Nanoscale Mixed-Component MetalâOrganic Frameworks with

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Nanoscale Mixed-Component Metal-Organic Frameworks with Photosensitizers Spatial Arrangement-Dependent Photochemistry for Multi-Modal Imaging-Guided Photothermal Therapy Xiaohua Zheng, Lei Wang, Ming Liu, Pengpeng Lei, Feng Liu, and Zhigang Xie Chem. Mater., Just Accepted Manuscript • DOI: 10.1021/acs.chemmater.8b03043 • Publication Date (Web): 12 Sep 2018 Downloaded from http://pubs.acs.org on September 12, 2018

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Chemistry of Materials

Nanoscale Mixed-Component Metal-Organic Frameworks with Photosensitizers Spatial Arrangement-Dependent Photochemistry for Multi-Modal Imaging-Guided Photothermal Therapy Xiaohua Zheng†,‡, Lei Wang*,†, Ming Liu†,§, Pengpeng Lei†,§, Feng Liu†,§, Zhigang Xie*,†

†

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022 (China) ‡

University of Science and Technology of China, Hefei 230026, PR China §

University of Chinese Academy of Sciences, Beijing 100049 (China)

ACS Paragon Plus Environment

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ABSTRACT: The introduction of multiple components into one crystalline metal-organic framework (MOF) provides a feasible approach to fully understand the correlation of component heterogeneity and the whole performance. Herein, photoactive tetratopic chlorin (TCPC) ligands with different geometry and connectivity have been successfully incorporated into Hf-UiO-66 archetype structure without altering the underlying topology by a facile strategy. Unlike previous porphyrin-NMOFs with homogeneous periodical porphyrin arrangements typically for photodynamic therapy (PDT) usage, we demonstrate that TCPC component heterogeneity

within

as-synthesized

TCPC-UiO

possesses

both

PDT

and

photothermal therapy (PTT) simultaneously, but PTT takes a more potent antitumor efficacy as proven in several photophysical characterizations and biological experiments in vitro. The high photothermal conversion efficiency, favorable photostability and biocompatibility, and strong X-rays attenuating ability of Hf element within TCPC-UiO make it a potential platform for further application in multi-modal CT/thermal/photoacoustic imaging. Additionally, TCPC-UiO shows an impressive anticancer activity against H22 tumor-bearing mice in vivo and its tumor inhibition rate is above 90%. We anticipate that current work may offer in-depth insight to the component heterogeneity and property relationship and also extend biological applications of NMOFs.


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INTRODUCTION Photosensitizers (PSs)-assisted phototherapy, further classified into photodynamic therapy (PDT) and photothermal therapy (PTT), is a promising alternative cancer treatment with relatively safe and minimally invasive features.1, 2 These therapies are based on the energy transfer of absorbed optical energy to the surrounding biological species to generate cytotoxic reactive oxygen species (ROS) for PDT or to induce local hyperthermia for PTT.3,4 Since the first PS agent-photofrin® approved for clinical trials, porphyrin derivatives and their nanosystems have been extensively explored for PDT.5-8 But the oxygen-dependent feature of PDT greatly reduces its therapeutic efficacy due to the local hypoxia in tumor regions.9,10 Benefiting from the strong chelation ability and the large π electron conjugated system of porphyrin macrocycle, various strategies have been applied in the development of porphyrin-based PTT agents, either by paramagnetic metals chelation to funnel excited

states

into

intramolecular

nonradiative

decay

or

porphyrin-based

nano-assembly with structure-dependent fluorescence self-quenching.11-14 Particular for the latter strategy, the assembly and aggregation could generate the ideal oxygen-independent photothermal activity, except for photodynamic effect. Metal-organic frameworks (MOFs) and their nanoscale forms (NMOFs), assembled from inorganic metal nodes and organic ligands into periodical networks in an isotropic manner, have been potentially utilized as promising platforms to introduce active PSs into their backbones or pores.15-18 The confinement effect of framework could restrict the self-quenching and molecular vibrations of these



PSs.19-21 Some MOFs with porphyrin as single building component have already been successfully prepared, and these order arrays of porphyrin ligands within NMOF have been demonstrated with superior ROS generation efficiency than their corresponding porphyrin ligands.22-24 Recently, great interests have been attracted in the design and preparation of mixed-component MOFs or multivariate MOFs (MTV-MOF) with isomorphously distributed multiple components into one crystalline structure without altering the underlying topology.25-27 The emergence of such mixed-component MOFs could greatly increase the diversity and versatility of traditional MOFs. Mixed-component MOFs delicately superimposes the physicochemical properties of each component to achieve an integral performance, which is better than each single component or their simple adducts.28-32 General requirement for the mixed-component strategy is that the ligand derivatives should have the same geometry and coordination connectivity. Remarkably, Zhou and co-workers developed a one-pot route to introduce multiple organic ligands with different molecular size, symmetry, and connectivity into a stable Zr-MOF without altering the topology,33 and reported a PS and photochromic switch co-doped mixed-component MOFs nanoplatform with reversible 1O2 generation for PDT against cancer cells by controlling the irradiation on/off of photochromic switch.34 However, how to control and better understand the structural correlation between component heterogeneity and the final physiochemical properties, particular for regulating the PDT or PTT performance in porphyrin-based NMOF, are needed to be well explored.


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Herein, a chlorin-based NMOF, named TCPC-UiO, has been prepared by mixed-component strategy. The correlation of spatial chlorin arrangements and photochemical properties within TCPC-UiO and its further usage for multi-modal imaging-guided photothermal antitumor therapies have been well investigated (Figure 1). Hf-UiO-66 as an isomorphic structure of Zr-UiO-66 archetype structure, constructed from the 12-connected building block and ditopic terephthalate (BDC), is selected due to its unprecedented chemical stability and high tolerated ability for introducing second ligands with diverse geometry and connectivity.35-37 Tetratopic chlorin

(TCPC)

with

improved

photophysical

properties

than

its

counterpart-porphyrin has been employed as the functional ligands for “proof of principle”. Besides strong X-rays attenuating ability for CT imaging, the high-Z element of Hf atom could effectively enhance intersystem crossing (ISC) of singlet-to-triplet by weakening spin prohibition due to the quite large spin-orbit coupling constant, which is beneficial for phototherapy theoretically.22,23,38 The current work is the first attempt to deeply investigate the possible correlation of the heterogeneous feature of TCPC-UiO and its phototherapy performance. Unlike that periodic arrangement of chlorin-based NMOFs with typically enhanced PDT, photophysical characterizations and biological experiments in this work indicate that photothermal behaviors play a leading role after the TCPC introduction. In addition, this nanotheranostic platform not only avoids the critical drawback of O2-dependent PDT but also offers valuable therapeutic advantages and expands space for further



development and regulation of phototherapy performance of NMOF in biological field.

Figure 1. Synthesis and the mechanism for cancer therapy of TCPC-UiO by light activation. (a) Synthesis of TCPC-UiO NMOF and schematic description of heat and singlet oxygen generation under laser irradiation. (b) The photophysical mechanism for cancer therapy under light activation (Phos., phosphorescence; NRR, nonradiative recombination; ISC, intersystem crossing) of combination therapy utilizing single light source in vivo guided by CT/thermal/photoacoustic imaging.

RESULTS AND DISCUSSION To address this hypothesis, chlorin ligand, tetrakis(4-carboxyphenyl)chlorin (TCPC), was firstly prepared by partial reduction of its corresponding porphyrin product via three-steps synthesis24 and characterized by 1H NMR spectroscopy and MALDI-TOF mass spectrometry (Figure S1, S2). Then this photoactive chlorin ligand was introduced into MOF framework by using a modulator-assisted mixed-component


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strategy in a one-pot solvothermal reaction of HfCl4, BDC, and TCPC in N, N-dimethylformamide (DMF) to give TCPC-UiO nanoparticles with grayish green color. A series of experiments in control the molar rate of BDC and TCPC have been carried out, and obtained products were further characterized by powder X-ray diffraction (PXRD) (Figure S3a). And Hf-TCPC was selected as control group in direct solvothermal reaction of Hf ions and TCPC (Figure S4). Transmission electron microscopy (TEM) and scanning electron microscope (SEM) images of TCPC-UiO (Figure 2a; Figure S3b, Figure S5a) reveal polyhedral geometries with a particle diameter of 100-130 nm, which is similar to its archetype Hf-UiO-66 without TCPC doped. Dynamic light scattering (DLS) profiles show that the hydrated diameter of TCPC-UiO dispersed in water is 183.7 nm with a polydispersity index (PDI) of 0.208 (Figure S5b). The ζ potential of TCPC-UiO is 14.3 ± 0.6 mV in aqueous solution, which is smaller than its Hf-UiO-66 archetype (26.1 ± 2 mV). The size, PDI and ζ potentials of TCPC-UiO NMOF in water, PBS, cell culture media (containing 10% FBS) and serum measured by DLS method have been listed in Table S1. After the MTV-treatment, the color of as-synthesized TCPC-UiO changes from the white of Hf-UiO-66 to the grayish green after the fully washing with DMF and water (insert in Figure 2b). To confirm the successful introduction of TCPC in the UiO-MOF framework, a control experiment has been done by immersing as-synthesized Hf-UiO-66 in the DMF solution of TCPC. After thoroughly washing with DMF, negligible color changes of Hf-UiO-66 powders can be observed, indicating that TCPC could act as co-ligands existing within the skeleton



of TCPC-UiO other than locating in the pores of Hf-UiO-66. The identical Bragg diffraction peaks of as-synthesized TCPC-UiO to that of simulated Hf-UiO-66 archetype in PXRD patterns, further validated the maintained UiO-typed topology after the TCPC introduction (Figure 2b). The contents of Hf and TCPC within TCPC-UiO are further determined by using element analysis and thermogravimetric analysis (TGA). Inductively coupled plasma mass spectrometry (ICP-MS) method calculates a 59.7% of Hf content in TCPC-UiO. A similar weight loss of TCPC-UiO compared with its Hf-UiO-66 archetype is observed in TGA curves and gives 8 wt% content of TCPC (Figure S5c). A high BET value of 1002 m2 g-1 for TCPC-UiO is observed, and no any blocking pores or channels are appeared (Figure S5d-e). After TCPC doping, FT-IR spectra of as-synthesized TCPC-UiO gives an enhanced stretching vibration at 3401 cm-1 from -NH (Figure S5f). The good colloidal and structure stability of those TCPC-UiO nanoparticles are evidenced by little changed DLS profiles in water for 7 days and the identical PXRD patterns in both PBS and culture media (containing 10% FBS) even after 48 hours soaking (Figure S5g-i). Moreover, the polyhedral shapes of TCPC-UiO (Figure S6) are also well retained even after immersion at PBS and culture media for 72 h, respectively.


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Figure 2. (a) TEM image of TCPC-UiO nanoparticles. Scale bar: 200 nm. (b) PXRD patterns and corresponding color changes (insets) of TCPC-UiO and Hf-UiO-66. (c) UV-Vis spectra of Hf-UiO-66, TCPC and TCPC-UiO dispersed in DMF, insets figures are photographs of Hf-UiO-66 solution (left) and TCPC-UiO solution (right). (d) The fluorescence spectra of TCPC, Hf-TCPC and TCPC-UiO dispersed in DMF excited at 420 nm. (e) Time-dependent 1O2 generation kinetics of TCPC, Hf-TCPC and TCPC-UiO. Plots of ln(Ao/A) versus irradiation time reveals a good linear relationship suggesting that the 1O2 generation process of photosensitizers follows first-order kinetics. Ao = absorption of the DPBF in dark. A = real-time absorption of the DPBF after different illumination time. Photothermal heating curves of water, Hf-UiO-66 and TCPC-UiO NMOF with (f) various concentrations upon laser illumination and (g) various laser power densities. (h) Photothermal heating curves of



TCPC in DMF, Hf-TCPC and TCPC-UiO in water at the same conditions. (i) Photothermal effect of the TCPC-UiO solution under laser irradiation, which was turned off after 5 min irradiation.

Conventionally, the periodicity repeated metal-chromophores coordination bonds and regular chromophores distributions within MOF frameworks may be beneficial to obtain fluorescent MOFs with strong brightness and high quantum yield due to the lengthening intramolecular distances between chromophores and confinement effects to avoid the self-quenching.19-21 For mixed-component MOFs or MTV-MOFs, the topological structures are unchanged during the second component introduction, but the introducing functional sites are irregular distribution within the MOF frameworks.39,40 Those irregular distributions of doping organic linkers could be further considered to form some “functional domains”,41 which may have some direct influences on the physicochemical properties. For TCPC-UiO, the situation is more complex, and there may bring some “short range order domains” in the framework of archetype Hf-UiO-66 due to the diverse coordination modes between TCPC and BDC linkers. The photophysical properties, photodynamic and photothermal activity have been well investigated on detailed comparisons with the TCPC molecules, Hf-TCPC, and our TCPC-UiO. And the Hf-TCPC control with chlorin as single building component and average particle size of 120 nm (similar that of TCPC-UiO) has been prepared by manipulating the added amount of BA modulators (Figure S4). Similar to TCPC, UV-vis spectra of TCPC-UiO also shows a typical split Soret band and four


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normalized absorbance from 500 nm to 700 nm (Q peaks), further proving the successful mixed-component strategy and retaining molecular structure of chlorin in TCPC-UiO (Figure 2c). The extinction coefficients (ε) at the lowest-energy Q bands of TCPC and TCPC-UiO have been calculated to be 41573 M-1 cm-1 in DMSO and 14949 M-1 cm-1 in water. Moreover, increased Q band absorbance of chlorin appeared ascribing to spin prohibition induced by heavy atom effect, which would be favorable for the improvement of light-to-heat conversion efficiency. Under the excitation at 420 nm, all TCPC-UiO, Hf-TCPC, and TCPC with the same TCPC concentration exhibit a similar red fluorescent emission around 660 nm. However, the fluorescence intensity of TCPC-UiO (Figure 2d) is about 18-fold and 4-fold weaker than both TCPC molecule and Hf-TCPC, respectively. Meanwhile, the tested fluorescence lifetime and quantum yield largely drop from 9.13 ns and 17.4% of TCPC, 2.86 ns and 1.82% of Hf-TCPC to 1.38 ns and 0.62% of TCPC-UiO (Figure S7). Those largely reduced fluorescence intensity, quantum yield, and quantum lifetime may attribute to the diminished electronic transition energy-gaps stemming from the interchromophoric interactions and the enhanced ISC between coordination of the carboxylate groups from TCPC ligands and Hf4+ ions, which could be beneficial for phototherapy performances in biological application. Under the irradiation, porphyrin and its derivatives could generate 1O2 for PDT or heat for PTT, which is largely dependent on the spatial arrangement of porphyrin.42,43 But for NMOF, little have been known on the inner correlation between the chromophores distribution and phototherapy performance.44,45 In vitro PDT and PTT



performance of TCPC-UiO and its TCPC and Hf-TCPC controls have been studied. Initially, 1, 3-diphenylisobenzofuran (DPBF) and 9,10-Anthracenediyl-bis(methylene) dimalonic acid (ABDA) has been selected as a ROS indicator to testify the 1O2 generation efficiency, respectively. Taking DPBF as an example, irradiation of small molecule and NMOF cause continuously decreased UV absorbance intensities of DPBF at 415 nm (Figure S8a-d). As is expected, negligible spectra changes have been detected for those in the control groups (DPBF + Laser, Hf-TCPC and TCPC-UiO in dark) (Figure S7d). The plot of absorbance value (the maximum absorbance Ao versus real-time absorbance A) against irradiation time (t) is fitted with an exponential function: Ao/A = ekt, giving a pseudo-first-order 1O2 generation behavior of both small molecule and NMOF (Figure 2e). The k values are further calculated to compare the 1

O2 generation efficiencies of TCPC, Hf-TCPC, and TCPC-UiO. Similar to the above

photophysical results, the 1O2 generation efficiency could be ordered as TCPC > Hf-TCPC > TCPC-UiO, which is good in agreement with the results using ABDA as ROS indicator (Figure S9). TCPC molecule and Hf-TCPC sample give a more 6-fold and 2-fold stronger than TCPC-UiO synthesized, respectively. That result is opposite from those reported homogeneous NMOFs with periodic porphyrin or chlorin arrangements.22,23 It could further indicate that the heterogeneous distribution of TCPC in the MTV-MOF frameworks may weaken the confinement effects of MOF framework itself and enhance the possible aggregation among PSs to lower the 1O2 generation ability. Heating curves of TCPC-UiO sample dispersed in water were recorded to study


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the influence of TCPC spatial arrangement on the photothermal performance under a 635 nm laser irradiation at a power density of 0.8 W cm−2. Photothermal heating curves of TCPC-UiO give a concentration and laser intensity dependent manner (Figure 2f, g). No obvious temperature variation (lower than 3 oC) is found both in water and Hf-UiO-66 control, validating that the heat mainly generate from the doped TCPC. In contrast to TCPC and Hf-TCPC, as-synthesized TCPC-UiO shows the best photothermal behavior at the same TCPC concentration (Figure 2h). A rapid temperature increase from 18 oC to 42 °C within 5 min irradiation appeared even at the lowest concentration of 80 µg mL-1. On the contrary, only 5 °C and 7 oC of temperature variations are observed for TCPC and Hf-TCPC controls under the same tested conditions after removing the contribution of used solvents, respectively. The photothermal conversion efficiency of TCPC-UiO (Figure 2i; Figure S8e) has been measured by monitoring the heating and cooling curve after 300 s irradiation, and about 25.2% value for TCPC-UiO is calculated from the schematic plot of cooling time versus negative natural logarithm of temperature variation.3 Besides of higher photothermal conversion efficiency, a potential PTT agent should also have good photostability for recycle usage. Negligible temperature variation is observed even after undergoing five cycles of heating and cooling (Figure S8f). Additionally, comparing with the fast color fading and UV absorption decreasing for indocyanine green (ICG) widely used in PTT, ignorable color and absorbance changes for TCPC-UiO are appeared even after a longer 20 min irradiation (Figure S10). Unlike the PDT process largely depending on the energy transfer from the triplet excited state



to ground state, the generated heat for PTT is essentially belong to the nonradiative recombination of adsorbed light energy, which may enhance through the supramolecular aggregation-induced self-quenching or molecular vibration of chromophores.42,43,46 Our current TCPC-UiO is just an example, which has high photothermal conversion efficiency, reusable ability, and excellent photostability for potential PTT agent. Cellular uptake of TCPC-UiO has been investigated in HepG2 cells. After incubation of TCPC-UiO with HepG2 cells at concentration of 100 µg mL-1, the Hf contents in HepG2 cells (Figure S11a) were determined by ICP-MS at each tested time interval, giving the increasing tendency from 1.01 to 6.37 µg/105 cells. The phototherapy efficacy of TCPC-UiO against HepG2, HeLa, 4T1 and MCF-7 cells was further evaluated by using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays. As displayed in Figure 3a-b and Figure S11b-c, the cytotoxicity of NMOF upon light irradiation shows a strongly dose-dependent behavior, while the cell viability is above 90% in the dark even at the TCPC concentration up to 40 µg mL-1. Cytotoxicity induced by laser irradiation itself has been excluded by the high viability (above 90%) of each tested cells (Figure S11d). With aim to reveal the mechanism of the phototherapy induced cytotoxicity, the low temperature (4 oC) phototoxic experiments for restraining the photothermal effect and using 1 mM of VC (Vitamin C) as the ROS scavenger for cells pretreatment to inhibit the photodynamic efficacy have been done. Under the laser irradiation, more than 80% of HepG2 and HeLa cells and 70% of 4T1 and MCF-7 cells are dead. But after


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pretreating with VC and lowering the experimental temperature to 4 oC, negligible cellular deaths as same as the above dark cytotoxicity are observed in all tested cell lines. We then take the HepG2 cell line as an example to make an elaborate investigation. In each individual experiment, only 30% cellular deaths are observed under the lower temperature at the TCPC concentration of 40 µg mL-1, ascribing to the PDT induced cytotoxicity. However, after pretreating with 1 mM Vitamin C at 37 o

C, cellular inhibition rates induced by PTT are rapidly increasing to 65%. Those

above results conclude that the pathways of cellular death might come from a combination effect of both PDT and PTT, but the PTT pathway plays a predominant role, further confirming in the live/dead staining experiments (Figure S12). The similar phenomenon has also been observed in other selected HeLa, 4T1, and MCF-7 cell lines (Figure 3b and Figure S11b-c).



Figure 3. In vitro cytotoxicity of TCPC-UiO against HepG2 cells (a) and HeLa cells (b) with or without laser illumination (0.8 W cm−2, 5 min, 635 nm). Statistical significance: (#) p > 0.05, (*) p ≤ 0.05, (**) p ≤ 0.01, (***) p ≤ 0.001. Flow cytometry analysis of HepG2 cells treated with only light illumination (c), TCPC-UiO only (d), TCPC-UiO + 4 oC + Vitamin C + L (e), TCPC-UiO + 4 oC + L (f), TCPC-UiO + Vitamin C + L (g), TCPC-UiO + L (h), respectively. Four areas (Q1, Q2, Q3, Q4) contain different phases of cells (necrotic, late-stage apoptotic, early apoptotic, and live).


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PDT induced cellular death is mainly from apoptosis pathway, and PTT can inhibit cell proliferation through both apoptosis and necrosis.47,48 This characteristic can be distinguished by flow cytometry analysis (Figure 3c-h). HepG2 cells were double-labeled with Annexin V-FITC (fluoresceine isothiocyanate) and PI (propidium iodide). Three control groups, including only laser irradiation, only TCPC-UiO, and TCPC-UiO with Vitamin C and irradiation at 4 oC, have high cell viability (Q4) above 80%. For TCPC-UiO at the low temperature (4 oC) under irritation, the increasing apoptotic rate as shown in Figure 3f reaches to 34%, ascribing to the PDT inducing pathway. To inhibit the influence of PDT pathway, Vitamin C has been added in the same tested conditions and a rapidly increasing necrosis rate (Q1) of about 72% is occurred in PTT pathway (Figure 3g). Under the normal conditions (TCPC-UiO + L in Figure 3h), the almost invariant apoptotic rate (Q2 + Q3) of 29.6% and decreasing necrosis rate (Q1) of 51.3% are presented. These results clearly demonstrate that the as-prepared TCPC-UiO could effectively possess both PDT and PTT efficiencies simultaneously, but PTT exerts more primary antitumor efficacy. A successful photosensitizer applicable in clinic must be biocompatible and non-toxic in vivo. Hemolysis activity of TCPC-UiO NMOF was firstly investigated according to a previous protocol.49 Triton X-100 solution (positive) and phosphate buffer saline (PBS) (negative) were used as control groups. The hemolysis rates of red blood cells (Figure S13a) are less than 5% even at the maximum concentration up to 1000 µg mL−1 in PBS, indicating the preeminent blood compatibility of TCPC-UiO NMOF. Prothrombin time (PT), activated partial thromboplastin time (APTT) and



fibrinogen (FIB, blood coagulation factor I) are three important plasma coagulation indicators, reflecting the effects of nanomedicine on the intrinsic and extrinsic coagulation pathways. All the PT values for various concentrations of TCPC-UiO (Figure S13b) almost keep a proximate range from 11 s to 12 s near the value of 11.8 s from the control. The values of APTT stay in the range of 29-33 s, similar to the positive control at 30.5 s. Besides, little variation of FIB values can be found after treatment of increasing concentrations of TCPC-UiO. All the blood coagulation screening profiles validate that the as-prepared TCPC-UiO will not interfere with the coagulation factors via intrinsic and extrinsic pathways, corroborating the favorable non-thrombogenic and biocompatible properties of TCPC-UiO on blood cells. Hematology and serum biochemistry analysis is an efficient pathway to obtain the health index of life entity. Nno obvious changes of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA) and uric acid (UA) in blood (Figure S14a) are observed after a TCPC-UiO administration at TCPC concentration of 7.2 mg kg-1 under each selected time point even up to 21 days, demonstrating the low systemic toxicities of as-synthesized TCPC-UiO to the function of liver and kidney. Mainly clinical parameters of blood tests at the same tested conditions are all in the normal region (Figure S14b). After administration, mice viabilities of four groups all keep 100% (Figure S14c), eliminating the undesirable systemic toxicity of nanotherapeutic drug. Besides, no abnormal mouse behavior or obvious mice weight changes are observed lasting up to 21 days (Figure S14d). Furthermore, major organs of mice, such as liver, spleen, heart, lung, and kidney, were collected and stained with


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H&E for subsequent histology analysis after 21 days of intravenous injection plus irradiation. No tissue damages or inﬂammatory lesions are presented in all major organs (Figure S15). Such wonderful results indicate that TCPC-UiO have negligible systematic toxicity potential for in vivo biological application.

Figure 4. (a) In vitro CT images of TCPC-UiO NMOF solution at different concentrations. (b) Corresponding CT signal intensity (HU) of TCPC-UiO with different concentrations. (c) The linear relationship between the CT values (HU) of TCPC-UiO and various concentrations. (d) CT imaging in vivo: preinjection (i-iii) and after injection (iv-vi) in a tumor-bearing mouse.

Computed tomography (CT) imaging is one of the most useful imaging/diagnostic



tools widely used in biomedical imaging modalities.50-52 Considering the high ability of Hf element for attenuating X-rays, aqueous solutions of TCPC-UiO at different concentrations ranging from 1.25 to 40 mg mL-1 were scanned using a Micro CT at 120 kV. With the increase of the TCPC-UiO concentration, both the parallel CT signals increase, giving a maximum of 511 Hounsfield unit (HU) at concentration of 40 mg mL-1 and brighter images exhibited (Figure 4a, b). A good linear dependence (R2 = 0.998) of the HU values on the amount of TCPC-UiO samples (Figure 4c) is obtained, and the simulated line slope is about 11.63 HU L g-1. This attenuated HU unit is higher than the value of the physiological tissue and other reported NMOFs,53, 54

ensuring the high visibility for using in CT imaging. The potential feasibility of

TCPC-UiO as in vivo CT contrast agent has been evaluated by intratumoral injection into the tumor-bearing mice at the concentration of 20 mg mL-1. Compared with the lower CT signal of 46 HU before injection, an obviously enhanced signal (iv-vi, 986 HU) positioned at the tumor region after injection could be observed (Figure 4d). Above results indicated that the TCPC-UiO could be utilized as CT imaging contrast media. Besides the CT imaging, the excellent photothermal efficiency of as-prepared TCPC-UiO make it a promising agent for further using in photothermal imaging. Photothermal imaging of TCPC-UiO and its water control has been firstly studied in vitro under continuous laser irradiation. In stark contrast, the aqueous solution of TCPC-UiO sample gives a bright thermal imaging and could maintain the imaging performance under continuous irradiation up to 40 min due to the high photostability,


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while water alone cannot give rise to efficient thermal imaging effect under laser illumination (Figure S16). We believe that as-prepared TCPC-UiO nanoplatform can be utilized for photothermal imaging-guided oncotherapy. As proof-of-concept, the tumor sites exhibited dazzling photothermal imaging after TCPC-UiO administration and laser irradiation, which could be used to guide the temperature changes and exclude the severe burns during the photothermal process (Figure 5a). As predicted, only PBS and laser irradiation lead to little temperature changes. It is well known that the photothermal ability could also be qualified by using photoacoustic tomography (PAT) technology, which could overcome the disadvantage of scattering of optical photons in living organisms, offering distinguishable contrast images of biological tissues.55-59 The increasing PA signal intensities versus various concentrations of TCPC-UiO aqueous solutions under the excitation at 680 nm are observed in Figure 5b, and a linear correlation with good dependence (R2 = 0.997) is achieved (Figure 5c), which could be used for the accurate quantitation of photothermal performance in TCPC-UiO. In vivo PA signals of TCPC-UiO in tumor tissue were investigated after injection. As displayed in Figure 5d-f, an obvious and strong PA signal is seen in tumor sections, in contrast to the result before TCPC-UiO administration. Comparing with the PA signal from blank mouse, TCPC-UiO administration brings significant differences (***p ≤ 0.001) (Figure 5f).



Figure 5. (a) Thermal images of mice (inoculated by H22 cells) after intratumor injection of PBS and TCPC-UiO and treated with laser illumination (635 nm) monitored at different time intervals. (b) PA images and (c) the linear relationship of PA signal intensity versus various concentrations. In vivo PA imaging efficacy (3D) before (d) and after (e) intratumoral injection of TCPC-UiO NMOF at the dosage of 30 mg Kg-1. (f) Normalized PA signal intensity in tumor before and after NMOF injection (30 mg kg-1). Statistical significance: (***) p ≤ 0.001.

The half-live of NMOFs in blood circulation is 1.52 h after in vein administration, calculating the Hf contents by ICP-MS method (Figure S17a). We further investigated


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the biodistribution of TCPC-UiO NMOF in various organs. Plenty of NMOF is spread in liver and spleen induced by the mononuclear phagocyte system (Figure S17b). At sixth hour, the content of NMOF in tumor region reaches its maximum, which could be used to offer guidance for the irradiation time after NMOF administration. To further evaluate the photothermal performances of TCPC-UiO, in vivo therapeutic efficacy of TCPC-UiO was evaluated by injection of NMOF into H22 tumor-bearing mice via tail vein and intratumor injections, respectively. Only PBS, only laser irradiation, and TCPC-UiO in dark were used as control groups. All the tumor-bearing mice were randomly divided in five groups (n = 4). For tail vein treatment (IV + Laser), TCPC-UiO aqueous solutions with a total TCPC concentration of 7.2 mg kg-1 are equally divided into three times to be injected into mice, and the tumor sites were subsequently irradiated with laser (635 nm, 480 J cm-2) after 6 h from administration (Figure S18). For the intratumor injection (IT + Laser), each tumor-bearing mouse is exposed to a 635 nm laser (300 J cm-2) for 1 h after injection (TCPC concentration: 0.8 mg kg-1). In the IT + Laser group, comparing with the PBS group with no obvious temperature elevation, a rapid increasing temperature to about 48.4 oC is recorded after intratumoral administration under light illumination (Figure 6a), indicating the good photothermal efficiency of TCPC-UiO in animal. To further evaluate the tumor inhibitory ability of used TCPC-UiO, tumor weight and body weight of mice in all five groups have been weighed and recorded at 2 days interval during the 21 days experimental period. At the end of experiments, the tumors of five groups were collected to take photographs. As shown in Figure 6b-d, remarkable decreasing of



tumor volumes and tumor weights in all experimental groups, IV + L and IT + L groups, are observed after 21 days treatment period, and a better result appears in the IT + L group. That difference may be ascribed to the more aggregation of TCPC-UiO in intratumor injection than tail vein administration. On the contrary, tumors in three control groups all grew rapidly. Additionally, tumor inhibitory rates (TIR) of IV + L and IT + L groups (Figure 6e) are further calculated from the tumor weight results to give the values of 91% and 99%, respectively. As shown in Figure 6f, there is about 12.5% of increasing of body weight in PBS group and only laser treated group due to the tumor progression, but no noticeable body weight changes are found in NMOF-treated groups, revealing few side effects of NMOF for tumor phototherapy. Finally, the immunohistochemical analyses have been employed to further assess the antitumor efficacy of TCPC-UiO samples. Hematoxylin and eosin (H&E) was adopted to stain the tumor sections. Large nucleus and spindle shapes are found in three control groups (PBS, laser only, and NMOF in dark), indicating the normal tumor growth (Figure 6g). By contrast, obviously decreased tumor cells, nuclear shrinkage, and fragmentation appear in two NMOF plus laser irradiation treated groups. Above results clearly demonstrate the cell proliferation inhibition of TCPC-UiO in the tumor tissues during the phototherapy.


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Figure 6. (a) Temperature changes of tumor regions monitored by an infrared thermal camera upon light illumination. (b) Tumor volume changes, (c) tumor photos, (d) tumor weight changes (e) tumor inhibitory rates and (f) body weight changes of mice treated with PBS, PBS + Laser, only TCPC-UiO, TCPC-UiO by intravenous and intratumor injection + Laser, Statistical significance: (***) p ≤ 0.001. (g) H&E staining images of tumor slices from five groups; scale bars: 100 µm.

CONCLUSIONS In summary, a facile mixed-component strategy has been utilized to incorporate photoactive chlorin into Hf-UiO-66 archetype structure without altering the underlying topology. Such TCPC-UiO possesses high photostability, good biocompatibility, and efficient photodynamic and photothermal therapy effect regulated by the spatial arrangement of TCPC ligands. Besides, Hf clusters could



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largely enhance the phototherapy performance under laser irradiation via heavy atom effect, and also endows TCPC-UiO with CT imaging function. Favorable photothermal conversion efficiency facilitates subsequent application of TCPC-UiO in photoacoustic imaging and PTT. In vivo experiments demonstrate that as-synthesized TCPC-UiO exerts obvious antitumor effect against H22 tumor-bearing mice with a tumor inhibition as high as 90%. We anticipate that present study could provide a new way to understand that the whole phototherapy behavior of NMOF can be regulated by altering the spatial arrangement of PS-ligands. This facile synthesis of TCPC-UiO could help for deepening the application of NMOF in cancer therapy.

ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/ acs.chemmater. Materials and physical measurements, experimental section, synthesis procedures, 1H NMR

spectrum,

MALDI-TOF

mass

spectrum,

power

X-ray

diffractions,

high-magnification TEM image, SEM image, DLS profiles, TGA analysis, nitrogen adsorption isotherms, Pore size distributions, FT-IR spectra, colloidal stability, fluorescence lifetime and Fluorescence quantum yield, ROS detection by DPBF and ABDA, photostability, cellular uptake, cytotoxicity against HeLa, HepG2, 4T1 and MCF-7 cells, live and dead staining, hemolytic percent of red blood cells, plasma coagulation screening profiles, serum biochemistry analysis, H&E staining images,


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photothermal imaging, in vivo blood circulation and biodistribution, in vivo antitumor therapy experiments AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. *E-mail: [email protected]. ORCID Lei Wang: 0000-0003-4395-5002 Zhigang Xie: 0000-0003-2974-1825 Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (Project No. 21771147 and 51522307). REFERENCES 1.

Cheng, L.; Wang, C.; Feng, L.; Yang, K.; Liu, Z., Functional Nanomaterials for

Phototherapies of Cancer. Chem. Rev. 2014, 114, 10869-10939. 2.

Lismont, M.; Dreesen, L.; Wuttke, S., Metal-Organic Framework Nanoparticles

in Photodynamic Therapy: Current Status and Perspectives. Adv. Funct. Mater. 2017, 27, 1606314. 3.

Zheng, X.; Wang, L.; Liu, S.; Zhang, W.; Liu, F.; Xie, Z., Nanoparticles of

Chlorin Dimer with Enhanced Absorbance for Photoacoustic Imaging and Phototherapy. Adv. Funct. Mater. 2018, 28, 1706507.



4.

Wang, W.; Wang, L.; Li, Z.; Xie, Z. BODIPY-Containing Nanoscale

Metal-Organic Frameworks for Photodynamic Therapy. Chem. Commun. 2016, 52, 5402-5405. 5.

Bonnett, R., Photosensitizers of the Porphyrin and Phthalocyanine Series for

Photodynamic Therapy. Chem. Soc. Rev. 1995, 24, 19-33. 6.

Huang, H.; Song, W.; Rieffel, J.; Lovell, J. F., Emerging Applications of

Porphyrins in Photomedicine. Front. Phys. 2015, 3, 23. 7.

Ma, Y.; Li, X.; Li, A.; Yang, P.; Zhang, C.; Tang, B., H2S-Activable MOF

Nanoparticle Photosensitizer for Effective Photodynamic Therapy against Cancer with Controllable Singlet-Oxygen Release. Angew. Chem. Int. Ed. 2017, 56, 13752-13756. 8.

Zheng, X.; Wang, L.; Pei, Q.; He, S.; Liu, S.; Xie, Z., Metal-Organic

Framework@Porous Organic Polymer Nanocomposite for Photodynamic Therapy. Chem. Mater. 2017, 29, 2374-2381. 9.

Zhou, Z.; Song, J.; Nie, L.; Chen, X., Reactive Oxygen Species Generating

Systems Meeting Challenges of Photodynamic Cancer Therapy. Chem. Soc. Rev. 2016, 45, 6597-6626. 10. Liu, M.; Wang, L.; Zheng, X.; Liu, S.; Xie, Z. Hypoxia-Triggered Nanoscale Metal-Organic Frameworks for Enhanced Anticancer Activity. ACS Appl Mater Interfaces 2018, 10, 24638-24647. 11. Lovell, J. F.; Jin, C. S.; Huynh, E.; Jin, H.; Kim, C.; Rubinstein, J. L.; Chan, W. C.; Cao, W.; Wang, L. V.; Zheng, G., Porphysome Nanovesicles Generated by Porphyrin Bilayers for Use as Multimodal Biophotonic Contrast Agents. Nat. Mater. 2011, 10, 324-332.


Page 28 of 36

Page 29 of 36 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


12. Ng, K. K.; Lovell, J. F.; Vedadi, A.; Hajian, T.; Zheng, G., Self-Assembled Porphyrin Nanodiscs with Structure-Dependent Activation for Phototherapy and Photodiagnostic Applications. ACS Nano 2013, 7, 3484-3490. 13. Huynh, E.; Leung, B. Y.; Helfield, B. L.; Shakiba, M.; Gandier, J. A.; Jin, C. S.; Master, E. R.; Wilson, B. C.; Goertz, D. E.; Zheng, G., In Situ Conversion of Porphyrin Microbubbles to Nanoparticles for Multimodality Imaging. Nat. Nanotechnol. 2015, 10, 325-332. 14. Zou, Q.; Abbas, M.; Zhao, L.; Li, S.; Shen, G.; Yan, X., Biological Photothermal Nanodots Based on Self-Assembly of Peptide-Porphyrin Conjugates for Antitumor Therapy. J. Am. Chem. Soc. 2017, 139, 1921-1927. 15. Furukawa, H.; Cordova, K. E.; O’Keeffe, M.; Yaghi, O. M., The Chemistry and Applications of Metal-Organic Frameworks. Science 2013, 341, 1230444. 16. Della Rocca, J.; Liu, D.; Lin, W., Nanoscale Metal-Organic Frameworks for Biomedical Imaging and Drug Delivery. Acc. Chem. Res. 2011, 44, 957-968. 17. He, C.; Liu, D.; Lin, W., Nanomedicine Applications of Hybrid Nanomaterials Built from Metal-Ligand Coordination Bonds: Nanoscale Metal-Organic Frameworks and Nanoscale Coordination Polymers. Chem. Rev. 2015, 115, 11079-11108. 18. Wang, L.; Zheng, M.; Xie, Z. Nanoscale Metal-Organic Frameworks for Drug Delivery: A Conventional Platform with New Promise. J. Mater. Chem. B 2018, 6, 707-717. 19. Shustova, N. B.; Ong, T.-C.; Cozzolino, A. F.; Michaelis, V. K.; Griffin, R. G.; Dincă, M., Phenyl Ring Dynamics in a Tetraphenylethylene-Bridged Metal-Organic Framework: Implications for the Mechanism of Aggregation-Induced Emission. J. Am. Chem. Soc. 2012, 134, 15061-15070.



Page 30 of 36

20. Wei, Z.; Gu, Z.-Y.; Arvapally, R. K.; Chen, Y.-P.; McDougald, R. N.; Ivy, J. F.; Yakovenko, A. A.; Feng, D.; Omary, M. A.; Zhou, H.-C., Rigidifying Fluorescent Linkers by Metal-Organic Framework Formation for Fluorescence Blue Shift and Quantum Yield Enhancement. J. Am. Chem. Soc. 2014, 136, 8269-8276. 21. Wang, L.; Wang, W.; Xie, Z., Tetraphenylethylene-Based Fluorescent Coordination Polymers for Drug Delivery. J. Mater. Chem. B 2016, 4, 4263-4266. 22. Lu, K.; He, C.; Lin, W., Nanoscale Metal-Organic Framework for Highly Effective Photodynamic Therapy of Resistant Head and Neck Cancer. J. Am. Chem. Soc. 2014, 136, 16712-16715. 23. 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. 24. Lu, K.; He, C.; Guo, N.; Chan, C.; Ni, K.; Weichselbaum, R. R.; Lin, W., Chlorin-Based Nanoscale Metal-Organic Framework Systemically Rejects Colorectal Cancers via Synergistic Photodynamic Therapy and Checkpoint Blockade Immunotherapy. J. Am. Chem. Soc. 2016, 138, 12502-12510. 25. Deng, H.; Doonan, C. J.; Furukawa, H.; Ferreira, R. B.; Towne, J.; Knobler, C. B.; Wang, B.; Yaghi, O. M., Multiple Functional Groups of Varying Ratios in Metal-Organic Frameworks. Science 2010, 327, 846. 26. Burrows, A. D., Mixed-Component Metal-Organic Frameworks (MC-MOFs): Enhancing

Functionality

Through

Solid

Solution

Formation

and

Surface

Modifications. CrystEngComm 2011, 13, 3623-3642. 27. Carné-Sánchez, A.; Bonnet, C. S.; Imaz, I.; Lorenzo, J.; Tóth, É.; Maspoch, D., Relaxometry Studies of a Highly Stable Nanoscale Metal-Organic Framework Made


Page 31 of 36 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


of Cu(II), Gd(III), and the Macrocyclic DOTP. J. Am. Chem. Soc. 2013, 135, 17711-17714. 28. Yuan, S.; Lu, W.; Chen, Y.-P.; Zhang, Q.; Liu, T.-F.; Feng, D.; Wang, X.; Qin, J.; Zhou, H.-C., Sequential Linker Installation: Precise Placement of Functional Groups in Multivariate Metal-Organic Frameworks. J. Am. Chem. Soc. 2015, 137, 3177-3180. 29. Liu, Q.; Cong, H.; Deng, H., Deciphering the Spatial Arrangement of Metals and Correlation to Reactivity in Multivariate Metal-Organic Frameworks. J. Am. Chem. Soc. 2016, 138, 13822-13825. 30. Chen, C.-X.; Wei, Z.-W.; Jiang, J.-J.; Zheng, S.-P.; Wang, H.-P.; Qiu, Q.-F.; Cao, C.-C.; Fenske, D.; Su, C.-Y., Dynamic Spacer Installation for Multirole Metal-Organic Frameworks: A New Direction toward Multifunctional MOFs Achieving Ultrahigh Methane Storage Working Capacity. J. Am. Chem. Soc. 2017, 139, 6034-6037. 31. Xia, Q.; Li, Z.; Tan, C.; Liu, Y.; Gong, W.; Cui, Y., Multivariate Metal-Organic Frameworks as Multifunctional Heterogeneous Asymmetric Catalysts for Sequential Reactions. J. Am. Chem. Soc. 2017, 139, 8259-8266. 32. Liu, L.; Zhou, T.-Y.; Telfer, S. G., Modulating the Performance of an Asymmetric Organocatalyst by Tuning Its Spatial Environment in a Metal-Organic Framework. J. Am. Chem. Soc. 2017, 139, 13936-13943. 33. Sun, Y.; Sun, L.; Feng, D.; Zhou, H.-C., An In Situ One-Pot Synthetic Approach towards Multivariate Zirconium MOFs. Angew. Chem. Int. Ed. 2016, 55, 6471-6475. 34. Park, J.; Jiang, Q.; Feng, D.; Zhou, H.-C., Controlled Generation of Singlet Oxygen in Living Cells with Tunable Ratios of the Photochromic Switch in Metal-Organic Frameworks. Angew. Chem. Int. Ed. 2016, 128, 7304-7309.



35. Cavka, J. H.; Jakobsen, S.; Olsbye, U.; Guillou, N.; Lamberti, C.; Bordiga, S.; Lillerud, K. P., A New Zirconium Inorganic Building Brick Forming Metal Organic Frameworks with Exceptional Stability. J. Am. Chem. Soc. 2008, 130, 13850-13851. 36. Jakobsen, S.; Gianolio, D.; Wragg, D. S.; Nilsen, M. H.; Emerich, H.; Bordiga, S.; Lamberti, C.; Olsbye, U.; Tilset, M.; Lillerud, K. P., Structural Determination of a Highly Stable Metal-Organic Framework with Possible Application to Interim Radioactive Waste Scavenging: Hf-UiO-66. Phy. Rev. B 2012, 86, 125429. 37. Bai, Y.; Dou, Y.; Xie, L.-H.; Rutledge, W.; Li, J.-R.; Zhou, H.-C., Zr-Based Metal-Organic Frameworks: Design, Synthesis, Structure, and Applications. Chem. Soc. Rev. 2016, 45, 2327-2367. 38. Zhou, L.; Wei, S.; Ge, X.; Zhou, J.; Yu, B.; Shen, J., External Heavy-Atomic Construction of Photosensitizer Nanoparticles for Enhanced in Vitro Photodynamic Therapy of Cancer. J. Phys. Chem. B 2012, 116, 12744-12749. 39. Kong, X.; Deng, H.; Yan, F.; Kim, J.; Swisher, J. A.; Smit, B.; Yaghi, O. M.; Reimer, J. A., Mapping of Functional Groups in Metal-Organic Frameworks. Science 2013, 341, 882. 40. Sue, A. C. H.; Mannige, R. V.; Deng, H.; Cao, D.; Wang, C.; Gándara, F.; Stoddart, J. F.; Whitelam, S.; Yaghi, O. M., Heterogeneity of Functional Groups in a Metal-Organic Framework Displays Magic Number Ratios. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 5591. 41. Osborn Popp, T. M.; Yaghi, O. M., Sequence-Dependent Materials. Acc. Chem. Res. 2017, 50, 532-534. 42. Rajora, M. A.; Lou, J. W. H.; Zheng, G., Advancing Porphyrin's Biomedical Utility via Supramolecular Chemistry. Chem. Soc. Rev. 2017, 46, 6433-6469.


Page 32 of 36

Page 33 of 36 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


43. Ng, K. K.; Zheng, G., Molecular Interactions in Organic Nanoparticles for Phototheranostic Applications. Chem. Rev. 2015, 115, 11012-11042. 44. Deria, P.; Gómez-Gualdrón, D. A.; Hod, I.; Snurr, R. Q.; Hupp, J. T.; Farha, O. K.,

Framework-Topology-Dependent

Catalytic

Activity

of

Zirconium-Based

(Porphinato)zinc(II) MOFs. J. Am. Chem. Soc. 2016, 138, 14449-14457. 45. Deria,

P.;

Yu,

J.;

Balaraman,

R.

P.;

Mashni,

J.;

White,

S.

N.,

Topology-Dependent Emissive Properties of Zirconium-Based Porphyrin MOFs. Chem. Commun. 2016, 52, 13031-13034. 46. Cai, Y.; Liang, P.; Tang, Q.; Yang, X.; Si, W.; Huang, W.; Zhang, Q.; Dong, X., Diketopyrrolopyrrole-Triphenylamine Organic Nanoparticles as Multifunctional Reagents for Photoacoustic Imaging-Guided Photodynamic/Photothermal Synergistic Tumor Therapy. ACS Nano 2017, 11, 1054-1063. 47. Kalluru, P.; Vankayala, R.; Chiang, C.-S.; Hwang, K. C., Photosensitization of Singlet Oxygen and In Vivo Photodynamic Therapeutic Effects Mediated by PEGylated W18O49 Nanowires. Angew. Chem. Int. Ed. 2013, 52, 12332-12336. 48. Liu, Y.; Liu, Y.; Bu, W.; Cheng, C.; Zuo, C.; Xiao, Q.; Sun, Y.; Ni, D.; Zhang, C.; Liu, J.; Shi, J., Hypoxia Induced by Upconversion-Based Photodynamic Therapy: Towards Highly Effective Synergistic Bioreductive Therapy in Tumors. Angew. Chem. Int. Ed. 2015, 127, 8223-8227. 49. 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, 11, 12849-12862. 50. Lee, N.; Choi, S. H.; Hyeon, T., Nano-Sized CT Contrast Agents. Adv. Mater. 2013, 25, 2641-2660.



51. Lusic, H.; Grinstaff, M. W., X-ray-Computed Tomography Contrast Agents. Chem. Rev. 2013, 113, 1641-1666. 52. Pritchard, A. C.; Gauthier, J. A.; Hanson, M.; Bever, G. S.; Bhullar, B.-A. S., A Tiny Triassic Saurian from Connecticut and the Early Evolution of The Diapsid Feeding Apparatus. Nat. Commun. 2018, 9, 1213. 53. deKrafft, K. E.; Xie, Z.; Cao, G.; Tran, S.; Ma, L.; Zhou, O. Z.; Lin, W., Iodinated Nanoscale Coordination Polymers as Potential Contrast Agents for Computed Tomography. Angew. Chem. Int. Ed. 2009, 121, 10085-10088. 54. Zhang, T.; Wang, L.; Ma, C.; Wang, W.; Ding, J.; Liu, S.; Zhang, X.; Xie, Z. BODIPY-Containing Nanoscale Metal-Organic Frameworks as Contrast Agents for Computed Tomography. J. Mater. Chem. B 2017, 5, 2330-2336. 55. Berends, A. C.; Meeldijk, J. D.; van Huis, M. A.; de Mello Donega, C., Formation of Colloidal Copper Indium Sulfide Nanosheets by Two-Dimensional Self-Organization. Chem. Mater. 2017, 29, 10551-10560. 56. Chiu, H.-T.; Chen, C.-H.; Li, M.-L.; Su, C.-K.; Sun, Y.-C.; Chiang, C.-S.; Huang, Y.-F., Bioprosthesis of Core–Shell Gold Nanorod/Serum Albumin Nanoimitation: A Half-Native and Half-Artificial Nanohybrid for Cancer Theranostics. Chem. Mater. 2018, 30, 729-747. 57. Geng, J.; Li, W.; Smaga, L. P.; Sottos, N. R.; Chan, J., Damage-Responsive Microcapsules for Amplified Photoacoustic Detection of Microcracks in Polymers. Chem. Mater. 2018, 30, 2198-2202. 58. Wang, W.; Liang, G.; Zhang, W.; Xing, D.; Hu, X., Cascade-Promoted Photo-Chemotherapy against Resistant Cancers by Enzyme-Responsive Polyprodrug Nanoplatforms. Chem. Mater. 2018, 30, 3486-3498.


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59. Zhang, M.; Chen, X.; Zhang, L.; Li, L.; Su, Z.-M.; Wang, C., Spadix-Bract Structured Nanobowls for Bimodal Imaging-Guided Multidrug Chemo-Photothermal Synergistic Therapy. Chem. Mater. 2018, 30, 3722-3733.



ToC graphic


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