Metal-Organic Framework Nanoparticles with NIR Dye for Multimodal

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Biological and Medical Applications of Materials and Interfaces

Metal-Organic Framework Nanoparticles with NIR Dye for Multimodal-Imaging and Guided Phototherapy Peng Yang, Yongzhi Men, Ye Tian, Yongbin Cao, Liren Zhang, Xianxian Yao, and Wuli Yang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.9b01286 • Publication Date (Web): 06 Mar 2019 Downloaded from http://pubs.acs.org on March 7, 2019

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ACS Applied Materials & Interfaces

Metal-Organic Framework Nanoparticles with NIR Dye for Multimodal-Imaging and Guided Phototherapy Peng Yang,† Yongzhi Men,‡ Ye Tian,§ Yongbin Cao,† Liren Zhang,† Xianxian Yao† and Wuli Yang*,† iD †State

Key Laboratory of Molecular Engineering of Polymers and Department of

Macromolecular Science, Fudan University, Shanghai, 200433, China ‡Shanghai

General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200433, China

§Department

of Chemistry, Stanford University, Stanford, CA 94305, United States

KEYWORDS: metal-organic framework, defect structure, multimodal imaging, photothermal therapy, photodynamic therapy

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ABSTRACT: From the conception of atom economy to develop multi-functional nanomaterial, it is important to construct nanomaterial by maximizing functional units while minimizing unnecessary components. Noteworthy, metal-organic framework (MOF) nanoparticles are an excellent example to meet this idea. Current approaches for multifunctional MOF are mainly based on encapsulation of functional molecules or multistep modification, however, high risk for leakage and burst release or time-consuming and complicated organic synthesis limit their applications. Here, we report a one-pot approach to build defect structure of metal organic framework with near infrared dye (cypate), which is based on the interaction between Fe3+ and carboxyl group of cypate molecules, to construct a multifunctional MOF. Moreover, this system can achieve a multimodal imaging guided phototherapy. Subsequently, the precise cancer phototherapy is investigated in vivo, and the tumors are entirely eliminated without obvious side effect, demonstrating the high efficacy and safety of this multifunctional platform. Hence, it is expected that not only this system is simple, safe and high effective, but also our method of defect structure of MOFs will open a new way to develop multifunctional nanoplatform for bioapplications.


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1. INTRODUCTION Metal-organic framework (MOF) nanomaterial is a new kind of porous nanomaterials, and has attracted many research interests in recent years, such as catalysis,1-2 sensing,3-4 separation and storage of gas5-6 or liquid,7 and drug delivery.8-11 The tailorability of metal ions, organic linkers and pore size endow MOFs nanomaterial several advantageous properties. Recently, MOFs have been developed to load metal nanoparticles,1, 12-13 drugs,8, 14 photosensitizers15-16 and proteins17-20 to develop multifunctional nanoplatform. The construction of functional MOFs conventionally has three approaches: 1) Post loading functional molecules after the synthesis of MOFs14, 21: this method is only suitable for the molecules with smaller size than that of the pores size, which is risky for leakage and burst release. And another problem is that the encapsulation of molecules bigger than the pore size is not suitable. 2) Functionalizing the surface of MOFs2223:

this method can be used for the MOFs with pendant active site on the organic linker, such as –

NH2, N3 or -COOH, however, this method is subject to chemical robust MOFs. 3) Construction of functional molecules as the linkers within the synthesis of MOFs15-16, 24-25: this method will realize a high loading content and avoid leakage before the degradation of carriers, however, time-consuming and complicated organic synthesis lead only limited molecules with strong interaction with ions can be applied. Hence, an ideal strategy to overcome these drawbacks is to combine MOF synthesis and molecule encapsulation into a facile one-pot process. Recently, engineered defects in MOFs have attracted researchers attention,26-29 which is because of the defects can be used to control the pore size, pore volume and functional of MOFs while retaining the chemical and physical properties of original material. Especially for the strategies, which employ a template where mesopore defects (> 2 nm) are formed within MOF.3031

This method is particularly attractive, because of the resulting materials will exhibit


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hierarchical micro- and meso-porosity, which is suitable for separation and catalysis applications. However, from the view of green chemistry, the unavailability of template is wasteful and uneconomical. Hence, how to take advantage of defects in MOFs rather than just template? Recently, Zou and co-workers reported a strategy of utilizing defects in MOFs for controlled drug delivery,9 which employ the interaction between the metal ions and functional molecules to form a defect in MOFs. As a result of developing and utilizing of defects in MOFs is a simple and green approach to construct multifunctional MOFs, however, the development of such multifunctional MOFs with defect structures is subjected to find appropriate molecules to form an interaction between metal ions and functional molecules. Near-infrared cyanine dyes, indocyanine green,32-33 cypate34-35 and their derivatives have been developed for clinically potential application, which is because of their multi-functions. For example, cyanine dyes can be used as imaging agents for photoacoustic imaging (PAI) and nearinfrared fluorescence (NIRF) imaging, meanwhile, they can also transform near infrared (NIR) laser to heat or generate reactive oxygen species (ROS) under NIR irradiation.34 However, several bottlenecks limit the application of cyanine dyes, such as non-selectivity to tumor region and low druggability and bioavailability.36 In order to solve these drawbacks, several nanocarriers have been developed to improve the bioavailability, druggability and tumor targeting ability of cyanine dyes.34-35, 37 Meanwhile, most of these nanocarriers take advantage of the reactivity of carboxyl group of cypate, which can react with amine to form an amide bond or form a weak coordination with Fe3+.35 Interestingly, such coordination between the carboxyl group of cypate and Fe3+ can be introduced to construct MOFs with defect structure. Surprisingly, no literature study developing multifunctional MOFs with defect structure, which


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root in cypate molecules and metal ions, has been reported to date, motivating a detailed investigation. Hence, we report here a simple and efficiency one-pot method to build defect structure of MIL-53 (Materials of Institut Lavoisier-53) with NIR cyanine dye (cypate) for multimodal imaging guided photothermal therapy/photodynamic therapy (PTT/PDT). Cypate molecule is selected as the functional organic molecule to coordinate with Fe3+ to form precursor complexes, then with the adding of organic linkers 1,4-benzenedicarboxylic acid (H2BDC), the stable structure of MIL-53 are formed. Subsequently, polyethylene glycol (PEG) and transferrin (Tf) are further modified on the surface of cypate@MIL-53 nanoparticles (for abbreviation as CMNPs) to achieve good biocompatibility and tumor targeting function. The fabrication of our system is shown in Scheme 1. This multifunctional system have the following advantages: 1) the defect structures introduced into MOFs fully applied the various and adjustable of MOFs and expand much functions into MOFs; 2) precursor complexes of Fe3+ and cypate solve the problem of the relatively low druggability and bioavailability of cypate molecules; 3) the constructed smart system CMNP-Tf, achieving multimodal imaging (NIRF, PAI and magnetic resonance tmaging (MRI)) guided tumor targeting PTT/PDT for cancer. We anticipate that this work will result in an efficient strategy to solve the problems of functional molecules loading encountered by defect structure of MOFs and expand the application of MOFs in biomedicine.


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Scheme 1. Schematic illustration of a) the preparation of Cypate@MIL-53/PEG-Tf (denoted as “CMNP-Tf”) nanoplatform and b) its bio-application for multi-modal imaging guided phototherapy.

2. EXPERIMENTAL SECTION 2.1 Materials: FeCl3·6H2O, 1,4-benzenedicarboxylic acid and were obtained from TCI Company (Shanghai, China). Glutaconaldehyde dianil monohydrochloride and 1, 1, 2-trimethyl[1H]-benz[e]indole were purchased from J&K Scientific Company (Shanghai, China).


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Transferrin

(Tf),

N-hydroxysuccinimide

(NHS),

1-(3-Dimethylaminopropyl)-3-

ethylcarbodiimide hydrochloride (EDC), and other biological reagents were purchased from Sigma Company (St. Louis, USA). 293T, A549, MCF-7 and Hela cells lines were purchased from Chinese Academy of Sciences Cells Bank. All reagents were analytical reagents (A.R.) and directly used if without special illustration. 2.2 Synthesis of CMNP-n: Briefly, 280.2 mg FeCl3·6H2O and a certain amount (10-70 mg) of cypate were mixed in ethanol for 30 min, then 172.5 mg H2BDC were added dropwise into the solution within 10 min. The mixture was stirred for 3 h at 40 oC. The brown products were washed with ethanol and disposed with centrifugation (11000 rpm, 15 min, 3 times). 2.3 Synthesis of CMNP/PEG-Mal38: Briefly, 30 mg CMNPs was dissolved in the DMF solution, then 50 mg EDC and 50 mg NHS was added into the above mixed solution and stirred 24 h to active the carboxyl group. Subsequently, 2 mg NHS ester of maleimide poly(ethylene glycol) (Mal-PEG-NHS) (Mw: 5000) and 8 mg amine-terminated poly(ethylene glycol) (PEGNH2) (Mw: 5000) were added to the mixture aqueous dispersion, and stirred at room temperature for 24 h. Excess impurities were rinsed with distilled water for three times. 2.4 Photothermal Effects of CMNPs: Briefly, different kind of CMNPs aqueous dispersion were placed in a 96-pore plates to assess their photothermal effects. With 785 nm NIR laser illumination for 5 min, the temperature was measured through the thermal infrared camera (InfraTec, VarioCAM®hr research, German). 2.5 Cytotoxicity assay: 293T, MCF-7, Hela and A549 cells were used to assess the cell cytotoxicity. In short, 293T, MCF-7, Hela and A549 cells were incubated in 96-pore plates with 24 h for attachment. Then, different concentrations of CMNPs aqueous dispersion were added in


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and co-incubated for different hours (24 or 48 h). At last, the cell viability was measured with standard 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. 2.6 Construction of A549 Tumor-Bearing Mouse: 4-5 weeks aged male Balb/c nude mice were got from Shanghai SLAC Laboratory Animal Co. Ltd. Meanwhile, all animal experiments in this paper were conducted under the Animal Care and Use Committee of Fudan University. A549 tumor-bearing mice were constructed by the followed method: briefly, 0.1 mL PBS solution which contains about 1×106 A549 cells were injected subcutaneously into the right buttock of nude mouse, after 2-3 weeks, the A549 tumor-bearing mouse were obtained for experiments. The volume of tumor was calculated by the following formula: Volume = (Width of tumor)2 × Length of tumor/2. 2.7 In vivo Multi-modal imaging: For in vivo NIRF imaging, A549 tumor-bearing mice were administrated with CMNP-Tf aqueous dispersion (100 μL, 2 mg mL-1) by tail vein injection. The near-infrared fluorescence signal of CMNP-Tf in vivo (Ex: 760 nm, Em: 830 nm) was obtained by the In Vivo Xtreme instrument (A38, Bruker). For in vivo PA and MR imaging, the same injection dose (100 μL, 2 mg mL-1) was administrated to A549 tumor-bearing mice. PA signal was photographed by the high resolution PA imaging Instrument (Vevo LAZR, A49, FujiFilm VisualSonics Inc.) and the MR signal was captured by a Siemens 3T MR imaging scanner. 2.8 In Vivo Phototherapy: To assess the phototherapy in vivo, A549 tumor-bearing mice were divided into 4 groups and each group contained 6 mice: Group-1: PBS with laser irradiated, Group-2: free cypate with laser irradiated, Group-3: CMNPs with laser irradiated, Group-4: CMNP-Tf with laser irradiated. Each groups of mice were administrated with different


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nanomaterials (100 μL, 2 mg mL−1) by tail vein, then irradiated with 785 nm NIR laser (1 W cm−2) for 5 min at 2 h post injection. After the phototherapy for 14 days, all groups of mice were treated with euthanasia, and the tumors and major organs were dissected for tissue slices. 2.9 Statistical Analysis: Results in this paper are given as mean result ± SD (standard deviation). The statistical analysis was conducted by unpaired student’s t-test, * P < 0.05, ** P < 0.01, and *** P < 0.001 indicated statistical difference.

3. RESULTS AND DISCUSSION 3.1. Preparation of cypate@MIL-53 Nanoparticles The process of synthesis cypate@MIL-53 nanoparticles (named as “CMNPs”) is illustrated in Scheme 1. At first, metal ions (Fe3+) and a certain amount of cypate molecules are blended for 30 min to form precursor complexes through interaction between Fe3+ and the carboxyl group of cypate.35 The UV-Vis absorbance of cypate-Fe3+ have a slightly red-shift compared to cypate solution alone, which show the formation of complexes (Figure S1, Supporting Information).9, 12, 39

Subsequently, a DMF solution of organic linkers (H2BDC) is dropwise added to crystallize

MOFs (see the Experimental section for experimental details) by coordination bond between metal ions (Fe3+) and organic linkers.40 The reaction mixture are stirred for 3 h, and CMNPs samples are collected by centrifugal separation. CMNP-n is used to name the sample, and the recipes used for CMNPs are given in Table 1, for example, CMNP-10 indicates the amount of cypate is 10 mg. The structure evolution of the CMNPs is shown in Figure 1a (and Figure S2 in the Supporting Information). With the increase of the content of cypate molecules, CMNPs keep similar size with MIL-53 nanoparticles, and of diameter is about 250 nm. However, the morphology of CMNP-60 is collapse (Figure S2, Supporting Information), which is because of


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the high content of cypate (carboxyl group) interfere the formation of crystal seed of MOFs and lead to collapse of the structure of MOFs. Meanwhile, a mesopore caused defect structure appears within the CMNPs, and the size of mesopore increase with the adding content of cypate. Notably, despite the presence of large amounts of mesopore, CMNPs keep same crystallinity behavior with MIL-53 nanoparticles. Powder X-ray diffraction (PXRD) results in Figure 1b verify the CMNPs are of high crystallinity with sharp diffraction peaks, which is in accordance with MIL-53 nanoparticles.41 Moreover, the crystallization behavior of CMNP-n decline with the increase of the content of cypate molecules, which is probably due to the presence of cypate molecules interfere the formation of crystal of MOFs. These results verify the collapse phenomenon of CMNPs is because the crystallinity of MOFs decline and even disappear. Hence, considering a stable morphology and the content of cypate loading into the MOFs for phototherapy, CNMP-50 is selected for the further study. Table 1. The recipes and particle size in the assembly process. Sample

FeCl3·6H2O (mg)

Cypate (mg)

H2-BDC (mg)

Size (nm)a)

PDIb)

MIL-53

280.2

0

172.5

234

0.088

CMNP-10c)

280.2

10

172.5

252

0.058

CMNP-20

280.2

20

172.5

239

0.108

CMNP-30

280.2

30

172.5

248

0.105

CMNP-40

280.2

40

172.5

257

0.192

CMNP-50

280.2

50

172.5

247

0.180

CMNP-60

280.2

60

172.5

239

0.152

CMNP-70

280.2

70

172.5

No particles


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a) The hydrodynamic diameter measured with dynamic light scattering (DLS) in PBS; b) Polydispersity index of the particle size, PDI = /Γ2. c) Amount of cypate employed in the assembly process.

Figure 1. Structure evaluation and characterization. (a) TEM images of MIL-53 and CMNP-n: MIL-53 (i, v), CMNP-10 (ii, vi), CMNP-30 (iii, vii) and CMNP-50 (iv, viii). The bar is 200 and 50 nm in i-iv and v-viii, respectively. (b) X-Ray diffraction pattern of MIL-53 and CMNP-n (n=10, 20, 30, 40, 50, 60). (c) X-ray photoelectron spectroscopy (XPS) spectra of MIL-53 and CMNP-50.


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X-ray photoelectron spectroscopy (XPS) verify that CMNP-n contains nitrogen element42 (Figure 1c and Figure S3 in Supporting Information), which is only belong to the cypate molecules. Moreover, the N element content increase with the increase of cypate content in CMNP-n (Table S1 and S2 in Supporting Information), indicating more cypate molecules are successfully loaded into MOFs. Meanwhile, in the Fourier-transform infrared (FT-IR) spectrum (Figure S4 in the Supporting Information), the 1425 cm-1 (C-N bond) and 1660 cm-1 (C=N bond) characteristic peak of cypate appears in the CMNP-50 spectrum, that also indicates the cypate is loading into MOFs. The UV-Vis spectra are shown in Figure 2a, CMNP-50 shows a strong absorption in the NIR region, which is in accordance with the absorption of free cypate, indicating that the CMNPs have the ability as photothermal agents and photosensitizers,34 which derived from cypate molecules. The hydrodynamic sizes of the CMNPs are about 250 nm (Table 1), which is a suitable size for enhanced penetration and retention (EPR) effect in vivo.43 Meanwhile, the particles stability of CMNP-50 in serum and RPMI-1640 cell medium verify the CMNPs is biocompatibility and can keep stable in complex physiological condition (Table S3 in the Supporting Information). 3.2. Phototherapy effects of CMNPs Notable, due to the existence of cypate molecules within MOFs, which endow the CMNPs the ability as photothermal agents and photosensitizers for phototherapy.34-35 Meanwhile, the PTT effects of CMNP-50 show negligible difference at 785 and 808 nm irradiation (Figure S5 in the Supporting Information). And considering the same NIR laser for simultaneous PDT and PTT, the photothermal effect of CNMPs is evaluated under 785 nm laser irradiation (1 W cm-2), the increased temperature of CMNPs aqueous dispersion is shown in Figure 2b. The blank aqueous solution and MIL-53 dispersion fails to generate heat under NIR irradiation (1 W cm-2).


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However, with the increase of the content of cypate molecules in CMNPs (Table S1 and S2, Supporting Information), the photothermal effects increase, which is because more cypate molecules are loaded into CMNPs and cypate content is a key point for the efficacy of phototherapy. Compared to other recipes, the CMNP-50 exhibits the best photothermal effects, which can rise the temperature to 59.5 oC. The temperature raised 20.4, 28.8, 33.5 and 39.3 oC for CMNP-50 with the concentration ranging from 10 to 100 μg mL-1 (Figure S6 in the Supporting Information), demonstrating the concentration-dependent characteristic of CMNP-50. Notably, the good photo-stability performances are shown even after 5 times on-off irradiation of NIR laser (Figure 2c), which is the result of the defect structure within MOFs protects from the cypate molecules photo-bleaching. Therefore, the wonderful temperature-rising and photostability performance of CMNPs make it have the potential to be used for PTT. Meanwhile, in order to detect the generation of reactive oxygen species (ROS) of CMNPs upon the NIR irradiation (785 nm), 1, 3-diphenylisobenzofuran (DPBF) is selected as ROS probe, which can be oxidized by ROS and quench the fluorescence of DPBF.44 Different nanomaterials are mixed with DPBF, after 785 nm laser irradiation for 5 min, the fluorescence intensity of DPBF is detected to assess the ability of ROS generation. As shown in Figure 2d, the fluorescence intensity of MIL-53 has a negligible change, which means the MIL-53 nanoparticles can’t generate ROS under NIR irradiation to oxidize the DPBF. Meanwhile, the fluorescence intensity of free cypate and CMNP-50 have a dramatic decline, demonstrating that the DPBF is oxidized by the generated ROS of free cypate molecules and CMNP-50 nanoparticles. Furthermore, another fluorescent probe is selected to investigate the intracellular ROS generation,45 dichlorofluorescein diacetate (DCFH-DA), which can be oxidized into dichlorofluorescein (DCF) by intracellular generated ROS and reveals a bright green


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fluorescence. The control group and pure CMNP-50 group both show a negligible green fluorescence, which suggest that the yield of generated ROS is less (Figure S7, Supporting Information). However, CMNP-50 + NIR group shows a brighter green fluorescence compared to control group and pure nanoparticle group, suggesting CMNPs can generate abundant ROS in live cells under NIR light. Hence, the property of ROS generation from CMNPs indicates it can be used for PDT.

Figure 2. Photothermal effects and ROS generation. (a) UV-Vis spectra of MIL-53, cypate and CMNP-50 aqueous dispersion. (b) Photothermal effects of CMNP-n at 785 nm laser irradiation (1W cm-2, 50 μg mL-1). (c) Photothermal stability of cypate and CMNP-50 after 5 times NIR


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laser irradiation. (The insert pictures are the graphs of cypate and CMNP-50 solutions before and after 5 time’s on-off heating). (d) The ability of ROS generation for different nanomaterials by determine the maximum of fluorescence intensity of DPBF. 3.3 In Vitro Phototherapy of CMNPs Before exploring phototherapy in vivo, we evaluate the biocompatibility of CMNPs in vitro by standard 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay.38 As shown in Figure 3a-c (and Figure S8 in the Supporting Information), there are no obvious toxic effects on different cells lines (293T, MCF-7, Hela and A549), and cell viability keep almost 90% after incubation for 24 or 48 h even with a high concentration up to 200 μg mL-1, which verify the excellent biocompatibility of CMNPs. Then, A549 cells lines is selected to investigate the phototherapy effect of CMNPs. As shown in Figure 3d, the cell viability of A549 show a dose dependent killing-manner after 785 nm laser treatment with CMNPs and the half maximal inhibitory concentration (IC50) is 21.2 ± 0.3 μg mL-1. Meanwhile, it has been proved that the CMNPs hold an ability of photothermal effects and ROS generation under NIR laser irradiation, the respective photothermal and photodynamic therapeutic effects of CMNP-50 are further detected on A549 cells. As shown in Figure 3d, the cell viability of 4 oC + NIR (PDT group) is about 61% at 50 μg mL-1, in which the generated heat is eliminated by the stationary temperature, the results are on behalf of the PDT effect. In the meanwhile, the 25 oC+NIR+NaN3 (PTT group) reveal the photothermal effect, which is because of NaN3 is a kind of ROS scavenger to avoid ROS generation,35 and the cell viability is about 39%. It’s worth noting that the cell viability of 25 oC + NIR (PDT+PTT group) is about 19% at 50 μg mL-1, demonstrating that the heat and ROS generated by the action of NIR irradiation on CMNPs can effective kill cancer cells with a synergistic effect of photothermal effect and photodynamic effect.


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Furthermore, confocal fluorescence imaging of calcein AM and propidium (PI) co-stained A549 cells also demonstrated the strong phototherapy effect of CMNPs (Figure S9, Supporting Information), cells in CMNPs + NIR group exhibits intense red fluorescence signal, which indicates of dead cells, however, the cells in control group showed bright green fluorescence, revealing the fluorescence signal of living cells.

Figure 3. In vitro experiments. Cell viabilities of 293T cells (a), MCF-7 cells (b), Hela cells (c) incubated with CMNP-50 at different concentrations for 24 or 48 h. (d) Cell viabilities of A549 cells incubated with different concentrations of CMNP-50 by different treatment, PDT group (4 oC+

NIR), PTT group (25 oC+NIR+NaN3), and combined PDT/PTT group (25 oC+ NIR).


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Subsequently, transferrin (Tf) is selected to modify the CMNPs to achieve a good tumor targeting, which is expected to enter the cells with the help of Tf receptor-mediated endocytosis.46 At first, the cellular uptake behavior of CMNP-Tf is evaluated with the A549 cell lines. After 4 h incubation, a weak red fluorescence signal appear treated with free cypate (Figure S10, Supporting Information), and the CMNPs show a little bright red signal compare to cypate group, which is own to a better cellular uptake of nanoparticles. Impressively, the CMNPTf group shows the brightest red fluorescence signal, which is due to the tumor targeting of transferrin units on the surface of CMNPs can improve the internalization efficiency of the nanoparticles through specific receptor mediated endocytosis. In addition, flow cytometry results (Figure S11, Supporting Information) further confirm that CMNP-Tf has a significant uptake efficiencies compared with free cypate and CMNPs, indicating that Tf is the key factor for tumor targeting. Furthermore, hemolysis experiments are measured (Figure S12, Supporting Information), the positive group (distilled water) shows an obvious red, which show the distilled water will break the red blood cell membrane, however, the negative group (phosphate buffered saline) and the CMNPs and CMNP-Tf group (200 μg mL-1) show a clear color, indicating the good biocompatibility and biosafety of CMNPs and CMNP-Tf for injection in vivo.


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3.4 Multimodal Imaging of CMNPs To demonstrate the tumor targeting and multimodal imaging properties of CMNP-Tf, we evaluate NIRF imaging on the A549 tumor-bearing mice at first. After intravenous injection, the free cypate group show negligible fluorescence (Ex: 760 nm, Em: 830 nm) at tumor region, although the CMNPs group exhibit a slightly brighter fluorescence at tumor site at about 4 h post injection due to the EPR effects of nanoparticles in vivo,43 the fluorescence signal mainly distributes in other organs, indicating non-selective accumulation ability of CMNPs in tumor tissues. While, the CMNP-Tf group show bright fluorescence at tumor region at 2 h post injection because of the EPR effects and the Tf receptor-mediated cellular uptake of cancer cells, indicating tumor targeting ability of CMNP-Tf in vivo (Figure 4a and Figure S13 in the Supporting Information). Subsequently, in order to verify the biodistribution of CMNP-Tf in vivo, mice are euthanized at two time points (maximum accumulation time for 2 h and metabolic time for 24 h) and the major organs (heart, liver, spleen, lung, kidneys and tumor) are excised. The tumor shows the brightest fluorescence signal at 2h (Figure 4b), indicating that the CMNPTf is most accumulated in tumor tissue. Meanwhile, when the time prolongs to 24 h, the fluorescence signal declines to a low level because of the metabolism from the body (Figure S14, Supporting Information). Moreover, the biodistribution of CMNP-Tf is also measured by inductively coupled plasma (ICP) techniques,47 which is also quantify the amount of CMNP-Tf within tissues. As shown in Figure 4c, the Fe3+ of CMNP-Tf is mainly distributed in tumor and liver tissues at 2 h post injection, which is accordance with NIRF imaging results, indicating the good tumor targeting ability of CMNP-Tf.


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Figure 4. (a) Near-infrared fluorescence images of A549 tumor-bearing mice after injection with free cypate, CMNPs and CMNP-Tf aqueous dispersion through tail vein at different times (Ex:760 nm, Em:830 nm). Red circles indicate tumor sites. (b) Ex vivo imaging of major organs and tumor tissues at 2 or 24 h post injection of CMNP-Tf. (c) Biodistribution of CMNP-Tf in


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A549 tumor-bearing mice at 2 or 24 h postinjection as determined by measuring total Fe content with ICP-AES. Photoacoustic imaging48 and T1-weighted magnetic resonance imaging49 are the technologies which own a capacity of good spatial resolution and high imaging depth. The PA signal of CMNP-Tf (Figure S15, Supporting Information) exhibits a linear enhancement with increasing the concentration of CMNP-Tf (R2=0.9959), indicating the CMNP-Tf can be used as a imaging contrast for PA imaging due to the existence of NIR dye cypate within the CMNP-Tf. Hence, we perform PAI of CMNP-Tf on A549 tumor-bearing mice. The tumor area shows a relatively low signal intensity before injection (Figure 5a-b). After intravenous injection of CMNP-Tf, the PA signal intensity of tumor area gradually increases and reaches the highest at 2 h post injection, then the PA signal declines with time increase to 24 h, which indicating the metabolism of nanoparticles from the mice body (Figure S14, Supporting Information). The change of post-to-pre ratio (ROIpost/ROI0) at tumor site is quantitatively calculated, showing 2.01-fold increase at 2 h (Figure 5b), illustrating the CMNP-Tf has an ability as imaging contrast for PAI in vivo and tumor selective accumulation. Apart from NIRF and PA imaging, the CMNP-Tf also possesses T1-weighted MRI contrast property due to the Fe3+ contribution to the longitudinal relaxivity in MRI. T1-weighted MR images of CMNP-Tf are obtained in vitro and in vivo. The T1 relaxation coefficient (r1) of CMNP-Tf is calculated to be 2.6 s-1 mM-1 (Figure S16, Supporting Information), which is lower than that of commercial T1-weighted contrast agent, gadolinium-tetraazacyclododecanetetraacetic acid (Gd-DOTA) (7.1 s-1 mM-1).50 Subsequently, T1-weighted MRI of CMNP-Tf is performed on A549 tumor-bearing mice, the MR signal intensity of tumor region gradually brightens and reaches the highest value at 2 h post injection (Figure 5c, d). The change of post-to-pre ration (ROIpost/ROI0) at tumor site is quantitatively


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calculated (Figure 5d), showing 1.56-fold increase at 2 h, which suggests the effective tumor accumulation of CMNP-Tf. After 24 h, the tumor MR signal intensity decreases to the level of preinjection.

Figure 5. In vivo multimodal imaging. PA images (a) and PA signal intensity change (b) of A549 tumor-bearing mice pre- and postintravenous injection of CMNP-Tf. Black circles highlight the tumor site. T1-weighted MR images (c) and T1-weighted MR signal intensity change (d) of A549 tumor-bearing mice pre- and postintravenous injection of CMNP-Tf. White circles highlight the tumor site. (e) Infrared thermal images of PBS, Cypate, CMNPs and CMNPTf under NIR laser irradiation (785 nm, 1 W cm−2) for 300 s. (f) Tumor temperature elevation curve as a function of irradiation time.


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3.5 In Vivo Phototherapy Multimodal imaging techniques (NIRF/PA/MR) provide the visual, accurate and comprehensive informations of tumor tissue,49 meanwhile, the informations verify the CMNP-Tf have the tumor targeting ability. Hence, the in vivo phototherapy is pre-performed on the A549 tumor-bearing mice, mice are irradiated with 785 nm laser (1 W cm-2) for 5 min at 2 h post injection. The temperature of tumor scarcely increases for the PBS group (Figure 5e, f), in contrast, the temperatures of tumor reach to 41.8, 49.8 and 56.7 oC for free cypate, CMNPs and CMNP-Tf group, respectively. The temperature-rising effect of free cypate and CMNPs are significantly lower than the CMNP-Tf group, which is due to non-tumor targeting distribution in vivo. Meanwhile, with the passive and active targeting, CMNP-Tf shows a stronger photothermal effects. The above experimental results prove CMNP-Tf holds high cell inhibition rate toward A549 cancer cells, low hemolytic toxicity and effective tumor accumulation ability. Therefore, the in vivo phototherapy is performed on A549 tumor-bearing BALB/c nude mice. The mice with tumor volume of  80 mm3 are separated into four groups, and each group contain 5 mice, then each group is administrated with different nanomaterials dispersion by tail vein injection. As shown in Figure 6a-d, the tumors grow rapidly and display no antitumor efficacy for PBS and cypate group, while the tumors in CMNPs group are re-growing at 6 day post-treatment, and the tumor inhibition rate is 44.8% through calculation of tumor weight, demonstrating a low efficient tumor ablation effect of CMNPs, which is probably because of their relatively worse tumor accumulation. However, the CMNP-Tf group show 100% tumor inhibition rate, the tumors are completely eliminated within 14 days observation and without any recrudescence. Subsequently, in order to verify the biosafty of CMNP-Tf, the body weights of mice are recorded every other


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day and each groups of mice increase in body weights (Figure 6b), which show that there are no systemic toxicity induced decline of body weights, verifying CMNP-Tf own a good biocompatibility. To further assess the biocompatibility, hematoxylin and eosin (H&E) test is measured.51 There is no obvious organ damage and inflammatory compared to PBS group (Figure 6e). Last but not least, the in vivo biosafety of CMNP-Tf is also evaluated by blood biochemistry and hematology test. Hematology analysis reveals no significant difference in the blood parameters between nanoparticle-treated group and control group at 24 h (Table S4, Supporting Information). Meanwhile, no significant difference is observed in blood biochemistry between control group and CMNP-Tf group (Figure S17, Supporting Information), further verifying the safety and low toxicity of CMNP-Tf. Hence, there data indicate that CMNP-Tf is a promising phototherapy agent in oncotherapy and with relatively low systemic toxicity.


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Figure 6. In vivo phototherapy. Tumor volumes (a) and body weight (b) for mice during the administration of different formulations (PBS, cypate, CMNPs and CMNPs-Tf). (c) Tumor


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weights and tumor inhibition ratios for mice treated with different formulations. (d) The final morphology of isolated tumors for these five groups at 14th day. The red circle stands for the tumor, which had been completely eliminated. (e) H&E stained results of major organs (heart, liver, spleen, lung, and kidney) for all tested groups. (40×). **, p < 0.01; ***, p < 0.001.

4. CONCLUSIONS In summary, we have developed a simple and facile approach to fabricate defect structure of MOFs with a functional NIR dye to achieve multimodal imaging guided phototherapy. In this system, cypate molecule can interact with Fe3+ to form a precursor complex to form a defect structure within MOFs, which solves the problem of low bioavailability and protects the NIR dye from photo-bleaching. PEG and Tf are modified on the surface of MOFs to target tumor region. The resultant CMNP-Tf possesses a multimodal imaging guided photothermal/photodynamic performance. In vivo anticancer experiments indicate CMNP-Tf can be efficiently deliver to tumor region and ablate tumors upon a low power laser, indicating that this nanoplatform has potential for cancer theranostic. The method, construction of defect structure of MOFs, is not only provide a multifunctional theranostic nanoplatform, but also presents a new concept to coating functional molecules within MOFs with the help of hierarchical structure.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website.


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Characterization, synthesis of cypate, CLSM and Flow cytometry data. ROS generation in vitro. Further informations, such as the UV, TEM, FT-IR, CLSM images, cellular uptake, hemolysis experiments, pharmacokinetic and blood biochemistry data about CMNPs. AUTHOR INFORMATION Corresponding Author *Telephone: +86-21-3124 2385. Fax: +86-21-3124 8888. Email: [email protected]

ORCID Wuli Yang: 0000-0003-0384-9213

Notes The authors declare no competing financial interest.

Acknowledgments This work was supported by the National Key R&D Program of China (Grant No. 2016YFC1100300) and National Science Foundation of China (Grant Nos. 51873041 and 51473037).


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Metal-Organic Framework Nanoparticles with NIR Dye for Multimodal

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