Investigation in loading 5-Fluorouracil ability of iron-organic frameworks - Hoai Phuong Nguyen Thi

Vietnam Journal of Science and Technology 56 (3B) (2018) 219-227 INVESTIGATION IN LOADING 5-FLUOROURACIL ABILITY OF IRON-ORGANIC FRAMEWORKS Hoai Phuong Nguyen Thi * , Duc Ha Ninh Institute of Chemistry and Materials, 17 Hoang Sam, Cau Giay, Ha Noi * Email: hoaiphuong1978@gmail.com Received: 16 July 2018; Accepted for publication: 7 September 2018 ABSTRACT Materials MIL-53(Fe), MIL-88(Fe) and MIL-100(Fe) have the ability to absorb many different compounds. In addition, the materials are small in size, highly bio-compatible, with no human toxicity. These materials were chosen to carry 5-fluorouracil (5-FU) for cancer treatment. Synthetic materials were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) and surface characteristics (BET). 5-FU loading and releasing ability of MIL- 53(Fe), MIL-88(Fe) and MIL-100(Fe) have been investigated by UV-Vis spectrophotometer. The results showed that the MIL-53(Fe), MIL-88(Fe), and MIL-100(Fe) are capable of carrying 5-FU with capacity exceeding 0.131 g/g, 0.28 g/g, 0.66 g/g respectively and mostly released after 10 days. The cancer cell toxicity and slow drug release ability of MIL(Fe)@5-FU were also tested by in-vitro method. Iron-organic frameworks are promising materials for cancer treatment. Keywords: MIL-53 (Fe), MIL-88 (Fe), MIL-100 (Fe), drug delivery, 5-FU, cancer treatment. 1. INTRODUCTION The 5-fluorouracil molecule (C4H3FN2O2) of molar mass 130.1 g is relatively small. Because it contains both hydrogen bond donors and acceptors (N-H and C=O groups) it has the ability to shape co-crystals or salts after combination with other molecules, that could enhance the biological properties. 5-Fluorouracil (5-FU) is a chemotherapeutic agent employed in the treatment of several solid, such as breast, colorectal, and head and neck cancers. It has a broad spectrum of activity against various types of cancer and has a mode of action based on interfering with thymidylate synthesis. This leads to apoptosis in cancerous cells. The main challenge of using 5-FU is its short biological half-life, low selectivity and toxic side effects on the bone marrow and gastrointestinal tract [1]. In order to reduce these limitations, drug delivery systems have been considered for the controlled release of 5-FU drug to target site [2, 3]. Literature precedent shows that mesoporous silica nanoparticles [4], nano-gels [5], chitosan nanoparticles [6], cationic cyclo-dextrin/alginate chitosan nano-flowers [7], magnetic nanoparticles [8], metal-organic frameworks (MOFs) (transition metal except iron) [9, 10] have been used as potential systems for 5-FU drug delivery. Recently, MOFs has become a hotspot in the field of material science and undergone a rapid development because of the multifunctional nature [11-19]. New ordered porous MOFs Hoai Phuong Nguyen Thi, Duc Ha Ninh 220 exhibit a series of advantages like large surface area, tunable structure and composition, adequate biocompatibility and natural biodegradability. A family of biodegradable MOFs, based on Fe(III) clusters and polycarboxylate ligands, has been synthesized [20, 21] and recently transposed under the nanoscale regime following “green” technology [22−24]. Such materials proved to act as efficient “molecular sponges”, rapidly soaking important amounts of hydrophilic and hydrophobic drugs directly from aqueous solutions [25]. Iron-organic frameworks - MIL(Fe) have been studied for its application in catalysis, environmental treatment, drug delivery, gas storage, etc. [26-29] In its application as a drug carrier, MIL(Fe) have been studied for the application of ibuprofen, acetaminophen [30, 31]. We have synthesized MIL-100(Fe), MIL-101(Fe) for gas (NOx, CO) and volatile organic compound adsorption. In this study, we present results of MIL(Fe) synthesis and applicability in drug delivery for 5-FU by evaluation of loading-release and toxicity of the drug carrier system. 2. EXPERIMENTAL SECTION 2.1. Chemicals Chemicals which were provided by Sigma-Aldrich: Terephtalic acid (C6H4(COOH)2), ≥ 99 %; trimesic acid (C6H3(COOH)3), ≥ 95 %; Iron (III) chloride hexahydrate (FeCl3.6H2O), ≥ 99 %; Dimethyl-formamide (DMF), HCON(CH3)2, ≥ 99.5 %; Ethanol (C2H5OH), 96 %; pure 5- fluorouracil (5-FU); phosphate buffered saline (PBS); Trichloroacetic acid (TCA); Sulforhodamine B (SRB). 2.2. Materials synthesis The synthesis process is referred from our previous studies with the highest efficiency conditions: - MIL-53(Fe) nanoparticles were synthesized at room temperature by ultrasonic method. 0.83 g of terephthalic acid (H2BDC) and 1.35 g of FeCl3.6H2O were dissolved in 25 ml of DMF in a glass beaker. It was sealed and placed in an ultrasonic tank with a frequency of 20 kHz and capacity of 100 W in 7 hours. - MIL-88(Fe) nanoparticles were synthesized at room temperature by ultrasonic method. 0.270 g FeCl3.6H2O is dissolved with distill water and add 0.166 g H2BDC in 5 ml DMF for 15 mins in ultrasonic machine with a frequency of 20 kHz and capacity of 400 W. - MIL-100(Fe) nanoparticles were synthesized at room temperature by sol-gel process. FeCl3.6H2O is dissolved with distill water and added slowly trimesic acid (H3BTC) 5.10 -3 M for 1 hour under magnetic stirring. - After the reaction, the product was repeatedly washed with double-distilled water and ethanol. The material was dried at 80 o C in 8 hours. 2.3. Characterization XRD patterns of materials were determined by the PXRD instrument (X’Pert Pro) using Cu-K radiation in a range of 5 to 40 o at the Institute of Chemistry and Materials, Academy of Military Science and Technology. Morphologies of the materials were investigated by scanning electron microscopy (SEM) with different magnification at Institute of Materials Science, The role of counter anions in anticorrosive properties of silica-polypyrrole composite 221 Vietnam Academy of Science and Technology. BET surface areas, pore size distribution, and pore volume were measured by nitrogen adsorption/desorption iso-therms, at 393 K on a Quantachrome instrument at Institute of Chemistry, Vietnam Academy of Science and Technology. The 5-FU concentrations were analyzed by UV-Vis spectroscopy from 200 nm to 400 nm at the Institute of Chemistry and Materials, Academy of Military Science and Technology. 2.4. Drug loading and release - Drug loading experiment was carried out with 0.01 g material in 1 ml 5-FU 10 g/l for 72 hours. The product was filtered, dried at 80 o C in 3 hours. - 0.01 g of loaded material was immersed in 20 ml DMF for 24 hours at room temperature. The drug-released MIL(Fe) was gotten out of mixture by centrifugation (15 min, 6000 round/min) and determined the drug concentration. The 5-FU concentration was determined by UV-Vis spectrometry at wavelength λmax = 265 nm. The equation of 5-FU calibration curve is defined as y = 20. (0.042x - 0.013) where y is the optical absorption Abs. The amount of drug loaded inside the material is calculated by the formula: Q = m5-FU/mMIL(Fe) (g/g). - The drug-loaded MIL(Fe) was placed in a vial and dipped in 5 mL of a dissolution medium (phosphate buffer solution - PBS), pH 7.4 at 37 o C. At predetermined time intervals, the dissolution medium was collected by centrifugation and determined the drug concentration. The 5-FU concentration was analyzed by UV-Vis spectroscopy. The efficiency of drug release from the material is calculated according to the following formula: Htime = 100×Q/Qmax (%) where: Qmax is the maximum load capacity of material. 2.5. In-vitro cytotoxic assay The cancer cell inhibition ability was evaluated by in-vitro cytotoxic assay designed by the National Cancer Institute, on breast carcinoma human cancer cell line - MCF7. The experiments were performed at Institute of Biotechnology, Vietnam Academy of Science and Technology. The goal of cytotoxicity assay is to screen, detect substances that inhibit the growth or destruction of cancer cells in in-vitro conditions, through determining cellular protein content after dyeing with sulforhodamine B by measuring optical density OD at 515-540 nm. MCF7 breast cancer cells were precultured in 96-well microplates (7000 cells per well) for 24 h and then incubated with 5-FU (20.0-0.8 μg/ml) for different times. 3. RESULTS AND DISCUSSION 3.1. Material characterization The chemical composition of the material was characterized by XRD technique showed in Figure 1. XRD pattern of the sample (Figure 1) can confirm that the crystal phase of the product is MIL(Fe) due to monoclinic symmetry [32]. Hoai Phuong Nguyen Thi, Duc Ha Ninh 222 Figure 1. The XRD pattern of the MIL(Fe) materials. Figure 2. The SEM images of the MIL-53(Fe), MIL-88(Fe), MIL-100(Fe) materials. The morphology of the synthesized materials was observed by SEM method and shown in Figure 2. The SEM images show that the morphology of the materials is different. These differences relate to the conditions of synthesis and crystallization of the product including the ratio of reagents, solvents, synthetic techniques. The synthesized MIL(Fe) crystals are small, complete, homogeneous and have diameters of 200 nm to 500 nm. This size makes the material easy to move in the human body, especially in blood vessels. The surface area and pore diameter are critical factors for drug adsorption and release in porous frameworks as drug delivery systems. The surface area of the materials measured by the N2 adsorption isotherm was shown in Table 1 below. The surface characteristics of the materials are different. The MIL-88(Fe) has the smallest surface area and pore diameter compared to the other two materials. Meanwhile, the surface area of MIL-100(Fe) material is much larger than MIL-53(Fe) and MIL-88(Fe). Table 1. Surface area, volume pore and diameter pore of the MIL(Fe) materials. Materials Surface area SBET (m 2 /g) Volume pore (cm 3 /g) Diameter pore (nm) MIL-53(Fe) 35.01 0.210 - 0.250 29.07 - 32.37 MIL-88(Fe) 17.42 0.032 - 0.034 8.05 - 9.00 MIL-100(Fe) 1,579.61 0.230 - 0.580 2.41 - 4.82 The role of counter anions in anticorrosive properties of silica-polypyrrole composite 223 The surface area of the materials are related to its morphological state. As can be seen, MIL-53 exists in the "inhaled" state, so the value of surface area is quite low, but when it is saturated, it is maximally dilated [33]. For the MIL-88, the shape exists in long form just like grain and flexible structure [34]. Meanwhile, the MIL-100 has unchanged structure under different conditions. The results were found that, MIL-100(Fe) had the highest surface area (BET) and best storage capacity out of three MIL(Fe) samples equivalent to ZIF and MOF(Zn) [35, 17]. These surface parameters are related to the ability to carry and release drugs. The higher the surface area, the higher the carrying capacity. However, the higher the pore size, the faster the drug is released. The ability to bring and release drugs (5-FU) of these materials is presented in the next section. 3.2. Drug loading - release ability evaluation By determining the 5-FU concentration in the DMF solution, the drug carrying capacity of MIL(Fe) materials was evaluated. The maximum load capacity of MIL-53(Fe), MIL-88(Fe) and MIL-100(Fe) corresponding to 0.131 g/g, 0.28 g/g and 0.66 g/g. This shows that the higher the surface area of the material, the higher the drug content in the material. However, this increase is not linear. Although the surface area of the MIL-100(Fe) is 90 times higher than the MIL- 88(Fe), and 45 times higher than the MIL-53(Fe), the drug loading of MIL-100(Fe) is 2 to 5 times more than that of the MIL- 88(Fe) and MIL-53(Fe). Part of this may be due to the fact that the MIL-53(Fe) and MIL-88(Fe) are present in the "inhaled" state, so the surface area of these two materials is low. When they are absorbents, they are in the "hatching" state, so they can carry more drugs. To determine the drug release ability, 0.01 g of the loaded material was soaked in 5 ml PBS solution at 37 o C in different times and 5-FU concentration was measured. The results of drug release capacity are shown in Table 2 below: Table 2. The results of 5-FU release of MIL(Fe) at different times. No. t, hours MIL-53(Fe) MIL-88(Fe) MIL-100(Fe) Ct, mg/l H, % Ct, mg/l H, % Ct, mg/l H, % 1 0.25 60.286 23.01 115.749 20.67 261.037 19.78 2 2 92.762 35.41 174.392 31.14 483.290 36.61 3 16 163.952 62.58 290.196 51.82 882.064 66.82 4 24 177.571 67.78 307.199 54.86 875.427 66.32 5 48 190.286 72.63 310.166 55.39 865.800 65.59 6 72 209.762 80.06 358.693 64.05 983.783 74.53 7 120 243.190 92.82 430.447 76.87 1,160.019 87.88 8 168 256.952 98.07 408.554 72.96 1,192.259 90.32 9 240 258.619 98.71 444.825 79.43 1,210.337 91.69 Drug release efficiencies of all three materials in the first 15 minutes were quite similar and reached about 20 %. However, the 5-FU release rate of the materials is different. To achieve more than 80 % efficiency, MIL-53(Fe) material takes only 3 days. Meanwhile, after 3 days Hoai Phuong Nguyen Thi, Duc Ha Ninh 224 MIL-100(Fe) only released 74.53 % drug content. And the drug release rate of MIL-88(Fe) only reached 79.43 % take up to 10 days. Other materials loading 5-FU had shorter release time, for example, NH2(CH3)2[Zn3(L)2·3.5DMF] loading 5-FU 0.22 g/g had released 92 % of the drug for only 120 hours [17]. 3.3. Activity of MIL-Fe@5-FU system on cancer cells The cytotoxicity of 5-FU in MCF7 cells was evaluated based on its effect on cell growth by using the cytotoxic assay. The cytotoxicity of 5-FU was dose-dependent, the maximum cell death seen at concentration of 20 μg/ml. The evaluated results of the suppression of cancer cell over time are presented in Table 2 below, with IC50 is concentration of drug at which 50 % of the target is inhibited: Table 3. IC50 of 5-FU and MIL(Fe)@5-FU system on MCF7 (µg/ml). Material Time, hours 5-FU MIL-53(Fe)@5-FU MIL-88(Fe)@5-FU MIL-100(Fe)@5-FU 24 3.38 0.32 8.97 1.01 16.27 2.41 13.72 2.53 48 3.09 0.48 6.72 0.45 9.64 1.52 9.41 1.63 72 2.48 0.17 5.25 0.73 7.09 0.68 6.09 0.97 96 2.38 0.19 3.77 0.11 6.48 0.57 5.87 0.67 120 1.65 0.18 3.75 0.40 5.18 0.61 4.68 0.51 The results of the cytotoxicity test show that the MCF7 cells inhibitory capacity of different systems is different. As time increases, the inhibitory capacity on the cancer cells of all materials increases. However, this increase from the material is different. This result is related to the slow release of drugs from the carrier materials. The slower the release of drugs, the lower the inhibitory capacity. In Ref. 36, the IC50 values of 5-FU@DsAgNCs on MCF7 cells was 1.5 μg/mL. This shows that the slow release of these carriers is limited. From the results in Table 3, MIL-100(Fe) has the best storage capacity. Meanwhile, MIL-53(Fe) release drugs out of the material faster. 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