Design and Synthesis of a Biocompatible 1D Coordination Polymer as

Research Article Cite This: ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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Design and Synthesis of a Biocompatible 1D Coordination Polymer as Anti-Breast Cancer Drug Carrier, 5‑Fu: In Vitro and in Vivo Studies Mahsa Rezaei,† Alireza Abbasi,*,† Rassoul Dinarvand,‡,§ Mahmood Jeddi-Tehrani,∥ and Jan Janczak⊥ †

School of Chemistry, College of Science, University of Tehran, Tehran 14155-6455, Iran Nanotechnology Research Center, Faculty of Pharmacy and §Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 14176-14411, Iran ∥ Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran 19615-1177, Iran ⊥ Institute of Low Temperature and Structure Research, Polish Academy of Sciences, P.O. Box 1410, Wroclaw 50-950, Poland ‡

S Supporting Information *

ABSTRACT: Designable coordination polymers with suitable chemical diversities and biocompatible structures have been proposed as a promising class of vehicles for drug delivery systems. Here, we hydrothermally synthesized a novel onedimensional (1D) coordination polymer, [Zn(H 2 O) 6 K 2 (H 2 BTC) 2 (H 2 O) 4 ](H 2 BTC) 2 ·2H 2 O, where H3BTC = benzene-1,3,5-tricarboxylic acid (trimesic acid), cp.1. As the hydrogen bonds stabilized 1D chains in three dimensions, the cp.1 could be a good candidate for delivering small-molecule chemotherapeutics such as 5-fluorouracil (5Fu). The synthesized cp.1 showed a remarkable 5-Fu loading of 66% with encapsulation efficiency of 98% and almost complete release process. The 5-Fu-loaded cp.1 displayed a time-dependent cytotoxicity effect against breast cancer cell lines MCF-7 and 4T1. The cellular uptake of cp.1 particles was investigated via confocal laser scanning microscopy using fluorescein isothiocyanate and LysoTracker Red staining. Furthermore, the in vivo antitumor impact of 5-Fu-loaded cp.1 was studied on 4T1 breast cancer BALB/c mice model. The intratumor treatment of 5-Fu-loaded cp.1 demonstrated beneficial antitumor efficacy by postponing tumor growth. These results suggest that the 5-Fu-loaded cp.1 microparticles with a great locoregional delivery can be efficient anticancer drug carriers for further clinical treatments. KEYWORDS: coordination polymer, 5-fluorouracil, in vitro and in vivo studies, drug loading, release process

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INTRODUCTION Coordination compounds with unbounded structures, constructed from metal (as inorganic part) and ligand (as organic part), have been severely studied. In 1960s, the term of coordination polymers appeared and was reviewed as the versatile compounds. These inorganic−organic hybrid materials are a potent and applicable category of materials with desired architecture in accordance with the specific application.1 Assembly of different building blocks, such as diverse metals and linkers, causes the formation of different porosities, including one-dimensional (1D), two-dimensional, and threedimensional networks.2 Therefore, these highly desirable compounds can be applied in various areas, including catalysis,3 gas storage,4 gas separation,5 imaging, sensing,6 and more importantly as drug carriers.7 Over the past 3 decades, various types of nanocarriers, such as diverse metal oxides,8,9 micelles,10 conventional inorganic nanostructures,11,12 and carbon-type carriers, e.g., carbon nanotubes13 and graphene oxide,14 have been made and investigated. Moreover, it has been proved that use of micronsized delivery systems, such as microvectors,15 microcapsules,16 microspheres,17 and mesoporous silicon microparticles,18 can © XXXX American Chemical Society

be a good approach for drug delivery. In a new perspective, coordination polymers, as a novel classification of carriers with a substantial loading capability, have been introduced.19−25 Microscale and nanoscale coordination polymers have demonstrated inimitable advantages in drug delivery systems. These advantages are nontoxic, well-controlled drug release behavior and stability, which can be the most pivotal characteristics of every efficient carriers.26 These mentioned properties make coordination polymers one of the most applicable carriers in anticancer drug delivery systems.7,27 5-Fluorouracil (5-Fu), an antimetabolite of the pyrimidine analogue type, has been applied as an anticancer agent against several cancers, such as colon, pancreas, liver, breast, gastrointestinal tract, brain, rectum, etc. for decades.28−31 Regarding the 5-Fu structure, it impedes nucleoside metabolism and can be incorporated into DNA and RNA, causing cell death.32 Using 5-Fu alone or in combination with chemotherapy regimens, as many other cytotoxic anticancer drugs, is Received: February 22, 2018 Accepted: May 3, 2018

A

DOI: 10.1021/acsami.8b03111 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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ACS Applied Materials & Interfaces Scheme 1. Schematic Illustrationa

associated with some significant challenges: (i) short biological half-life, leading to the implementation of high drug doses and (ii) toxic side effects like hair loss, exhaustion, and liver disorders due to lack of specificity in its systemic biodistribution.28 The drug resistance of tumor cells, which is observed during the past decades, is one of the major reasons that have extensively restricted 5-Fu clinical applications.33 These unfavorable properties frequently cause treatment failures, especially in patients with malignancies who are more sensitive to chemotherapeutic agents, for instance, breast cancer.34 Thus, the 5-Fu delivery was studied by a large number of groups who investigated various complicated formulations to improve the 5-Fu delivery in the simulated body fluids.17,35−38 Therefore, designing a simple novel carrier with an astonishing loading capacity and complete delivery, including active or passive approach, can be very helpful in this area. In this study, we focused on the design and synthesis of a new microscale coordination polymer utilizing both covalent and hydrogen bonds. To achieve the biocompatible network, we applied zinc(II) nitrate as a metal source, trimesic acid as a biodegradable linker, and potassium hydroxide as a base. The attractive point of this work is the formation of a 1D novel coordination polymer consisting of two kinds of biocompatible divalent (Zn) and monovalent (K) metals in which all of the chains are strongly connected by hydrogen bonds (cp.1). In the next step, we applied 5-Fu as a globally applicable anti-breast cancer drug and investigated the loading and release process of this small molecule in appropriate media. Regarding the high 5Fu loading and approximately complete drug release, we studied the in vitro performance of the novel carrier against mouse mammary carcinoma cell line (4T1) and human breast cancer cell line (MCF-7). Consequently, we investigated antitumoral activities of 5-Fu-loaded cp.1 on breast cancer BALB/c mouse model to gain comprehensive knowledge about the proficiency of the synthesized carrier (Scheme 1).

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a Schematic illustration of (a) hydrothermal synthesis of cp.1 using Zn2+, K+, and 1,3,5-BTC; (b) 5-Fu loading process; and (c) drug release from 5-Fu-loaded cp.1 during 72 h, which was associated with collapse of crystalline structure of the synthesized cp.1.

device detector, using graphite monochromatic Mo Kα (λ = 0.71073 Å) radiation. Powder X-ray diffraction (PXRD) was performed by Philips, PW1730 with 2θ range of 2−20°, with 0.02° step width and wavelength of Cu Kα (λ = 1.5409 Å). Thermogravimetric analysis (TGA) of dried synthesized compound (5−6 mg) was performed in an argon atmosphere in the temperature range 20−600 °C with a heating ramp of 20 °C/min using a thermal analyzer (TA, TGA Q50). The cellular uptake of FITC-loaded cp.1 was investigated by confocal laser scanning microscopy (CLSM; Nikon Eclipse Ti, Japan). Animals. The mice used in the research were obtained from Royan Institute; 15 female BALB/c syngeneic mice (21−23 g) were housed under ambient temperature and standard diet. The study was conducted according to the ethical guidelines approved by the ethical committee of Pharmaceutical Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, which are based on the NIH guide for the care and use of laboratory animals. Synthesis of Compound [Zn(H 2 O) 6 K 2 (H 2 BTC) 2 (H 2 O) 4 ](H2BTC)2·2H2O (cp.1). A mixture of Zn(NO3)2·6H2O (0.1 mmol), H3BTC (0.3 mmol), KOH (0.5 mmol), and H2O (5 mL) was placed in a Teflon-lined autoclave. It was held at 200 °C for 3 days with cooling ramp of 96 h. In the purification step, the colorless needle crystals were centrifuged, washed with fresh distilled water three times, and then dried at room temperature. The structure was solved by the direct method using SHELXS-97 and refined by the SHELXL-2014/7 program. All nonhydrogen atoms were refined using anisotropic thermal parameters. Visualization of the structure was made by the Diamond 3.1 program.39 Crystallographic data for the structure have been deposited in the Cambridge Crystallographic Data Center with CCDC number: 1530592. The detailed crystallographic data and structure refinement parameters for cp.1 are summarized in Table S1. Additionally, synthesized cp.1 compound was characterized by PXRD, FT-IR, TGA, and ζ-potential measurement. 5-Fu Impregnation Process. 5-Fu (5 mg) was completely dissolved in 4 mL of distilled water, followed by addition of 2.5 mg of synthesized cp.1. The prepared suspension was then sealed and stirred (650 rpm) for 24 h at room temperature. After all, the 5-Fu-loaded cp.1 particles were filtered under vacuum with a 0.2 μm cellulose acetate (Whatman CA) membrane filter. The loaded particles were

MATERIAL AND METHODS

Materials. All employed reagents and solvents were of analytical grade purity, purchased from commercial sources and used as received. Zn(NO3)2·6H2O (Merck), 1,3,5-benzenetricarboxylic acid (1,3,5H3BTC), KOH, 5-Fu, dimethyl sulfoxide (DMSO), and formaldehyde were all purchased from Merck (Merck, MA). LysoTracker Red DND99 was purchased from Thermo Fisher (MA), and fetal bovine serum (FBS), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), penicillin, 0.25% trypsin−ethylenediaminetetraacetic acid (EDTA), Dulbecco’s modified Eagle’s medium (DMEM) cell culture medium, 4′,6-diamidino-2-phenylindole (DAPI), fluorescein isothiocyanate (FITC) were all purchased from Sigma-Aldrich (MO). 4T1, mouse mammary breast cancer cell line and MCF-7, human breast cancer cell line were obtained from National Cell Bank of Iran (Pasteur Institute of Iran, Tehran, Iran). Instrumentation. The quantitative determination of 5-Fu concentration in either loading or release process was accomplished by UV−visible spectrophotometry (CECIL 7500, U.K.). The ζpotential of the synthesized and loaded microparticles was measured by dynamic light scattering method using a Malvern Nano ZS, Zetasizer, U.K. The morphology of particles was observed by field emission scanning electron microscopy (FE-SEM) using a HITACHI S-4160 apparatus, Japan. Fourier transform infrared (FT-IR) spectra were recorded using a Bruker, Equinox 55 spectrometer equipped with an attenuated total reflectance accessory over the range of 600−4000 cm−1. Single-crystal X-ray diffraction (SXRD) measurement for cp.1 was performed on a four-circle κ geometry KUMA KM-4 diffractometer equipped with a two-dimensional area charge-coupled B


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Histological Analysis. The animals were euthanized 28 days posttreatment, and the harvested mammary glands were fixed in 10% neutral-buffered formalin (pH 7.26) for 48 h, then processed, and embedded in paraffin. Thick sections (5 μm) were prepared and stained with hematoxylin and eosin (H&E). The histological slides were evaluated by an independent reviewer using light microscopy (Olympus, Japan). Histopathological evaluation was performed using Nottingham histologic grading system (Elston−Ellis modification of Scarff−Bloom−Richardson grading system) for breast cancer.42 This scoring system grades the malignancy of breast tumor between 3 and 9 based on the following features: the amount of gland formation (acinar or tubular differentiation), the nuclear features (pleomorphism), and the mitotic activity, which were scaled from 1 to 3. Tumors with a sum of 3−5 were considered as grade 1 (well differentiated). Tumors with a sum of 6−7 and 8−9 were considered as grade 2 (moderately differentiated) and grade 3 (poorly differentiated), respectively. Moreover, any changes, including inflammatory response, coagulative necrosis, hemorrhage, and hyperemia, were assessed in tumor samples, comparatively. Statistical Analysis. All results were expressed as the mean ± standard deviation from four individual experiments. Statistical analysis was accomplished using one-way analysis of variance (ANOVA) test. The half-maximal inhibitory concentrations (IC50) and P value were obtained using the SigmaPlot software, and P < 0.001 was considered as significant difference.

dried overnight. The unloaded drug concentration in clear supernatant was then quantified by UV−vis spectrophotometry at λmax = 266 nm in triplicates. In addition, 5-Fu-loaded particles were characterized by PXRD, FTIR, and ζ-potential measurement to determine the changes after the loading process. In Vitro 5-Fu Release Study. 5-Fu release from the synthesized cp.1 particles was studied through suspending 1 mg/mL of 5-Fuloaded cp.1 in 10% FBS solution. The suspension was kept under rotative agitation for different incubation times (45 min to 4 days). At each time interval, the release medium was recovered by centrifugation (14 000 rpm, 10 min) and replaced with 1 mL of fresh medium. When the experiment was finished, all media were centrifuged again (20 000 rpm, 10 min) to collect any residual particles. Finally, the concentration of the released 5-Fu at each time was quantified by UV−visible spectrophotometry at λmax = 296 nm. The experiments were performed in triplicates. Cell Culture Experiments. The cells MCF-7 and 4T1 as human and mouse breast cancer cell lines, respectively, were used for in vitro cytotoxicity assay. DMEM supplemented with 10% FBS and 5% penicillin−streptomycin was utilized as the cell culture medium. Before the experiment, cells were cultivated in a humidified environment at 37 °C with 5% CO2 to reach desirable confluence. Afterward, the cells were detached from the flask using trypsin− EDTA, collected by centrifugation (1500 rpm, 5 min), resuspended in culture media, counted, and used for further cell culture studies. Cellular Uptake Studies. FITC fluorescent dye was used for labeling the cp.1 particles, and the protocol involves the overnight incubation of FITC (100 nM) with cp.1 particles in the dark. The unloaded FITC was removed by centrifugation (14 000 rpm, 5 min). For cellular internalization process, MCF-7 cells were seeded in glass dishes with a density of 80 000−100 000 cells. After 24 h, the cells were treated with FITC-loaded cp.1 particles (10 μg/mL) for 3 h. For lysosome detection, the cells were incubated with LysoTracker Red (300 nM) for 1 h. The cells were washed by phosphate-buffered saline (PBS) three times and then fixed by 4% paraformaldehyde for 4 min. Cells were then stained with DAPI for 5 min and washed three times with PBS. Confocal microscopy was performed on a FluoView in a sequential scanning mode using a 20−40× objective. MTT Assay. The cytotoxicity of 5-Fu as free drug, synthesized cp.1s, and 5-Fu-loaded cp.1s, was investigated against MCF-7 and 4T1 cells by MTT assay. For this measurement, the cells were seeded into 96-well plates at about 8000−10 000 cells per well. At first, the cells were incubated for 24 h. Then, cell treatment was performed at the drug concentration range of 0.01, 0.1, 0.5, 1, 10, 50, and 100 μg/mL. According to the 5-Fu release profile, the cells were incubated for 24, 48, and 72 h at 37 °C and 5% CO2. After each time interval, the old medium was replaced with 50 μL of MTT/PBS solution (0.5 mg/mL). The plates were incubated for 2−4 h at 37 °C and 5% CO2. Afterward, DMSO was added to each well to dissolve the purple insoluble formazan crystals. Eventually, the absorbance of the solution was quantified by a microplate reader (BioTEK ELX800) at the wavelengths of 570 and 630 nm as reference. Tumor Treatment and in Vivo Evaluation of Antitumor Efficacy. Mouse tumor models of mammary breast cancer 4T1 were established by injecting 2 × 106 of tumor cells subcutaneously into the mammary gland of 4 week old mice. The treatment was started on the 10th day after tumor cell transplantation when 80% of the tumors reached a volume of 150−200 mm3. The mice were randomly divided into three groups, which were named as 5-Fu (free drug), 5-Fu.cp.1 (5-Fu-loaded cp.1), and control (untreated group), and each group contained five mice. On day 0 (the day was designated as “day 0”), two groups of the mice (5-Fu and 5-Fu.cp.1) were intratumorally (it) treated with a dose normalized to be equivalent to 11 mg/kg 5-Fu, which was given once. Tumor growth was followed every 3 days by measuring two tumor diameters (D and d were the longest and the shortest diameters of the tumors in millimeters, respectively) with a caliper, and the tumor volume was calculated by the formula V = D × d2/2.40,41

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RESULTS AND DISCUSSION Crystal Structure of [Zn(H2O)6K2(H 2BTC) 2(H2O) 4](H2BTC)2·2H2O. We could obtain single-rodlike colorless

Figure 1. Oak Ridge thermal ellipsoid plot view of [Zn(H2O)6K2(H2BTC)2(H2O)4](H2BTC)2·2H2O, cp.1, with the labeled atom scheme and displacement of ellipsoids.

crystals by hydrothermal method (crystallographic details are given in Table S1). The asymmetric unit contains one Zn2+ (in 2c special position), one K+ (in 4e general position), two H2BTC− (in 4e general position), and six water molecules (Figure S1). Every Zn(H2O)62+ entity is connected to two K+ ions by six bridged water oxygen atoms. The potassium ions constructed one-dimensional chain along b axis. Each K+ ion was connected to seven oxygen atoms, two from water, three C


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Figure 4. FT-IR spectra of cp.1 (a, black), 5-Fu-loaded cp.1 (b, red), and 5-Fu (c, blue).

Figure 2. View of the packing diagram of cp.1 along a axis (a) and c axis (b).

Figure 5. PXRD patterns of simulated cp.1 (a, green), synthesized cp.1 (b, black), 5-Fu-loaded cp.1 (c, red), and 5-Fu (d, blue). Figure 3. FE-SEM images of hydrothermally synthesized cp.1 before (a, b) and after (c, d) sieving.

and 98.26 wt %, respectively. The adsorption of 5-Fu on the chains of cp.1 leads to an obvious decrease in adsorption intensity43 (Figure S3). This outstanding amount of loading might be due to the small size of 5-Fu molecules and more importantly the existence of host−guest interactions, such as Hbonding (between amine groups of 5-Fu and COOH groups of cp.1) and π−π stacking between 5-Fu molecule and cp.1.44,45 To the best of our knowledge, the successful 5-Fu loading amount in cp.1 is not only comparable but also much higher than most of the other reported 5-Fu-loaded micro- and nanocarriers. Herein, there are some examples of examined formulations with their loading capacities: nanofibers (2.6 mg/g of nanofibers),46 nanohydrogels (97−99.5%),35 carbon-based nanocarriers such as graphene oxide (32.4%),14 newly synthesized metal−organic frameworks (MOFs) (34.32%),43 (22.5%)44 and mixed formulated MOFs such as metal−organic polyhedra, colloid, MOF; ∼40%,45 hollow microsphere with

bridged water atoms from Zn(H2O)62+, and two more from two different H2BTC− ions in a distorted monocapped octahedral geometry, see Figure 1. Besides, there were one free water molecule and one H2BTC− ion in the asymmetric unit that held the parallel chains together by relatively strong hydrogen bonds and π−π stacking interactions, stabilizing the crystal structure in threedimensional network (Figures 2a,b and S2). 5-Fu Loading Process. 5-Fluorouracil (5.3 × 5.0 Å2) is a small and widely used anticancer drug, which is applied for treatment of various cancer tumors. The loading process with 1:2 ratio of cp.1/5-Fu was examined in distilled water. The drug loading (DL) and encapsulation efficiency (EE) were investigated by UV−vis spectroscopy with the correlation coefficient of R2 = 0.999, which were obtained as 66.27 ± 2.1 D


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charged. This positive value is in agreement with the high loading of 5-Fu with cationic nature, which has excess amounts of amine groups (NH).50−52 As shown in Figure 4a, the FT-IR spectra of cp.1 reveal that the peaks at 1680 cm−1 correspond to CO bands and the peaks around 1430 and 1560 cm−1 are assigned to the stretching vibrations of O−C−O group.53 Also, ν(ArC−H) at 682 and 749 cm−1 and ν(ArCC) at 1617 cm−1 are observed as aromatic bending vibrations and aromatic stretching vibrations, respectively. Moreover, the various types of O−H groups, including six water molecules in Zn(H2O)6, four water molecules around K, and two solvated water molecules, in which some of the water molecules are strongly polarized, and also protonated COOH groups may cause broadening of the stretching O−H vibrations. The elemental analysis data also support the FT-IR output to confirm successful synthesis of cp.1, C36H44K2O36Zn: calculated (%): C, 36.14; H, 3.68; found (%): C, 36.56; H, 3.65. The vibrational bands of synthesized cp.1 around 727, 782, 1424, 1601, and 1681 cm−1 were all observed in the FT-IR spectrum of the 5-Fu-loaded cp.1 with a little shift in aromatic bending vibrations of C−H, which might be due to the hydrogen bonding and van der Waals interactions between cp.1 and 5-Fu.54 This accordance confirmed the stability of the synthesized cp.1 after loading process without any chemical reaction with 5-Fu molecule. Also, 5-Fu loading in cp.1 is confirmed by the appearance of N−H bending vibration at 654 cm−1 and C−F stretching vibration at 1286 cm−1. Moreover, deformation vibrations of CFCH group was observed at 782 and 727 cm−1 in 5-Fu after loading, which are shifted to the lower stretching frequency because of the host−guest interactions and increase of bond length35 (Figure 4b). The peaks at 1725, 1654, and 1429 cm−1 are attributed to the ketoimide ring structure, enolic form, and C−N stretching vibrations in 5-Fu, respectively. Also, the stretching vibration of N−H as a broad band was observed at 3135 cm−1 14,37 (Figure 4c). The PXRD pattern of the synthesized cp.1 is totally in accordance with the simulated XRD pattern and confirmed that the crystalline integrity of the synthesized powder is similar to the synthesized single crystal (see Figure 5a,b). As shown in Figure 5c,d, loading of 5-Fu causes interspace between 1D chains and also decreases long-range order of its crystallinity, which led to shifting and weakening some of Miller indices, respectively. On the other hand, the powder X-ray reflections of 5-Fu-loaded cp.1 confirmed the successful loading process due to indexing a strong peak at about 27−28° 2θ. TGA of synthesized cp.1 was carried out to check the thermal stability of this novel coordination polymer (Figure S5). The curve shows three weight loss steps in which the first weight loss began at 24 °C and was completed at about 200 °C. This weight loss of 10.1% belonged to the surface and subsequently clathrated water molecules. The second and main weight loss of 33.2% was finished at 320 °C and might be attributed to the elimination of the organic part of the molecule, such as unbounded 1,3,5-H3BTC ligand (calcd: 34.9%). According to the curve, upon heating to 600 °C, twostep weight loss occurred, which could correspond to removing bonded 1,3,5-H3BTC molecules and continuous whole decomposition of the synthesized cp.1, which led to formation of unidentified product(s) above 320 °C. The result suggests that the synthesized coordination polymer structure is thermally stable and applicable as a drug vehicle.

Figure 6. 5-Fu release from cp.1 in 10% FBS at 37 °C.

Figure 7. Powder XRD patterns of FBS (a) and 5-Fu-loaded cp.1 after 72 h release process in 10% FBS at 37 °C (b).

MOF shell; 51%,47 Fe-MIL-53-NH2-FA-5-FAM; 23%48 and polymeric microspheres (5−20%).17 The drug loading (DL) and encapsulation efficiency (EE) accounts were calculated according to the well-known previously reported formulas in which DL was calculated as the percentage of entrapped drug to the total weight of dried particles and EE was accounted as the percentage of entrapped drug to the total amount of drug in feed.49 Characterization of Synthesized cp.1 and 5-FuLoaded cp.1. Colorless crystals of cp.1 with the regular rodlike morphology were synthesized in water via the facile hydrothermal method. We applied a laboratory sieve with mesh 500 (25 μm) to achieve a uniform particle size distribution, which was confirmed by FE-SEM images in Figure 3. ζ-Potential of the hydrothermally synthesized cp.1 was 0.341 ± 3.54 mV (Figure S4). This neutral value changed after 5-Fu loading to 8.10 ± 4.39 mV, which indicates that it is positively E


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Figure 8. MTT assays of 5-Fu, 5-Fu-loaded cp.1 as 5-Fu.cp.1, and cp.1 in 24, 48, and 72 h at the concentration range of 0 as control to 100 μg/mL against MCF-7 cells (a) and 4T1 cells (b). ★ indicates P < 0.001 for 5-Fu vs 5-Fu.cp.1 at the same concentrations and same incubation times. Cell viability (%) comparison of 5-Fu.cp.1 at different incubation times on MCF-7 cells (c) and 4T1 cells (d). The images of MCF-7 and 4T1 cells before and after treatment with 5-Fu.cp.1 (e) (asterisks show the statistical significance).

Table 1. IC50 (μg/mL) Values of 5-Fu as Free Drug and 5-Fu-Loaded cp.1 Against the Two Cell Lines MCF-7 and 4T1 IC50 (μg/mL) 5-Fu

5-Fu.cp.1

incubation times (h)

MCF-7

4T1

MCF-7

4T1

24 48 72

10.73 ± 2.21 1.54 ± 0.77 0.38 ± 2.45

0.40 ± 1.72 0.39 ± 1.23 0.96 ± 1.53

14.18 ± 3.21 6.72 ± 1.03 3.83 ± 2.59

4.99 ± 1.09 3.85 ± 2.01 1.54 ± 2.72

In Vitro 5-Fu Release Profile. The drug release experiment of 5-Fu-loaded cp.1 was carried out at 37 °C in 10% FBS as simulated human body fluid and was monitored via UV−vis spectroscopy, which was performed in FBS 10% as analysis medium at λmax = 296 nm (the calibration curve is displayed in Figure S6). As shown in Figure 6, the release rate has a great relationship with the position of 5-Fu molecules between the chains of cp.1 in which two kinds of interactions exist. The first

5-Fu release phase during initial 24 h (43.1%) belongs to the 5Fu−5-Fu intermolecular interactions, which are dominated between 5-Fu molecules that are away from the chain structure, and even to the considerably weak interactions between the 5Fu and cp.1. The other forces are the undeniable host−guest interactions, which are the hydrogen bonds and π−π stacking between 5-Fu molecules and cp.1.43 Therefore, the second phase of 5-Fu release during the latter 48 h can correspond to F


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Figure 9. Confocal images of MCF-7 cells after being incubated with cp.1 as blank (a), FITC-loaded cp.1 (b), and LysoTracker Red for lysosome detection (c). From the left side, BF is the bright-field images of the cells. Green, red, and blue panels are dedicated to the fluorescent images, which are filtered by the green, red, and blue filters in CLSM. Merge is the overlays of fluorescent images in each incubations. Scale bars: 100 μm.

As shown in Table 1, after 72 h, the inhibitory concentrations of 5-Fu-loaded cp.1 and free 5-Fu were calculated to be 3.83 ± 2.59, 0.38 ± 2.45 (MCF-7) and 1.54 ± 2.72, 0.96 ± 1.53 (4T1), respectively. These results demonstrate that the 5-Fu sustained release process against MCF-7 cells occurred in a dosedependent manner slightly more effectively than 4T1 cells. It may be due to the cell-associated particles, including the internalized and adhered ones, which can provide the additional opportunities for the synthesized carrier to achieve greater intracellular drug levels.56 According to the one-way ANOVA statistical analysis, three groups were compared to each other. It should be noted that the differences observed in control vs 5-Fu and control vs 5Fu.cp.1 groups were statistically significant (P < 0.001) at all concentrations and all incubation times. The statistically significant differences (P < 0.001) in 5-Fu vs 5-Fu.cp.1 groups are shown with asterisks in Figure 8. Cellular Uptake. The in vitro cellular uptake of cp.1 and FITC-loaded cp.1 in MCF-7 cells was studied by confocal imaging (Figure 9). Here the BF, green, red, blue, and merge panels represent the bright field, green filter to detect FITCstained cells, red filter to detect stained lysosomes, blue filters to detect DAPI-stained nuclei of cells, and overlays of fluorescent images, respectively. As shown in Figure 9a, the cellular uptake of cp.1 particles was examined and the images revealed that the synthesized particles have little emissions in green and red channels, which are saturated in overlaid image and detectable with yellow filter. The results with bright fluorescence in Figure 9b confirmed the presence of FITCloaded cp.1 particles in the MCF-7 cells, which proved the cellular uptake of 5-Fu-loaded cp.1 in MCF-7 cells. As it has been widely reported, the microparticle internalization into cells is dependent on the size, shape, and surface charge that

these mentioned interactions. Thus, with releasing 88.7% of the loaded drug, the 5-Fu release process was completed in 72 h and it was associated with collapsing of cp.1 crystalline structure, which is confirmed by PXRD pattern of cp.1. As observed in Figure 7a, the crystalline structure of 5-Fu-loaded cp.1 was totally ruined after 72 h and showed a noisy background in accordance with FBS PXRD pattern (Figure 7b). Noteworthy, the 5-Fu release profile was in good agreement with the other reported carriers.28,43,47,48,54,55 Cytotoxicity Assay. The cytotoxicity effect of synthesized cp.1 as the blank carrier, 5-Fu-loaded cp.1, and 5-Fu as the free drug was examined against two breast cancer cell lines namely MCF-7 and 4T1 by MTT assay. All three formulas were investigated at the 5-Fu concentration range of 0.01, 0.1, 0.5, 1, 10, 50, and 100 μg/mL, and the nontreated cells served as control. As depicted in Figure 8a,b, the synthesized cp.1 showed no cytotoxicity on both cell lines, which revealed that the synthesized coordination polymer could be a potent biocompatible carrier. As previously reported,33,34 the expression and activity of thymidylate synthase and dihydropyrimidine dehydrogenase as two main factors in the molecular signaling pathway of chemoresistance to 5-Fu restrict the 5-Fu efficiency against the tumor cells. Moreover, it was observed in our experiments that the free drug, 5-Fu, exhibited a notable drug resistance against both cell lines at 10 μg/mL, which is limiting the treatment process at all times, including 24, 48, and 72 h, whereas 5-Fu-loaded cp.1 had a consistent 5-Fu release and consequently showed effective cytotoxicity on both MCF-7 and 4T1 cells with increasing concentration during the treatment time. The IC50 of free 5-Fu and 5-Fu-loaded cp.1 against both MCF-7 and 4T1 cell lines was measured by the SigmaPlot software at all examined incubation times of 24, 48, and 72 h. G


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Figure 10. (a) Effect of intratumoral application of 5-Fu-loaded cp.1 (red) and 5-Fu (blue) on the growth of mammary adenocarcinoma 4T1 transplanted subcutaneously into BALB/c mouse mammary glands. 5-Fu-loaded cp.1 and 5-Fu were injected with a dose of 11 mg/kg once on day 0 (10 days after tumor transplantation). ″Black diamond minus white X″ indicates P < 0.05 significant differences between each treatment and control. ″Double black diamond minus white X″ indicates P < 0.05 significant differences between 5-Fu-loaded cp.1 and 5-Fu treatments on a particular day. Each experimental group consisted of five animals. (b) Photographs of stripped tumor tissues and (c) female BALB/c mice bearing breast cancer.

because of the chosen low dose in the experiment.41 On day 28, the mice were sacrificed and the mean tumor volumes were measured as 2463.35 for 5-Fu group and 1900.11 for 5-Fu.cp.1 group. One-way ANOVA statistical analysis revealed that the tumor sizes in the 5-Fu.cp.1 group were significantly smaller (P < 0.05) than those in the 5-Fu group. Histopathological Study. Tumor sections from different treatment groups were graded histologically using the Nottingham histologic grading system. The results are shown in Figure 11. Many disproportionate tumor cells (anisocytosis), nuclear polymorphism (anisokaryosis, +3), and prominent nucleoli were seen in untreated animals (control). Glandular (acinar/tubular) differentiation (GF) is low (+3), and the mitotic index in 10 HPF (400×) is +3. Overall, the tumors in these groups were considered as grade 3 (poorly differentiated). In free drug (5-Fu) group, mitotic index was lower than that of the control group (+2). In this group, the GF was low (+2) and nuclear polymorphism and the anisocytosis were decreased in comparison with the control group (+2). Moreover, some apoptotic tumor cells and necrosis (asterisks) were seen in this group. Grade 2 (moderately differentiated) was considered for the tumor sections in free drug group. In the group treated with

positively charged microparticles are preferentially taken up by cells.57−59 Therefore, the positive surface charge of synthesized cp.1s on one hand and its rodlike shape with high aspect ratio on the other can lead to the successful cellular uptake results.60,61 Moreover, to investigate the destination of internalized cp.1s, LysoTracker Red probes were applied to detect lysosomes. The colocalization of cp.1s with lysosomes was observed in Figure 9c. The images confirmed the efficient cellular uptake of cp.1s through endocytosis mechanism. In Vivo Antitumor Activity of 5-Fu-Loaded cp.1s. The in vivo antitumor efficacy of the 5-Fu-loaded cp.1 particles was evaluated on the 4T1 female BALB/c tumor model.62 In our study, intratumoral (it) injections of 5-Fu as free drug and 5Fu-loaded cp.1s were chosen as the locoregional treatment. The treatment was performed on day 0 in a single dose (11 mg/kg), and the tumor size was followed every 3 days during the 28 days. The untreated group was set as control. As displayed in Figure 10, the speed of tumor growth was in the same manner during 9 days after treatment in both 5-Fu and 5Fu.cp.1 groups. During the next 20 days, the tumor growth in 5-Fu.cp.1 group slowed down because of the sustained release of 5-Fu from cp.1 compared to the 5-Fu group, which may be H


Research Article


Figure 11. Histopathology of breast cancer in different groups. Thick arrows: mitotic figures; asterisks (*): necrosis area; thin arrows: infiltration of inflammatory cells. H&E stain.

affirmed the effective antitumoral activity of 5-Fu-loaded cp.1, which was intratumorally administrated in 4T1 tumor BALB/c mouse model. Thus, this study introduced a novel anticancer drug delivery vehicle for locoregional breast cancer chemotherapy and its possibility for further clinical application.

5-Fu-loaded cp.1 (named as particle drug), nuclear polymorphism (+1), GF (+2), and the mitotic index in 10 HPF (+1) of tumor tissue sections were decreased in comparison to the other groups. Furthermore, massive necrosis of breast cancer cells was seen in these groups. The histopathological findings and scoring system showed a considerable difference between particle drug-treated animals and the other groups. Several inflammatory cells had also infiltrated into necrotic areas. The tumor in this group was considered as grade 1 breast cancer (well differentiated).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.8b03111.

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CONCLUSIONS Herein, we synthesized a novel 1D coordination polymer, cp.1, by one-pot hydrothermal method. The synthesized cp.1 was applied as a biocompatible microcarrier for anticancer drug delivery purposes. Therefore, we used 5-Fu, a small and widely used anticancer agent against breast cancer. Interestingly, we achieved 66% drug loading with 98% encapsulation efficiency, which may be due to the effective interactions, such as π−π stacking and H-bonding between 5-Fu molecule and cp.1. The release process was carried out in 10% FBS as a simulated body fluid, and the cp.1 showed an almost complete release profile associated with collapsing the network. In vitro cytotoxicity effects of the synthesized cp.1, 5-Fu, and 5-Fu-loaded cp.1 were examined against human and mouse breast cancer cell lines MCF-7 and 4T1. The results indicated that the synthesized cp.1 had no significant cytotoxic effect on either of the cell lines. Also, the 5-Fu-loaded cp.1 showed a time-dependent 5Fu release, which is confirmed by the effectiveness of 5-Fuloaded cp.1 against cancer cells. CLSM images revealed that the synthesized cp.1 had a significant cellular uptake. In vivo study

View of the asymmetric unit, noncovalent interactions of cp.1, UV−visible spectra, ζ-potentials, TGA profile (PDF) Crystallographic data (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: +98-21-61113644. Fax: +9821-66495291. ORCID

Alireza Abbasi: 0000-0002-0331-0202 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The financial support from University of Tehran and Tehran University of Medical Sciences is gratefully appreciated. I


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(18) Salonen, J.; Laitinen, L.; Kaukonen, A. M.; Tuura, J.; Björkqvist, M.; Heikkilä, T.; Vähä-Heikkilä, K.; Hirvonen, J.; Lehto, V. P. Mesoporous Silicon Microparticles for Oral Drug Delivery: Loading and Release of Five Model Drugs. J. Controlled Release 2005, 108, 362−374. (19) Zhao, J.; Yang, Y.; Han, X.; Liang, C.; Liu, J.; Song, X.; Ge, Z.; Liu, Z. Redox-Sensitive Nanoscale Coordination Polymers for Drug Delivery and Cancer Theranostics. ACS Appl. Mater. Interfaces 2017, 9, 23555−23563. (20) Lian, H. Y.; Hu, M.; Liu, C. H.; Yamauchi, Y.; Wu, K. C. W. Highly Biocompatible, Hollow Coordination Polymer Nanoparticles as Cisplatin Carriers for Efficient Intracellular Drug Delivery. Chem. Commun. 2012, 48, 5151−5153. (21) Imaz, I.; Rubio-Martínez, M.; García-Fernández, L.; García, F.; Ruiz-Molina, D.; Hernando, J.; Puntes, V.; Maspoch, D. Coordination Polymer Particles as Potential Drug Delivery Systems. Chem. Commun. 2010, 46, 4737−4739. (22) Wang, H. N.; Meng, X.; Yang, G. S.; Wang, X. L.; Shao, K. Z.; Su, Z. M.; Wang, C. G. Stepwise Assembly of Metal-Organic Framework Based on a Metal-Organic Polyhedron Precursor for Drug Delivery. Chem. Commun. 2011, 47, 7128−7130. (23) Cao, L. H.; Li, H. Y.; Xu, H.; Wei, Y. L.; Zang, S. Q. Diverse Dissolution-Recrystallization Structural Transformations and Sequential Förster Resonance Energy Transfer Behavior of a Luminescent Porous Cd-MOF. Dalton Trans. 2017, 46, 11656−11663. (24) Ma, M. L.; Qin, J. H.; Ji, C.; Xu, H.; Wang, R.; Li, B. J.; Zang, S. Q.; Hou, H. W.; Batten, S. R. Anionic Porous Metal-Organic Framework with Novel 5-Connected vbk Topology for Rapid Adsorption of Dyes and Tunable White Light Emission. J. Mater. Chem. C 2014, 2, 1085−1093. (25) Mallick, A.; Garai, B.; Díaz, D. D.; Banerjee, R. Hydrolytic Conversion of a Metal-Organic Polyhedron into a Metal-Organic Framework. Angew. Chem., Int. Ed. 2013, 125, 14000−14004. (26) Ma, Z.; Moulton, B. Recent Advances of Discrete Coordination Complexes and Coordination Polymers in Drug Delivery. Coord. Chem. Rev. 2011, 255, 1623−1641. (27) Xing, L.; Zheng, H.; Cao, Y.; Che, S. Coordination Polymer Coated Mesoporous Silica Nanoparticles for pH-Responsive Drug Release. Adv. Mater. 2012, 24, 6433−6437. (28) Lakkakula, J. R.; Matshaya, T.; Krause, R. W. M. Cationic Cyclodextrin/Alginate Chitosan Nanoflowers as 5-Fluorouracil Drug Delivery System. Mater. Sci. Eng., C 2017, 70, 169−177. (29) Ekberg, H.; Tranberg, K. G.; Persson, B.; Jeppsson, B.; Nilsson, L. G.; Gustafson, T.; Andersson, K. E.; Bengmark, S. Intraperitoneal Infusion of 5-FU in Liver Metastases from Colorectal Cancer. J. Surg. Oncol. 1988, 37, 94−99. (30) Gamelin, E. C.; Danquechin-Dorval, E. M.; Dumesnil, Y. F.; Maillart, P. J.; Goudier, M. J.; Burtin, P. C.; Delva, R. G.; Lortholary, A. H.; Gesta, P. H.; Larra, F. G. Relationship between 5-Fluorouracil (5FU) Dose Intensity and Therapeutic Response in Patients with Advanced Colorectal Cancer Receiving Infusional Therapy Containing 5-FU. Cancer 1996, 77, 441−451. (31) Taylor, S. G.; Murthy, A. K.; Griem, K. L.; Recine, D. C.; Kiel, K.; Blendowski, C.; Hurst, P. B.; Showel, J. T.; Hutchinson, J. C.; Campanella, R. S. Concomitant Cisplatin/5-FU Infusion and Radiotherapy in Advanced Head and Neck Cancer: 8-Year Analysis of Results. Head Neck Oncol. 1997, 19, 684−691. (32) Longley, D. B.; Harkin, D. P.; Johnston, P. G. 5-Fluorouracil: Mechanisms of Action and Clinical Strategies. Nat. Rev. Cancer 2003, 3, 330−338. (33) Li, X.; Kong, X.; Kong, X.; Wang, Y.; Yan, S.; Yang, Q. 53BP1 Sensitizes Breast Cancer Cells to 5-Fluorouracil. PLoS One 2013, 8, No. e74928. (34) Arias, J. L. Novel Strategies to Improve the Anticancer Action of 5-Fluorouracil by Using Drug Delivery Systems. Molecules 2008, 13, 2340−2369. (35) Ha, W.; Yu, J.; Song, X.; Chen, J.; Shi, Y. Tunable TemperatureResponsive Supramolecular Hydrogels Formed by Prodrugs as a Codelivery System. ACS Appl. Mater. Interfaces 2014, 6, 10623−10630.

ABBREVIATIONS cp.1, coordination polymer 1; 5-Fu, 5-fluorouracil; MTT, 3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; 1,3,5-H3BTC, 1,3,5-benzenetricarboxylic acid; FBS, fetal bovine serum

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REFERENCES

(1) Bailar, J. C., Jr. Coordination Polymers. In Preparative Inorganic Reactions; Interscience Publishers, 1964; Vol. 1, pp 1−27. (2) Kitagawa, S.; Kitaura, R.; Noro, S. I. Functional Porous Coordination Polymers. Angew. Chem., Int. Ed. 2004, 43, 2334−2375. (3) Huang, X.; Yao, H.; Cui, Y.; Hao, W.; Zhu, J.; Xu, W.; Zhu, D. Conductive Copper Benzenehexathiol Coordination Polymer as a Hydrogen Evolution Catalyst. ACS Appl. Mater. Interfaces 2017, 9, 40752−40759. (4) Wang, F.; Kusaka, S.; Hijikata, Y.; Hosono, N.; Kitagawa, S. Development of a Porous Coordination Polymer with a High Gas Capacity Using a Thiophene-Based Bent Tetracarboxylate Ligand. ACS Appl. Mater. Interfaces 2017, 9, 33455−33460. (5) Li, P.; Liu, W.; Dennis, J. S.; Zeng, H. C. Synthetic Architecture of MgO/C Nanocomposite from Hierarchical-Structured Coordination Polymer toward Enhanced CO2 Capture. ACS Appl. Mater. Interfaces 2017, 9, 9592−9602. (6) Tan, H.; Liu, B.; Chen, Y. Lanthanide Coordination Polymer Nanoparticles for Sensing of Mercury (II) by Photoinduced Electron Transfer. ACS Nano 2012, 6, 10505−10511. (7) Rieter, W. J.; Pott, K. M.; Taylor, K. M. L.; Lin, W. Nanoscale Coordination Polymers for Platinum-Based Anticancer Drug Delivery. J. Am. Chem. Soc. 2008, 130, 11584−11585. (8) Nam, J.; La, W. G.; Hwang, S.; Ha, Y. S.; Park, N.; Won, N.; Jung, S.; Bhang, S. H.; Ma, Y. J.; Cho, Y. M.; et al. pH-Responsive Assembly of Gold Nanoparticles and “Spatiotemporally Concerted” Drug Release for Synergistic Cancer Therapy. ACS Nano 2013, 7, 3388− 3402. (9) Wu, K. C. W.; Yamauchi, Y.; Hong, C. Y.; Yang, Y. H.; Liang, Y. H.; Funatsu, T.; Tsunoda, M. Biocompatible, Surface Functionalized Mesoporous Titania Nanoparticles for Intracellular Imaging and Anticancer Drug Delivery. Chem. Commun. 2011, 47, 5232−5234. (10) Saravanakumar, G.; Lee, J.; Kim, J.; Kim, W. J. Visible LightInduced Singlet Oxygen-Mediated Intracellular Disassembly of Polymeric Micelles co-Loaded with a Photosensitizer and an Anticancer Drug for Enhanced Photodynamic Therapy. Chem. Commun. 2015, 51, 9995−9998. (11) Paris, J. L.; Cabañas, M. V.; Manzano, M.; Vallet-Regí, M. Polymer-Grafted Mesoporous Silica Nanoparticles as UltrasoundResponsive Drug Carriers. ACS Nano 2015, 9, 11023−11033. (12) Wu, K. C. W.; Yamauchi, Y. Controlling Physical Features of Mesoporous Silica Nanoparticles (MSNs) for Emerging Applications. J. Mater. Chem. 2012, 22, 1251−1256. (13) Arora, S.; Saharan, R.; Kaur, H.; Kaur, I.; Bubber, P.; Bharadwaj, L. M. Attachment of Docetaxel to Multiwalled Carbon Nanotubes for Drug Delivery Applications. Adv. Sci. Lett. 2012, 5, 1−6. (14) Wang, J.; Liu, C.; Shuai, Y.; Cui, X.; Nie, L. Controlled Release of Anticancer Drug Using Graphene Oxide as a Drug-Binding Effector in Konjac Glucomannan/Sodium Alginate Hydrogels. Colloids Surf., B 2014, 113, 223−229. (15) Ferrati, S.; Shamsudeen, S.; Summers, H. D.; Rees, P.; Abbey, J. V. A.; Schmulen, J.; Liu, X.; Wong, S. T. C.; Bean, A. J.; Ferrari, M.; Serda, R. E. Inter-endothelial Transport of Microvectors using Cellular Shuttles and Tunneling Nanotubes. Small 2012, 8, 3151−3160. (16) Palankar, R.; Skirtach, A. G.; Kreft, O.; Bédard, M.; Garstka, M.; Gould, K.; Möhwald, H.; Sukhorukov, G. B.; Winterhalter, M.; Springer, S. Controlled Intracellular Release of Peptides from Microcapsules Enhances Antigen Presentation on MHC Class I Molecules. Small 2009, 5, 2168−2176. (17) Floyd, J. A.; Galperin, A.; Ratner, B. D. Drug Encapsulated Polymeric Microspheres for Intracranial Tumor Therapy: a Review of the Literature. Adv. Drug Delivery Rev. 2015, 91, 23−37. J


Research Article

ACS Applied Materials & Interfaces (36) Yang, Q.; Yang, Y.; Li, L.; Sun, W.; Zhu, X.; Huang, Y. Polymeric Nanomedicine for Tumor-Targeted Combination Therapy to Elicit Synergistic Genotoxicity against Prostate Cancer. ACS Appl. Mater. Interfaces 2015, 7, 6661−6673. (37) Yu, S.; Gao, X.; Baigude, H.; Hai, X.; Zhang, R.; Gao, X.; Shen, B.; Li, Z.; Tan, Z.; Su, H. Inorganic Nanovehicle for Potential Targeted Drug Delivery to Tumor Cells, Tumor Optical Imaging. ACS Appl. Mater. Interfaces 2015, 7, 5089−5096. (38) Shen, B.; Ma, Y.; Yu, S.; Ji, C. Smart Multifunctional Magnetic Nanoparticle-Based Drug Delivery System for Cancer ThermoChemotherapy and Intracellular Imaging. ACS Appl. Mater. Interfaces 2016, 8, 24502−24508. (39) Najafi, M.; Abbasi, A.; Masteri-Farahani, M.; Janczak, J. Two Novel Octamolybdate Nanoclusters as Catalysts for Dye Degradation by Air under Room Conditions. Dalton Trans. 2015, 44, 6089−6097. (40) Ivankovic, S.; Stojkovic, R.; Galic, Z.; Galic, B.; Ostojic, J.; Marasovic, M.; Milos, M. In Vitro and In Vivo Antitumor Activity of the Halogenated Boroxine Dipotassium-Trioxohydroxytetrafluorotriborate (K2[B3O3F4OH]). J. Enzyme Inhib. Med. Chem. 2015, 30, 354− 359. (41) Wu, P.; Liu, Q.; Li, R.; Wang, J.; Zhen, X.; Yue, G.; Wang, H.; Cui, F.; Wu, F.; Yang, M.; et al. Facile Preparation of Paclitaxel Loaded Silk Fibroin Nanoparticles for Enhanced Antitumor Efficacy by Locoregional Drug Delivery. ACS Appl. Mater. Interfaces 2013, 5, 12638−12645. (42) Elston, C. W.; Ellis, I. O. Pathological Prognostic Factors in Breast Cancer. I. The Value of Histological Grade in Breast Cancer: Experience from a Large Study with Long-term Follow-up. Histopathology 1991, 19, 403−410. (43) Du, X.; Fan, R.; Qiang, L.; Xing, K.; Ye, H.; Ran, X.; Song, Y.; Wang, P.; Yang, Y. Controlled Zn2+-Triggered Drug Release by Preferred Coordination of Open Active Sites within Functionalization Indium Metal Organic Frameworks. ACS Appl. Mater. Interfaces 2017, 9, 28939−28948. (44) Li, Q. L.; Wang, J. P.; Liu, W. C.; Zhuang, X. Y.; Liu, J. Q.; Fan, G. L.; Li, B. H.; Lin, W. N.; Man, J. H. A New (4, 8)-Connected Topological MOF as Potential Drug Delivery. Inorg. Chem. Commun. 2015, 55, 8−10. (45) Ahmad, N.; Younus, H. A.; Chughtai, A. H.; Van Hecke, K.; Danish, M.; Gaoke, Z.; Verpoort, F. Development of Mixed Metal Metal-Organic Polyhedra Networks, Colloids, and MOFs and their Pharmacokinetic Applications. Sci. Rep. 2017, 7, No. 832. (46) Fu, G. D.; Xu, L. Q.; Yao, F.; Li, G. L.; Kang, E. T. Smart Nanofibers with a Photoresponsive Surface for Controlled Release. ACS Appl. Mater. Interfaces 2009, 1, 2424−2427. (47) Gao, X.; Hai, X.; Baigude, H.; Guan, W.; Liu, Z. Fabrication of Functional Hollow Microspheres Constructed from MOF Shells: Promising Drug Delivery Systems with High Loading Capacity and Targeted Transport. Sci. Rep. 2016, 6, No. 37705. (48) Gao, X.; Zhai, M.; Guan, W.; Liu, J.; Liu, Z.; Damirin, A. Controllable Synthesis of a Smart Multifunctional Nanoscale MetalOrganic Framework for Magnetic Resonance/Optical Imaging and Targeted Drug Delivery. ACS Appl. Mater. Interfaces 2017, 9, 3455− 3462. (49) Shen, S.; Wu, Y.; Li, K.; Wang, Y.; Wu, J.; Zeng, Y.; Wu, D. Versatile Hyaluronic Acid Modified AQ4N-Cu (II)-Gossypol Infinite Coordination Polymer Nanoparticles: Multiple Tumor Targeting, Highly Efficient Synergistic Chemotherapy, and Real-Time SelfMonitoring. Biomaterials 2018, 154, 197−212. (50) Zhao, H. Q.; Qiu, G. H.; Liang, Z.; Li, M. M.; Sun, B.; Qin, L.; Yang, S. P.; Chen, W. H.; Chen, J. X. A Zinc (II)-Based TwoDimensional MOF for Sensitive and Selective Sensing of HIV-1 dsDNA Sequences. Anal. Chim. Acta 2016, 922, 55−63. (51) Ding, Y.; Shen, S. Z.; Sun, H.; Sun, K.; Liu, F.; Qi, Y.; Yan, J. Design and Construction of Polymerized-Chitosan Coated Fe3O4 Magnetic Nanoparticles and its Application for Hydrophobic Drug Delivery. Mater. Sci. Eng., C 2015, 48, 487−498. (52) Sahu, P.; Kashaw, S. K.; Jain, S.; Sau, S.; Iyer, A. K. Assessment of Penetration Potential of pH Responsive Double Walled

Biodegradable Nanogels Coated with Eucalyptus Oil for the Controlled Delivery of 5-Fluorouracil: In Vitro and Ex Vivo Studies. J. Controlled Release 2017, 253, 122−136. (53) Rezaei, M.; Abbasi, A.; Varshochian, R.; Dinarvand, R.; JeddiTehrani, M. NanoMIL-100 (Fe) Containing Docetaxel for Breast Cancer Therapy. Artif. Cells, Nanomed., Biotechnol. 2017, 1−12. (54) Liu, S.; Zhang, J.; Cui, X.; Guo, Y.; Zhang, X.; Hongyan, W. Synthesis of Chitosan-Based Nanohydrogels for Loading and Release of 5-Fluorouracil. Colloids Surf., A 2016, 490, 91−97. (55) El-Hammadi, M. M.; Delgado, Á . V.; Melguizo, C.; Prados, J. C.; Arias, J. L. Folic Acid-Decorated and PEGylated PLGA Nanoparticles for Improving the Antitumour Activity of 5-Fluorouracil. Int. J. Pharm. 2017, 516, 61−70. (56) Li, S.; Wang, K.; Shi, Y.; Cui, Y.; Chen, B.; He, B.; Dai, W.; Zhang, H.; Wang, X.; Zhong, C.; et al. Novel Biological Functions of ZIF-NP as a Delivery Vehicle: High Pulmonary Accumulation, Favorable Biocompatibility, and Improved Therapeutic Outcome. Adv. Funct. Mater. 2016, 26, 2715−2727. (57) Patiño, T.; Soriano, J.; Barrios, L.; Ibáñez, E.; Nogués, C. Surface Modification of Microparticles Causes Differential Uptake Responses in Normal and Tumoral Human Breast Epithelial Cells. Sci. Rep. 2015, 5, No. 11371. (58) Fröhlich, E. The Role of Surface Charge in Cellular Uptake and Cytotoxicity of Medical Nanoparticles. Int. J. Nanomed. 2012, 7, 5577−5591. (59) Qiu, Y.; Liu, Y.; Wang, L.; Xu, L.; Bai, R.; Ji, Y.; Wu, X.; Zhao, Y.; Li, Y.; Chen, C. Surface Chemistry and Aspect Ratio Mediated Cellular Uptake of Au Nanorods. Biomaterials 2010, 31, 7606−7619. (60) He, Y.; Park, K. Effects of the Microparticle Shape on Cellular Uptake. Mol. Pharmaceutics 2016, 13, 2164−2171. (61) Zhang, X.; Dong, Y.; Zeng, X.; Liang, X.; Li, X.; Tao, W.; Chen, H.; Jiang, Y.; Mei, L.; Feng, S. S. The Effect of Autophagy Inhibitors on Drug Delivery Using Biodegradable Polymer Nanoparticles in Cancer Treatment. Biomaterials 2014, 35, 1932−1943. (62) Wang, Q.; Du, X.; Zhou, B.; Li, J.; Lu, W.; Chen, Q.; Gao, J. Mitochondrial Dysfunction is Responsible for Fatty Acid Synthase Inhibition-Induced Apoptosis in Breast Cancer Cells by PdpaMn. Biomed. Pharmacother. 2017, 96, 396−403.

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Design and Synthesis of a Biocompatible 1D Coordination Polymer as

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