-NP-treated zebrafish larvae, cancer-cell-targeted turn-on fluorescence was

further evaluate the in vivo therapeutic effects of PS@MOF199 NPs. Hyperplasic liver tumor model based on transgenic zebrafish was established for in vivo tumor photodynamic therapeutic efficacy assessment. As zebrafish embryos are translucent, it is possible to perform real-time optical monitoring of PS release and activation as well as to visualize liver tumor volume change.69 It is also reported that essential gene similarity between embryonic zebrafish and human reaches a high level of 99%, and substantial tumor signaling pathways are conserved.70 More importantly, cancer cells in zebrafish possess upregulated GSH, which make it suitable to study the GSH influence on PSs.29−31,69,71,72 In our study, healthy edema-free EGFP-krasv12 transgenic zebrafish larvae were selected and treated with mifepristone at 5-day postfertilization (dpf) to overexpress enhanced green fluorescent protein-modified kras oncogene. Thereafter, the liver tumor tissue carried by zebrafish is GFP positive. To study the toxicity of PS@MOF-199 NPs for zebrafish embryos, 7 dpf zebrafish embryos were, respectively, soaked with Ce6@MOF199 and TPAAQ@MOF-199 NP suspensions at different concentrations for 24 h. As indicated in Figure S22, the Ce6@ MOF-199 NPs and TPAAQ@MOF-199 NPs showed good biocompatibility even at 100 μg mL−1 based on Ce6 and TPAAQ toward tumor-carrying zebrafish embryos. 6886


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body weight and normal organs of tumor-bearing mice were observed (Figures S26 and S27), which show low systematic toxicity of TPAAQ@MOF-199 NPs toward mice.

observed after the release of Ce6 from 0 dpi to 1 dpi, which indicates that Ce6@MOF-199 NPs are promising for cancer cell detection and monitoring of Ce6 release. Besides, in group 4, TPAAQ@MOF NPs could light up almost all the blood vessels throughout zebrafish body at 0 dpi and 1 dpi, comparable with that achieved by Ce6 NPs and TPAAQ NPs in groups 1 and 3, which reveals that TPAAQ@MOF-199 NPs could serve as fluorescent probes to monitor TPAAQ delivery. To find the statistical significance of liver-tumor volume variation before at 8 dpf and after treatment at 9 dpf, t test was carried out, and the P value was found to be 60% tumor shrinkage from 1 dpi to 2 dpi, respectively, which were significantly higher than 27% and 37% resulting from bare Ce6 and TPAAQ, respectively. These results indicate that highly effective and activatable image-guided PDT has been successfully realized for PS-loaded MOF-199 NPs. To confirm activatable image-guided PDT endowed by PS@ MOF-199 NPs, in vivo experiments through either intratumoral or intravenous administration of TPAAQ@MOF-199 NPs into the 4T1 tumor-bearing mice were conducted. As shown in Figure S23A, after intratumoral administration, TPAAQ@MOF-199 NPs lighted up the 4T1 tumor, showing good imaging capability of TPAAQ@MOF-199 NPs. Besides, as shown in Figure S23B, after intravenous injection of TPAAAQ@MOF-199 NPs and white light irradiation, TPAAQ@MOF-199 NPs caused obvious cell apoptosis in tumors, compared with PBS. However, after subcutaneous injection of TPAAQ@MOF-199 NPs to normal skin, followed by the same light illumination, the NPs did not induce phototoxicity to normal skin cells, similar to PBS, indicating its low phototoxicity. On the other hand, as shown in Figure S23C, upon white light irradiation, TPAAQ@MOF-199 NPs could evidently inhibit the growth of mouse tumors, which indicates the tumor-activated PDT effects of TPAAQ@MOF199 NPs. Additionally, upon intravenous administration of TPAAQ@ MOF-199 NPs into 4T1 tumor-bearing mice, ex vivo ICP-mass analyses of copper content (Figure S24) and fluorescence imaging (Figure S25) in different organs after 1 and 7 days of intravenous administration were conducted. It was found that PS@MOF-199 NPs were cleared from the body with time, and the copper ions did not tend to accumulate in the body under the dose we administrated. Besides, negligible impacts on the

CONCLUSION In conclusion, we demonstrate a general approach for PSs to realize activatable image-guided PDT. This approach diminishes endogenous GSH levels and thereby significantly boosts the efficacy of cancer therapy with minimum non-targeted toxicity. The approach started using MOF-199 to load PSs and block photosensitization of PSs via isolation of oxygen. F-127 was subsequently utilized to encapsulate PS@MOF-199 to yield PS@MOF-199 NPs. After PS@MOF-199 NPs were endocytosed, MOF-199 was decomposed by GSH, and thus the loaded PSs were released from MOF-199 to recover photosensitization and trigger PDT. Meanwhile, Cu(II) from MOF-199 effectively scavenged GSH intracellularly, rendering PS-generated ROS free from depletion by GSH. After light irradiation, well-preserved ROS generated by PSs afforded highly effective PDT. Together with fluorescence emission from TPAAQ in TPAAQ@MOF-199 NPs regardless of GSH levels, the TPAAQ delivery process is monitored, and with the fluorescence turn-on feature of Ce6 in PS@MOF-199 NPs, the Ce6 release process has also been successfully monitored. We believe that the as-reported MOF-assisted PS strategy will provide notable perspectives on how to fully take advantage of PSs for image-guided photodynamic therapy. METHODS Facile Fabrication of MOF-199. 4.5 mL of 0.1 M Cu(NO3)2 aqueous solution and 3 mL of 0.1 M benzene-1,3,5-tricarboxylate (btc) triethylammonium salt aqueous solution were added, respectively, to 150 mL of 1:1 (v/v) mixture of ethanol and deionized water. The reaction mixture was stirred vigorously for 10 min at room temperature. The product was washed with ethanol for 3 times to eliminate unreacted reagents. The final purified products were stored in anhydrous ethanol at room temperature. Synthesis of Compound TPAAQ. A mixture of compound 1 (222.7 mg, 0.60 mmol), 2 (143.6 mg, 0.50 mmol), potassium carbonate (680 mg, 5.0 mmol), 15 mL of THF, 5 mL of water, and Pd(PPh3)4 (3 mol %) were carefully degassed and charged with nitrogen. Then the reaction mixture was stirred at 60 °C for 24 h. After cooling to ambient temperature, the reaction was stopped by the addition of water, extracted with dichloromethane, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate and purified by column chromatography using n-hexane/dichloromethane (1/2, v/v) as the eluent to afford TPAAQ (183.1 mg, 81.2%) as a red solid. NMR spectra of TPAAQ are shown in Figures S28 and S29. 1H NMR (400 MHz, CDCl3, 298 K), δ (TMS, ppm): 8.49 (d, J = 2.0 Hz, 1H, ArH), 8.30 (m, 3H, ArH), 7.97 (m, 1H, ArH), 7.79 (m, 2H, ArH), 7.61 (d, J = 8.8 Hz, 2H, ArH), 7.31 (t, J = 7.2 Hz, 4H, ArH), 7.17 (d, J = 7.6 Hz, 6H, ArH), 7.09 (t, J = 7.2 Hz, 2H, ArH). 13C NMR (100 MHz, CDCl3, 298 K), δ (ppm): 183.3, 182.8, 148.8, 147.3, 146.3, 134.1, 133.9, 133.7, 133.6, 131.9, 131.5, 131.5, 129.5, 128.1, 128.0, 127.2, 127.2, 125.0, 124.7, 123.7, 122.9. F-127 Coating PS@MOF-199. PSs were dissolved in benign solvents (Ce6 and TPAAQ in THF) and then soaked with MOF-199 suspended in ethanol, with a final concentration of 2 and 1 mg mL−1 for PSs and MOF-199, respectively. The soaking mixtures were centrifuged to take 1 μL supernatant for real-time analyses of loading capacity via absorption of PSs. The loading capacity of MOF-199 was calculated using the following equation: ij APSs in the supernatant yzz C PSs zz × wt % = jjjj1 − j APSs before loading zz C MOF − 199 k {

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ACS Nano As indicated in the caption of Figure S4, CPSs = 2 mg mL−1, and CMOF‑199 = 1 mg mL−1. Before Ce6 loading, the absorbance of Ce6 at 400 nm (A400 nm) = 0.402, and after 12 h, Ce6 left in the supernatant has an A400 nm = 0.305. Therefore, for Ce6, the maximum loading weight percent after 12 h incubation with MOF-199 is

ORCID

Wenbo Wu: 0000-0002-6794-217X Bo Wang: 0000-0001-9092-3252 Bin Liu: 0000-0002-0956-2777

i 0.305 yz 2 zz × = 0.49 wt % = jjj1 − 0.402 { 1 k

Author Contributions ∥

These authors contributed equally.

Notes

The authors declare no competing financial interest.

Similarly, before TPAAQ loading, the absorbance of TPAAQ at 470 nm, A470 nm = 0.144, and after 12 h TPAAQ loading, the TPAAQ in the supernatant has an A470 nm = 0.102. Therefore, for TPAAQ, the maximum loading weight percent after 12 h incubation with MOF199 is

ACKNOWLEDGMENTS The authors thank the Singapore National Research Foundation (R279-000-444-281 and R279-000-483-281) and the National University of Singapore (R279-000-482-133) for financial support.

i 0.102 yz 2 zz × = 0.58 wt % = jjj1 − 0.144 { 1 k

Loading capacity at other time points in Figure 2E was also evaluated using the same approach. When the desirable loading weight percentage was met, all of the supernatants were discarded, and the residues were added by 10 mg mL−1 F-127 dissolved in ethanol (concentration of MOF-199 is at 1 mg mL−1). The suspension was then vigorously stirred for 20 min. Subsequently, rotary evaporation was conducted to remove the solvents, and the dried mixture was added with Milli-Q water and then stirred to afford an aqueous dispersion of NPs (final concentration of MOF-199 is at 1 mg mL−1). Titration of GSH Treated with MOF-199, Ce6@MOF-199, and TPAAQ@MOF-199. Aliquots of 3 mL of 10 mM GSH were, respectively, treated with MOF-199, Ce6@MOF-199, and TPAAQ@ MOF-199 with concentrations of 0, 80, 160, 240, 320, 400, 480, 560, 640, 720, and 800 μg mL−1 based on MOF-199. After 40 min of reaction, the mixtures were centrifuged, and the clear supernatant was analyzed via high-performance liquid chromatography (HPLC). Specifically, an aliquot of 0.5 mL of GSH solution was added to 0.5 mL of 0.5 mM 5,5′-dithio-bis(2-nitrobenzoic acid) (DTNB or Ellman’s reagent). The solution was allowed to react for 30 min at 60 °C, followed by injecting into the HPLC at a flow rate of 1.5 mL min−1. The separation was performed at ambient temperature, and the detection was carried at 280 nm. Eluent: 0−14−20 min, 60% B−60% B−90% B (A: H2O containing 0.1% CF3COOH, B: acetonitrile containing 0.1% CF3COOH). Statistical Analysis: Quantitative data were expressed as mean standard deviation. ANOVA analysis and Student’s t test were utilized for statistical contrast. P < 0.05 was figured statistically significant.

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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/acsnano.9b01665. Synthetic route to TPAAQ and photostability of TPAAQ; stability evaluation of Ce6@MOF-199 and TPAAQ@MOF-199; characterization of as-synthesized Ce6@MOF-199 NPs and TPAAQ@MOF-199 NPs; enlarged white-arrow-enclosed images in Figures 4 and S16; time-lapse imaging of the cells treated with Ce6@ MOF-199 NPs and TPAAQ@MOF-199 NPs; quantitative analyses of cellular uptake, intracellular GSH depletion, and ROS generation inside cells; toxicity evaluation in zebrafishes; activatable image-guided PDT data and in vivo biodistribution and biocompatibility evaluation based on mouse model (PDF)

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. 6888


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