药学学报, 2021, 56(6): 1712-1718
引用本文:
王勤, 王彩芬, 伍丽, 陈晓锦, 孙宏宇, 桂双英, 张继稳. 交联环糊精金属有机骨架负载甲氨蝶呤缓释微粒的制备及体内外评价[J]. 药学学报, 2021, 56(6): 1712-1718.
WANG Qin, WANG Cai-fen, WU Li, CHEN Xiao-jin, SUN Hong-yu, GUI Shuang-ying, ZHANG Ji-wen. Preparation and evaluation of methotrexate sustained-release particles using crosslinked cyclodextrin metal-organic frameworks[J]. Acta Pharmaceutica Sinica, 2021, 56(6): 1712-1718.

交联环糊精金属有机骨架负载甲氨蝶呤缓释微粒的制备及体内外评价
王勤1,2, 王彩芬2, 伍丽2, 陈晓锦1,2, 孙宏宇2, 桂双英1, 张继稳1,2*
1. 安徽中医药大学, 安徽 合肥 230012;
2. 中国科学院上海药物研究所, 上海 201210
摘要:
甲氨蝶呤(methotrexate,MTX)注射给药的半衰期短,毒副作用大。为了改善MTX注射给药的缺陷,本研究将MTX装载在交联环糊精金属有机骨架(crosslinked cyclodextrin metal-organic framework,COF)中,得到载药微粒MTX@COF,采用溶剂蒸发法将阳离子脂质材料(2,3-二油酰基-丙基)-三甲胺[(2,3-dioleyl-propyl)-trimethylamine,DOTAP]包裹在MTX@COF表面,MTX@COF@DOTAP的微粒形态没有显著改变,但具有不同的表面电荷特征。以水和磷酸盐缓冲液(pH 7.4)为释放介质考察缓释微粒的体外释放,并通过大鼠药代动力学评价其体内释放特征。体外释放结果显示,在水中MTX、MTX@COF和MTX@COF@DOTAP于6 h的累积释放量分别为92.70%、36.31%和18.19%;在磷酸盐缓冲液中MTX、MTX@COF和MTX@COF@DOTAP于4 h的累积释放量分别为90.82%、79.37%和58.30%,表明MTX@COF可显著延缓MTX的释放,经DOTAP修饰后的MTX@COF可进一步延缓MTX的释放。大鼠药代动力学研究结果显示,皮下注射MTX@COF@DOTAP组与MTX@COF组及MTX组相比,其平均滞留时间MRT(0-t和达峰时间Tmax明显延长,且MTX@COF@DOTAP组的药时曲线下面积[AUC(0-t]是MTX组的1.8倍。本研究制备的MTX@COF@DOTAP微粒经皮下注射给药具有一定的缓释效果,并提高了MTX的生物利用度,为MTX的新剂型开发提供一个新的思路。
关键词:    交联环糊精金属有机骨架      甲氨蝶呤      阳离子脂质材料      缓释制剂      体外释放      药代动力学     
Preparation and evaluation of methotrexate sustained-release particles using crosslinked cyclodextrin metal-organic frameworks
WANG Qin1,2, WANG Cai-fen2, WU Li2, CHEN Xiao-jin1,2, SUN Hong-yu2, GUI Shuang-ying1, ZHANG Ji-wen1,2*
1. Anhui University of Chinese Medicine, Hefei 230012, China;
2. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, China
Abstract:
Methotrexate (MTX) injection has a short half-life and significant toxic side effects. In order to overcome the demerits of MTX injection, MTX@COF was prepared for subcutaneous injection by loading MTX in crosslinked cyclodextrin metal-organic framework (COF) in this study. The cationic lipid material (2, 3-dioleoyl-propyl)-trimethylamine (DOTAP) was then coated on the MTX@COF surface by solvent evaporation. Different surface charge characteristics were observed in the coated MTX@COF@DOTAP with no significant change in particle morphology. The in vitro release behaviors of sustained-release particles were investigated in water and phosphate buffer (pH 7.4), and the in vivo release characteristics were evaluated for pharmacokinetics in rats. The in vitro release results showed that the cumulative release of MTX, MTX@COF and MTX@COF@DOTAP within 6 h was 92.70%, 36.31% and 18.19% in water, respectively; the cumulative release of MTX, MTX@COF and MTX@COF@DOTAP within 4 h was 90.82%, 79.37% and 58.30% in phosphate buffer, respectively; the results showed that MTX@COF can significantly delay the release of MTX, the modification to MTX@COF by DOTAP can further delay the release of MTX. Pharmacokinetic studies in rats showed that the mean retention time [MRT(0-t)] and the time to peak (Tmax) of the subcutaneous injection of MTX@COF@DOTAP group were significantly prolonged compared with the MTX@COF group and the MTX group. The area under the concentration-time curve [AUC(0-t)] of the MTX@COF@DOTAP subcutaneous injection group was 1.8 times high as that of the MTX group. In this study, MTX@COF@DOTAP particles had a certain sustained-release effect, and could prolong the bioavailability of MTX by subcutaneous injection, which provided a new idea for the development of new MTX dosage forms.
Key words:    crosslinked cyclodextrin metal-organic framework    methotrexate    cationic lipid material    sustained-release preparation    release in vitro    pharmacokinetics   
收稿日期: 2021-02-06
DOI: 10.16438/j.0513-4870.2021-0216
基金项目: 国家自然科学基金资助项目(81773645,81803441);“重大新药创制”科技重大专项“新辅料关键技术研究及产业化生产”(2018zx09721002-009).
通讯作者: 张继稳,Tel/Fax:86-21-20231980,E-mail:jwzhang@simm.ac.cn
Email: jwzhang@simm.ac.cn
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参考文献:
[1] Alsdorf W, Karagiannis P, Langebrake C, et al. Standardized supportive care documentation improves safety of high‐dose methotrexate treatment[J]. Oncologist, 2020, 26: e327-e332.
[2] Guo ZR. Chemical synthesis driven development of pemetrexed[J]. Acta Pharm Sin (药学学报), 2020, 55: 2486-2490.
[3] Boyce J, Tawagi K, Cole J. Primary colon adenocarcinoma with choriocarcinoma differentiation: a case report and review of the literature[J]. J Med Case Rep, 2020, 14: 220.
[4] Barei M, Jei I, Simeti L, et al. Rituximab as a treatment option in a patient with rheumatoid arthritis and a history of malignancy-intracranial chondrosarcoma/osteochondroma-case based review[J]. Rheumatol Int, 2020, 41: 463-468.
[5] Xing E, Du Y, Yin J, et al. Multi-functional nanodrug based on a three-dimensional framework for targeted photo-chemo synergetic cancer therapy[J]. Adv Healthc Mater, 2021, 10: e2001874.
[6] Li J, Chen D, Zhang T, et al. Highly sensitive electrochemical determination of methotrexate based on a N-doped hollow nanocarbon sphere modified electrode[J]. Anal Methods, 2021, 13: 117-123.
[7] Paroha S, Verma J, Dubey R, et al. Recent advances and prospects in gemcitabine drug delivery systems[J]. Int J Pharm, 2021, 592: 120043.
[8] Zhao XF. Synthesis of pH-Sensitive Nanocomposite and Its Application in Drug Delivery (pH敏感的纳米复合材料合成及其在药物递送中的应用)[D]. Nanjing: Nanjing Normal University, 2019.
[9] Liu XX, Gao L, Xia LY, et al. Methotrexate sustained-release implants for delay of sarcoma recurrence in mice[J]. Chin New Drug J (中国新药杂志), 2017, 26: 2846-2852.
[10] Modu LR, Chen H, Li XM, et al. Preparation and the in vitro and in vivo release of PLGA microspheres containing methotrexate for intra-articular injection[J]. Chin New Drug J (中国新药杂志), 2007, 16: 1187-1191.
[11] Madhwi,Kumar R, Kumar P, et al. In vivo pharmacokinetic studies and intracellular delivery of methotrexate by means of glycine-tethered PLGA-based polymeric micelles[J]. Int J Pharm, 2017, 519: 138-144.
[12] He Y, Hou X, Liu Y, et al. Recent progress in the synthesis, structural diversity and emerging applications of cyclodextrin-based metal-organic frameworks[J]. J Mater Chem B, 2019, 7: 5602-5619.
[13] Zhang W, Guo T, Wang C, et al. MOF capacitates cyclodextrin to mega-load mode for high-efficient delivery of valsartan[J]. Pharm Res, 2019, 36: 117.
[14] He Y, Zhang W, Guo T, et al. Drug nanoclusters formed in confined nano-cages of CD-MOF: dramatic enhancement of solubility and bioavailability of azilsartan[J]. Acta Pharm Sin B, 2019, 9: 97-106.
[15] Hu X, Wang C, Wang L, et al. Nanoporous CD-MOF particles with uniform and inhalable size for pulmonary delivery of budesonide[J]. Int J Pharm, 2019, 564: 153-161.
[16] Li H, Zhu J, Wang C, et al. Paeonol loaded cyclodextrin metal-organic framework particles for treatment of acute lung injury via inhalation[J]. Int J Pharm, 2020, 587: 119649.
[17] Zhao K, Guo T, Wang C, et al. Glycoside scutellarin enhanced CD-MOF anchoring for laryngeal delivery[J]. Acta Pharm Sin B, 2020, 10: 1709-1718.
[18] Singh V, Guo T, Wu L, et al. Template-directed synthesis of a cubic cyclodextrin polymer with aligned channels and enhanced drug payload[J]. RSC Adv, 2017, 7: 20789-20794.
[19] He Y, Xiong T, He S, et al. Pulmonary targeting crosslinked cyclodextrin metal-organic frameworks for lung cancer therapy[J]. Adv Funct Mater, 2020, 31: 2004550.
[20] Pawar V, Manjappa A, Murumkar P, et al. Drug-fortified liposomes as carriers for sustained release of NSAIDs: the concept and its validation in the animal model for the treatment of arthritis[J]. Eur J Pharm Sci, 2018, 125: 11-22.
[21] San Roman B, Gomez S, Irache JM, et al. Co-encapsulated CpG oligodeoxynucleotides and ovalbumin in PLGA microparticles; an in vitro and in vivo study[J]. J Pharm Pharm Sci, 2014, 17: 541-553.
[22] Ye L, Ye J, Lu J, et al. Co-loaded docetaxel and verapamil liposomes to reverse tumor drug resistance[J]. Acta Pharm Sin (药学学报), 2020, 55: 1035-1041.
[23] Ou G, Ma JQ, Zhu L, et al. Preparation of adenosine triphosphate liposome nasal gel and its anti-hypoxia effect[J]. Acta Pharm Sin (药学学报), 2020, 55: 1288-1295.
[24] N'Diaye M, Michel J, Rosilio V. Relevance of charges and polymer mechanical stiffness in the mechanism and kinetics of formation of liponanoparticles probed by the supported bilayer model approach[J]. Phys Chem Chem Phys, 2019, 21: 4306-4319.
[25] Maity P, Saha B, Suresh Kumar G, et al. Effect of zwitterionic phospholipid on the interaction of cationic membranes with monovalent sodium salts[J]. Langmuir, 2018, 34: 9810-9817.
[26] Liu B, Li H, Xu X, et al. Optimized synthesis and crystalline stability of γ-cyclodextrin metal-organic frameworks for drug adsorption[J]. Int J Pharm, 2016, 514: 212-219.
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