MetalâOrganic Frameworks@Polymer Composites Containing

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Metal-Organic Frameworks@Polymer Composites Containing Cyanines for Near-infrared Fluorescence Imaging and Photothermal Tumor Therapy Weiqi Wang, Lei Wang, Shi Liu, and Zhigang Xie Bioconjugate Chem., Just Accepted Manuscript • DOI: 10.1021/acs.bioconjchem.7b00508 • Publication Date (Web): 03 Oct 2017 Downloaded from http://pubs.acs.org on October 8, 2017

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Bioconjugate Chemistry

Metal-Organic Frameworks@Polymer Composites Containing Cyanines for Near-infrared Fluorescence Imaging and Photothermal Tumor Therapy Weiqi Wang,†, ‡ Lei Wang,† Shi Liu† and Zhigang Xie*, † †

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied

Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, Jilin 130022, P. R. China ‡

University of Chinese Academy of Sciences, Beijing 100049, P. R. China

* [email protected]

ABSTRACT: As a noninvasive treatment method, photothermal therapy (PTT) has been widely investigated for cancer therapy. In this work, metal-organic frameworks@polymer composites (UiO-66@CyP) with bioimaging and PTT activity were prepared by introducing cyaninecontaining polymer (CyP) via multi-component passerini reaction in the presence of Zr-based nanoscale metal-organic frameworks (UiO-66). As-prepared UiO-66@CyP not only possesses uniformed size, controllable morphology and excellent dispersibility in aqueous media, but also indicates strong near-infrared absorption and high photothermal conversion efficiency. Due to these combined merits, UiO-66@CyP appears to be an excellent phototherapy agent for ablation

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tumor cells under a low-power laser irradiation and near-infrared fluorescence imaging agent This work might open up a new avenue to develop multifunctional composites by integrating metal-organic frameworks with carboxyl, aldehyde and isocyano-containing materials.

INTRODUCTION Benefitting from its noninvasive and spatiotemporal-controlling modes, photothermal therapy (PTT) holds great promise for cancer therapy, employing the hyperthermia generated by phototherapy agents (PTAs) to ablate cancer cells upon irradiation.1-8 Highly effective PTAs have been intensively explored. Most of PTAs are inorganic materials, such as gold nanotube

13-17

, graphene

18-20

and sulfur (selenium) metal semiconductors

21-23

9-12

, carbon

. However, the

limitations of conventional inorganic materials include poor dispersibility in water, nonspecificity to cancer cells and nonbiodegradable nature, which severely hinder their biomedical applications. Alternatively, some organic dyes

24-30

with absorption around near-

infrared (NIR) region are suitable for PTT. For example, indocyanine green (ICG)

31-34

has

already been approved by the United States Food and Drug Administration (FDA), which possess strong NIR absorbance and high thermal conversion capacity. However, the clinical application of ICG still has some disadvantages, such as poor stability and solubility, low cancer specificity, and rapid blood clearance. To address these issues, PTAs in nanoformulations were widely investigated.35-38 Although great advance have been made in nanotechnology for PTT, little attention was paid on the tuning morphology and size of nanoscale PTAs.39-40 Recently, metal-organic frameworks (MOFs) were used as templates for tuning the size of polymers in our group.41-42 MOFs are promising carriers taking advantages of their tunable composition, structural diversity, intrinsic biodegradability and well-defined sizes/shapes but their biomedical


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application was much less studied

43-46

partly because of the high cytotoxicity and low water

stability of some MOFs. Noticeably, Zr-based nanoscale MOFs UiO-66 (UiO = University of Oslo) shows obvious advantages, such as high water stability, considerable biocompatibility and versatile modification. 47-48 Recently, MOFs@polymer composites have attracted wide attention because it combined both advantages between robust MOFs and flexible polymer materials.49-54 Few works reported about the MOFs@polymer composites used in tumor PTT. The MIL-100(Fe) and polypyrrole composites indicate an outstanding photothermal activity for ablating cancer cells upon NIR irradiation.55 Similarly, hyaluronic acid decorated nanoscale MIL-100(Fe) loaded with ICG was successfully developed for imaging-guided anticancer PTT.56 Very recently, our group reported the UiO-66(Zr) and polyaniline composites for PTT treatment.57 However, the main limitation for constructing MOFs@polymer composites is that most polymerization reaction cannot be realized in aqueous solution. It is imperative to devise a universal and simple strategy for synthesizing functional MOFs@polymer composites. Multi-component reactions (MCRs), such as the Passerini and Ugi reaction, have brought wide attention in polymer chemistry due to their modularization, high efficiency, atomic economy.58-61 MCRs have already been applied in the total synthesis of natural products or macromolecules.6263

Zhang et al demonstrate polypeptoids prepared by Ugi reaction of natural amino acids.58 Our

group have synthesized a series of cross-linked polymer by the Passerini reaction for drug delivery.64 The MCRs is perfect for combining various molecules bearing carboxyl, aldehyde and isocyano groups into one polymer. So, we hypothesized the polymer MOFs hybrids could be made through MCRs in the presence of MOFs as template.


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In this study, MOFs@polymer composites (UiO-66@CyP) have been successfully obtained for imaging-guided PTT by utilizing multi-component passerini reaction on the surface of UiO66 nanocrystal. UiO-66 nanocrystals have been firstly synthesized and then the polymerization of NIR dye Cy, o-nitrobenzaldehyde and 1,6-diisocyanatohexane in the presence of UiO-66 nanocrystals to form the composites. UiO-66@CyP with strong NIR absorbance could be used in fluorescence imaging guided photothermal cancer treatment in vitro and in vivo. We expect that more functional MOFs@polymer composites could be developed through multi-component polymerization reaction with MOFs.

Scheme 1. Schematic illustration of the fabrication of UiO-66@CyP nanostructures and their application in PTT.

RESULTS AND DISCUSSION


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Fabrication of UiO-66@CyP. Carboxyl-functionalized cyanine (Cy) with strong adsorption around 800 nm was synthesized by following the procedure described in the experimental section and its molecular structure was confirmed by 1H NMR (Figure S1, supporting information).65 UiO-66 nanocrystals were readily prepared under solvothermal conditions at 120 o

C in DMF starting from ZrCl4 and terephthalic acid,66 and its powder X-ray diffraction (PXRD)

pattern is identical to the simulated one. CyP has been synthesized according to our previous work via an one-pot multi-component Passerini reaction, and its optical property and PTT effects are similar to Cy.64 But it cannot self-assemble into nanoparticles in absence of surfactant and adjuvants. As illustrated in Scheme 1, UiO-66@CyP is successfully obtained by multicomponent Passerini reaction on the surface of UiO-66 nanocrystal for combining NIR activated bioimaging and PTT treatment. The morphology of UiO-66@CyP has been investigated by the transmission electron microscopy (TEM), scanning electron microscopy (SEM) images, and high resolution TEM (HR-TEM). These results show that UiO-66@CyP is octahedral geometry with an average diameter of ∼100 nm, which is similar to UiO-66 nanocrystal (Figure 1). Besides, UiO-66@CyP doesn’t show any aggregation behavior and maintains a homogeneous size. Dynamic light scattering (DLS) measurement presents the hydrodynamic diameter of UiO-66 nanocrystal and UiO-66@CyP (Figure S2), which are similar to that of those observed in TEM and SEM. Zeta potential of UiO-66 nanocrystal and UiO-66@CyP are -17 mV and -12 mV, respectively (Figure S3). The chemical composition of UiO-66@CyP was further determined by energy dispersive Xray spectroscopy (EDS) and X-ray photoelectron spectroscopy (XPS). EDS mapping spectrum gives clear homogeneous distribution of zirconium, carbon, oxygen, nitrogen and chlorine elements (Figure S4). XPS was also conducted to explore the composition of UiO-66@CyP,


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giving two strong peaks at 284.55 and 531.66 eV corresponding to C 1s and O 1s and other peaks at 399.46, 200.45 and 182.37 eV are assigned to N 1s, Cl 2p and Zr 3d5, respectively (Figure S5 and Table S1). Additionally, elements analysis shows that N content increase from 1.29 to 3.84 % after introducing CyP, while Zr contents decrease from 38.94 to 32.65 % (Table S2).

Figure 1. The morphology of UiO-66 nanocrystal and UiO-66@CyP. As-synthesized UiO-66 (a) and UiO-66@CyP (d) dispersed into water, TEM images of UiO-66 nanocrystal (b) and UiO66@CyP (e), SEM images of UiO-66 nanocrystal (c) and UiO-66@CyP (f). Scale bar 200 nm for SEM and TEM images. The physicochemical properties of UiO-66@CyP have been further investigated by UV-vis absorbance (UV-vis), fluorescence emission (FL), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), gas sorption measurements, etc. The UV absorption spectra of UiO-66 nanocrystal, Cy and UiO-66@CyP are shown in Figure 2a, and the characteristic


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absorption of UiO-66@CyP dispersed into DMF centers at 795 nm, which shows 5 nm red-shift compared with Cy. At the same time, the absorption peak rises slowly towards low wavelength, which is in accordance with the absorption of UiO-66 nanocrystal. These results verify that UiO66@CyP containing Cy and UiO-66 nanocrystal simultaneously. Similar behavior is also observed in the FL spectra of Cy and UiO-66@CyP in DMF (Figure 2b), showing bathochromic shift from 820 to 825 nm under excitation at 780 nm. The red-shift of maximum emission possibly results from the aggregates of Cy in UiO-66@CyP. PXRD is used to characterize the crystallizability of the as-synthesized samples. The Bragg diffraction peaks position of UiO66@CyP are identical to that of simulated UiO-66 and UiO-66 nanocrystal, indicated the crystal structure of UiO-66 maintains well after formation of CyP (Figure 2c). The intensity of diffraction peak weakens obviously mainly due to the formation of CyP. The color of powder changes from white to dark green after CyP formation on the surface of UiO-66 nanocrystal (inserted Figure 2c). The TGA analysis reveals that the UiO-66@CyP has more weight loss than UiO-66 at air atmosphere (Figure 2d). The Cy content in UiO-66@CyP is caculated nearly to be 16 wt%, which is agreement with the result of 15 wt% obtained by UV-vis standard curve (Figure S6 and Scheme S1). The permanent porosity of as-synthesized UiO-66@CyP has been examined by gas sorption measurements after degassed at 393 K for 12 hours. UiO-66@CyP exhibits type Ⅱ curve, the BET surface area decreased from 1591 m2 g-1 for UiO-66 nanocrystal to 691 m2 g-1 for UiO-66@CyP. The pore-size distribution of UiO-66 nanocrystal and UiO66@CyP gives maxima around of 2.1 Å and 5.03 Å, respectively (Figure 2d-e, and Table S3). The decreased BET surface area and increased pore size of UiO-66@CyP may imply that some structural defects have been produced after formation of CyP on the surface of UiO-66 nanocrystal.


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Figure 2. The basic properties of UiO-66@CyP. (a) UV-vis spectra of UiO-66, Cy, and UiO66@CyP dispersed in DMF. (b) FL spectra of Cy and UiO-66@CyP dispersed in DMF. (c) PXRD of UiO-66 and UiO-66@CyP. (d) The thermogravimetric curves of UiO-66 and UiO66@CyP under air atmosphere. (e) The nitrogen adsorption isotherm curves and (f) pore size distributions (HK method) of UiO-66 and UiO-66@CyP at 77 K. (f) Pore size distributions (HK method) of UiO-66 and UiO-66@CyP determined from nitrogen uptake measurements at 77 K. In addition, the solid 13C NMR of UiO-66@CyP sample exhibits peaks belong to the aromatic benzene of terephthalic acid ligands (125, 137 and 170 ppm), and some new peaks belong to the introduced CyP (Figure S7). The characteristic peaks around 750 cm-1 and bands from 1200 to


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1000 cm-1 for CyP are appeared in FT-IR spectra (Figure S8). To further verify the formation of CyP, the absorbed Cy were used as control. As shown in Figure S9, no significant change of colour indicated that Cy is hard to be absorbed by UiO-66 nanocrystal. In Vitro Photothermal Performance. The photothermal performance of UiO-66@CyP was investigated in water upon laser irradiation. Temperature elevation of UiO-66@CyP aqueous solutions with various concentrations (5 ~ 100 µg mL-1) have been recorded upon irradiation with 808 nm laser at 1 W cm-2 for 5 min, indicating that UiO-66@CyP possess good photothermal response. As shown in Figure 3a, UiO-66@CyP solution exhibits an obvious concentration dependent photothermal effect, and temperature increase (∆T, defined as the temperature difference between UiO-66@CyP solution and aqueous solution) reach to 14.0 °C under irradiation of 300 s even at a low Cy concentration of 5 µg mL-1. The photothermal response of UiO-66@CyP under various laser densities is also investigated and shows an obvious laser density dependent behavior (Figure 3b). The temperature increase reach to 32.3 °C at a Cy concentration of 25 µg mL-1 upon 808 nm laser irradiation at 1 W cm-2 for 5 min, which is high enough to cause hyperthermia in malignant cancer cells. A quantitative study of the photothermal performance of UiO-66@CyP at 25 µg mL-1 with a power density of 1 W cm-2 (Figure 3c-d) was carried out. The photothermal conversion efficiency is calculated to be ∼ 27.3 % using a previously reported method.67 The photothermal stability is another important parameter for PTAs. The UV-vis absorbance of UiO-66@CyP and control groups (ICG and Cy) were recorded upon irradiation with an 808 nm laser at 1 W cm-2 for 5 min. As shown in Figure S10, the NIR absorbance stability (I/Io) of UiO-66@CyP is higher than that of ICG and Cy under the same conditions. Importantly, the photothermal reproducibility of UiO-66@CyP maintained well


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after three ON/OFF cycles. The moderate heating reproducibility and high photothermal conversion efficiency of as-synthesized UiO-66@CyP demonstrate the great potential as PTAs.

Figure 3. The PTT performance of UiO-66@CyP. Temperature rise curves of UiO-66@CyP at (a) various concentrations under irradiation (808 nm, 1 W cm-2) and (b) fixed concentrations (25 µg mL-1) with various irradiation intensities along with time. (c) The photothermal response of UiO-66@CyP in water (25 µg mL-1) with laser irradiation (808 nm, 1.0 W cm-2, 5 min) and then the laser was shut off. (d) Linear time data versus –Lnθ obtained from the cooling period. Cellular Uptake and Cytotoxicity. The cellular uptake of UiO-66@CyP was investigated by confocal laser scanning microscopy (CLSM) and flow cytometry analyses (FCS). The cell nuclei of Human ovarian cancer (HeLa) cells was visualized by blue channel for 4’, 6’-diamidino-2phenylindole (DAPI) (λex = 405 nm), and red channel for UiO-66@CyP (λex = 633 nm). CLSM images indicate that UiO-66@CyP nanoparticles could be internalized in a time-dependent manner and mainly locate in the cytoplasm (Figure 4a). The quantitative analysis of FCS results demonstrates a time-dependent endocytosis behavior. Both free Cy and UiO-66@CyP show the


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enhanced cellular uptake with increasing the incubation time from 0.5 to 4 h (Figure 4b-c). The mean fluorescence intensity (MFI) of UiO-66@CyP is slightly higher than Cy for this three time points. The enhanced cellular uptake of UiO-66@CyP is beneficial for improving the phototherapeutic effect.

Figure 4. Cellular uptake behavior against HeLa cells. (a) CLSM images of HeLa cells treated with UiO-66@CyP at a concentration of 10 µg mL-1 for 0.5, 2 and 4 h at 37 oC. Scale bars: 20 µm. (b) FCS of cells incubated with UiO-66@CyP at 37 oC for 0.5, 2 and 4 h respectively. (c) Mean fluorescence intensity (MFI) quantification analyses against cellular uptake.


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Figure 5. Cytotoxicity of UiO-66@CyP. Relative cell viabilities (a) without NIR laser irradiation or (b) with NIR laser irradiation only against HeLa, CT26 and HCT116 cells. Fluorescence images of calcein AM (green, live cells) and propidium iodide (red, dead cells) costained. Scale bar stands for 100 µm. The favorable photothermal effect of UiO-66@CyP inspired us to assess their in vitro therapeutic effect by standard methyl-thiazolyl-tetrazolium (MTT) assays. No significant dark cytotoxicity was observed in the presence of UiO-66@CyP even at a Cy concentration up to 15 µg mL-1 after incubation for 48 h against all tested cell lines (HeLa, CT26 and HCT116 cells).


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Meanwhile, the control groups only with NIR irradiation at different times also do not show obvious cytotoxicity after incubation for 48 h (Figure 5a). After irradiated by 808 nm laser at 1.5 W cm-2 for 5 min, nearly 70% cells have been ablated (Figure 5b). Then the live/dead cells were determined after treatment by calcein AM and propidium iodide (PI) (Figures 5c). Before irradiation, the cells are in healthy state. Most of cells treated with UiO-66@CyP in dark or only exposed to the 808 nm laser are alive with plentiful green fluorescence. After irradiation, the cells within the laser region display red fluorescence, indicating that the cells are killed completely after PTT treatment. These results are in accordance with the results measured by MTT, which indicate that UiO-66@CyP has potential as highly efficient and low-toxic PTT materials for in vitro cancer treatment.

In Vivo Fluorescent Imaging and Photothermal Therapy. In light of the photothermal performance of UiO-66@CyP in vitro, subcutaneous CT26 tumor xenografts model has been used to evaluate the in vivo PTT effect. As a noninvasive modality for cancer treatment, PTT occurs only at the tumor sites with low side effects and systemic toxicity. After the tumor size reached ∼150 mm3, the CT26 tumor-bearing mice (4 mice per group) were randomly divided into three groups: combinations of UiO-66@CyP + NIR laser, UiO-66@CyP only, and control. In the treatment group, the mice are intratumorally injected with UiO-66@CyP (1 mg mL-1, 200 µL), following with 10 min of irradiation by the 808 nm laser at a power density of 1 W cm-2. Other groups of mice include mice administered with UiO-66@CyP without laser irradiation, and mice administered with saline irradiated as control. The feasibility of UiO-66@CyP for in vivo fluorescent imaging was investigated. As displayed in Figure S12, intense fluorescence is only observed in tumor for 5 days and exhibits slow elimination at the tumor site. The time for drug content in blood reaching to 50% is about 3 h, and the half-life (t1/2) is about 25 h (Figure s13). Upon laser irradiation (808 nm, 1 W cm-2), the temperature change in tumors under laser irradiation is monitored by infrared thermal camera (Figure S11). Elevation of temperature could


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be seen directly, indicating the photothermal activity is kept in vivo. For tumor-bearing mice injected with UiO-66@CyP, the local tumor temperature is adjusted between 42 to 45 °C for 10 min, which is higher enough to kill the tumor in vivo. As a control, the tumor temperature is slightly altered under the same laser condition towards the mice treated with saline. As shown in Figures 6a, after UiO-66@CyP injection and laser irradiation, the tumors are effectively ablated and only black scars are left at tumor lesions. Notably, no recurrent is found in UiO-66@CyP + NIR irradiation treatment group. Nevertheless, other groups have similar tumor growth ratio, which indicates that neither UiO-66@CyP nor laser irradiation could hinder the tumor growth. The tumor size in UiO-66@CyP group and control group are much bigger than that in the group treated with UiO-66@CyP + NIR irradiation (Figure 6a, c-d and Figure S12). Body weight of the mice in the test group increased gradually, meaning that no significant toxic effects were observed for PTT treatment (Figure 6b). Especially, the tumors weight in UiO-66@CyP + NIR irradiation group is much lighter than that of the tumors weight in control groups or UiO66@CyP groups after 10 days (Figure 6e). The tumor inhibitory rate of UiO-66@CyP + irradiation groups is concluded to be as high as 93%, and the survival rates of all groups were 100%. H&E staining of tumor tissues show that UiO-66@CyP + NIR irradiation have obvious region of necrosis (Figure 6f). These findings confirm that UiO-66@CyP possess the great potential for effectively ablated tumor cells.


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Figure 6. In vivo PTT study of BALB/c mouse bearing CT26 tumors. (a) Tumor volume growth rates of each group mice upon various treatments. (b) Changes in body weight of mice. (c) Representative photos of the PTT treated mice. (d) Representative photos of the tumor, (e) Quantitative analysis of tumor weight of each group. (f) Histologic assessments of H&E staining of the mice after intratumorally injection physiological saline, UiO-66@CyP only and UiO66@CyP combined with NIR laser. Furthermore, mice were injected through tail vein with UiO-66@CyP (1 mg mL-1, 200 µL), and the imaging of NIRF and PTT treatment was recorded. As shown in Figure 7a, UiO66@CyP could effectively distribute into tumor at 4 h and NIR fluorescence imaging weakened after 24 h. After 24 h postinjection, the mouse was sacrificed, and major organs (heart, liver, spleen, lung, and kidneys) and the tumor were excised and subjected to ex vivo fluorescent imaging and quantify the fluorescence biodistribution (Figure 7g-h). After UiO-66@CyP injection and laser irradiation, the tumors are effectively ablated without recurrent and body weight of the mice in the test group increased gradually. The tumors weight in UiO-66@CyP + NIR irradiation group is much lighter than that in control groups or UiO-66@CyP groups, and the tumor inhibitory rate of UiO-66@CyP + irradiation groups is concluded to be as high as 81% according to tumor weight.


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Figure 7. In vivo PTT study of BALB/c mouse bearing CT26 tumors. (a) Time based in vivo NIR fluorescence images after the intravenous injection of UiO-66@CyP. (b) Mean fluorescence intensity of tumor along with time extending. (c) Tumor volume growth rates of each group mice with CT26 tumors upon various treatments. (d) Changes in body weight of mice. (e) Quantitative analysis of tumor weight of each group. (f) Representative photos of the tumor. (g) Ex vivo imaging of the tissues 24 h postinjection (from left to right: tumor, heart, liver, spleen, and kidney). (h) Mean fluorescence intensity of tissues along with time extending. Furthermore, the safety of materials was evaluated by histological section. H&E staining showed that UiO-66@CyP and UiO-66@CyP + NIR irradiation exert no significant damages to main tissues, including heart, liver, spleen, lung and kidney (Figure S14). These results suggested that UiO-66@CyP showed no obvious toxicity to living systems at tested dose. Although much more effort is still required to systematically examine any potential long-term toxicity, UiO-66@CyP still holds great potential for effective PTT treatment.


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CONCLUSION In summary, we have successfully devised a universal and simple strategy for developing MOFs@polymer composites, which combine the advantages of robust crystalline MOFs and flexible polymers. MOFs@polymer composites, UiO-66@CyP, were obtained by the multicomponent Passerini reactions in the presence of UiO-66. We speculated that this method might be used to integrate other therapeutic or imaging agents containing functional carboxyl, aldehyde, and isocyano groups into MOFs. Obtained UiO-66@CyP possesses several potential advantages: appropriate size, good water-dispersibility, strong NIR absorbance, and high PTT performance. The UiO-66@CyP is highly effective for PTT based cancer treatment as evidenced in vitro and in vivo experiments. Synthesis of MOFs@polymer composites opens the promise of producing diversified nanostructures for a variety of application. METHODS Materials and Measurements. All starting materials were purchased from commercial suppliers and used without further purification unless otherwise noted. Carboxyl-functionalized heptamethine indocyanine (Cy) was synthesized as described in the literature.65 UiO-66 nanocrystals were synthesized according to our previous works.66 N,N-dimethylformamide (DMF) was stored over activated molecular sieves and was distilled under reduced pressure. Ultrapure water was deionized using a Millipore Simplicity System (Millipore, Bedford,USA). Some of the instruments used in this work have been provided in our previous work.57 The temperature change in tumors under laser irradiation was monitored by infrared thermal camera (FLIR). Animal fluorescence images were obtained using a Maestro 500FL in vivo optical imaging system. Synthesis of UiO-66@CyP. Cy and UiO-66 nanocrystals were prepared according to previous work.65,66 UiO-66@CyP was prepared by multi-component passerini reaction containing Cy, o-


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nitrobenzaldehyde and 1,6-diisocyanatohexane on the surface of UiO-66 nanocrystals. In typical experiment, UiO-66 (40 mg), o-nitrobenzaldehyde (30.2 mg, 0.2 mmol), 1,6-diisocyanatohexane (14 µL, 0.1 mmol), Cy (68.4mg, 0.1mmol) were added to DCM (1 mL). After ultrasoundded homogeneously, the mixture was stirred at room temperature for another 96 h. The terminal products was collected through centrifugation (8000 rpm × 10 min) and washed several times with methanol. In vitro PTT effects. UiO-66@CyP in aqueous solution with different concentrations (5, 15, 25, 50, 100 µg mL-1) was irradiated with NIR laser (808 nm, 1 W cm-2, 5 min) and temperatures were recorded every 30 s. To a fixed UiO-66@CyP concentration (25 µg mL-1), the influence from different power density (0.5 W cm-2, 1 W cm-2, 1.5 W cm-2) was recorded as well. The photothermal response of UiO-66@CyP in water (25 µg mL-1) was recorded with laser irradiation (808 nm, 1 W cm-2, 5 min) and then shut off. The photostability was investigated by determining their absorbance changes upon continuous NIR laser irradiation (808 nm, 1 W cm-2). Cell Culture. Cell culture procedures were according to the guidelines of ATCC. The human cervical carcinoma cell HeLa was grown in Dulbecco's modified Eagle's medium. The murine colon cancer cell CT26 was routinely grown in RPMI-1640 Medium and the human colon cancer cell HCT116 was cultured in McCoy's 5a Medium. Both of them were cultured in medium containing 10 % fetal bovine serum (FBS) and 1% penicillin/streptomycin at 37 °C under 5 % CO2. Cellular uptake. Cellular uptake was investigated by CLSM and FCS according to the previous work.57 The concentration of UiO-66@CyP used was 10 µg mL-1. Cells were visualized using blue channel for DAPI (λex 405 nm), red channel for Cy (λex 633 nm) under a confocal


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laser scanning microscope (Carl Zeiss LSM 700). The cells for flow cytometry assay were analysed by Flow cytometer (Beckman, California, USA). Cytotoxicity. The cytotoxicity was measured via MTT assay and live-dead cell staining assay according to the previous work.57 Cells were incubated with UiO-66@CyP for 4 h, then irradiated by the NIR laser (808 nm, 1W cm-2 , 5 min), then cells were incubated for another 48 h for MTT assays. Finally, the absorbance at 490 nm was recorded by microplate reader (BioTek, ELX808). Live-dead cell staining assay was performed according to Live-Dead Cell Staining Kit. After 4 h of incubation with UiO-66@CyP and irradiated with NIR laser (808 nm, 1 W cm-2, 5 min). Then, cells were stained with Calcein-AM/PI for 30 min at room temperature and the result was detected by a fluorescence microscope (Nikon Eclipse Ti, Optical Apparatus Co., Ardmore, PA, USA). Animal Model. Animal care and handing procedures were according to the guidelines established by Jilin University Studies Committee. Healthy male Balb/c mice (~25g) were purchased from the Laboratory Animal Center of Jilin University (Changchun, China). The Subcutaneous CT26 tumor models were generated by subcutaneously injection of 5 × 106 cells in 100 µL of PBS into the back of male BALB/c mice for the NIR fluorescence imaging and PTT treatment. After about 7 days, mice with tumor volumes at about 150 mm3 were selected for imaging and therapy experiments. NIR Fluorescence Imaging and Therapeutic Assay: NIR fluorescence signals were acquired on a commercial Maestro in vivo fluorescence imaging system (CRI Maestro 500FL). The mice were injected with UiO-66@CyP (1 mg mL-1, 100 µL) intratumorally, in vivo spectral imaging from 650 to 800 nm was carried out with an exposure time of 3000 ms. CT26 tumor bearing mice were intravenously injected with 200 µL of 1 mg mL-1 UiO-66@CyP and imaged


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was carried out with an exposure time of 5000 ms. The mice were monitored with in vivo fluorescent imaging system at different time point. After 24 h, tumor and main organs of mice intravenously injected with UiO-66@CyP were harvested and imaged. Auto-fluorescence was removed by using the spectral unmixing software. Auto-fluorescence was removed by using the spectral unmixing software. For photothermal imaging and therapeutic assays, the tumors of mice were exposed to 808 nm laser for 10 min at 1.0 W cm−2. Photothermal imaging was captured by a FLIR Ax5 camera. The tumor sizes were monitored by a caliper every day for 10 days and body weights were also recorded during the therapeutic process. Histological Assessment: After10 days postinjection, mice from the treatment group were sacrificed and then major organs from those mice were harvested, processed routinely into frozen tissue slice, stained with hematoxylin and eosin (H&E) and examined by microscope (Nikon Eclipse Ti, Optical Apparatus Co., Ardmore, PA, USA). Examined tissues include heart, liver, spleen, lung, kidney and tumor. Statistical Analysis: Quantitative data were expressed as mean ±standard deviation (SD). Statistical significance analysis was assessed by SPSS via one-way ANOVA test，*P ≤ 0.05， **P ≤ 0.01， ***P ≤0.001was considered statistically highly significant; ns stand for no significant. ASSOCIATED CONTENT Supporting Information. Supporting Information is available from the Internet at http://pubs.acs.org or from the author. Synthesis scheme, 1H NMR, solid

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C NMR, DLS, Zeta potential, HR-TEM, XPS, FTIR,

photothermal image, biodistribution, H&E staining, tumor images and mice body weight changes (PDF)


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AUTHOR INFORMATION Corresponding Author *Zhigang Xie E-mail: [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (Project No. 51522307).

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