靶向小肠转运体的聚合物胶束的制备与表征

doi:10.5246/jcps.2018.07.050

中国药学(英文版) ›› 2018, Vol. 27 ›› Issue (7): 490-497.DOI: 10.5246/jcps.2018.07.050

靶向小肠转运体的聚合物胶束的制备与表征

何楚瑜, 靳尧, 邓运强, 邹洋, 韩诗迪, 周楚杭, 周远航, 李馨儒, 周艳霞, 刘艳^*

北京大学医学部药学院分子药剂学与新释药系统北京市重点实验室, 北京 100191

收稿日期:2018-04-01 修回日期:2018-04-28 出版日期:2018-07-25 发布日期:2018-05-18
通讯作者: Tel.: +86-010-82801508, E-mail: yanliu@bjmu.edu.cn
基金资助:
The National Natural Science Foundation of China (Grant No. 81673366) and the National Key Science Research Program of China (973 Program, Grant No. 2015CB932100).

Preparation and characterization of intestinal transporter-targeted polymeric micelles

Chuyu He, Yao Jin, Yunqiang Deng, Yang Zou, Shidi Han, Chuhang Zhou, Yuanhang Zhou, Xinru Li, Yanxia Zhou, Yan Liu^*

Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2018-04-01 Revised:2018-04-28 Online:2018-07-25 Published:2018-05-18
Contact: Tel.: +86-010-82801508, E-mail: yanliu@bjmu.edu.cn
Supported by:
The National Natural Science Foundation of China (Grant No. 81673366) and the National Key Science Research Program of China (973 Program, Grant No. 2015CB932100).

摘要/Abstract

摘要：

小肠上皮是难溶性药物口服递送的主要屏障, 本研究基于小肠上皮表达的新型有机阳离子转运体2(OCTN2), 设计并制备了由肉毒碱修饰的聚(2-乙基-2-噁唑啉)-聚乳酸(Car-PEOz-PLA)与聚乙二醇-聚乳酸(mPEG-PLA)构成的聚合物胶束。用¹H NMR、TLC、硫氰酸铬铵(雷氏盐)沉淀法确证了所合成的Car-PEOz-PLA的结构, 用GPC测定其分子量为7260 g/mol, PDI = 1.44。采用薄膜水化法制备包载香豆素6的肉毒碱修饰的聚合物胶束, 其粒径约为31 nm, 载药量和包封率分别为0.098%±0.03%和92.67%±2.80%。其在模拟胃液和肠液中具有相似的体外释放行为, 并明显增强了难溶药物的小肠吸收。因此, 靶向OCTN2的聚合物胶束在口服递送难溶药物方面具有潜在的优势。

关键词: 肉毒碱, 新型有机阳离子转运体2, 聚合物胶束, 体外释放, 小肠吸收

Abstract:

The intestinal epithelium is the main barrier to the oral delivery of poorly water-soluble drugs. Based on the specific transporters expressed on the apical membrane of the intestinal epithelium, novel polymer micelles targeting to the organic cation transporter 2 (OCTN2) were constructed by combining carnitine conjugated poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) (Car-PEOz-PLA) with monomethoxy poly(ethylene glycol)-poly(D,L-lactide) (mPEG-PLA). The structure of the synthesized Car-PEOz-PLA was confirmed by ¹H NMR, TLC and ammonium reineckate precipitation reaction, and the number-average molecular weight determined by GPC was 7260 g/mol with a low PDI of 1.44. Coumarin 6-loaded carnitine modified polymeric micelles prepared by film hydration method were characterized to have a nano-scaled size of about 31 nm in diameter, uniform spherical morphology, high drug loading content of 0.098%±0.03% and encapsulation efficiency of 92.67%±2.80%. Moreover, the carnitine-modified micelles exhibited the similar in vitro release behavior in SGF and SIF, and evidently enhanced intestinal absorption of poorly water-soluble agent. Therefore, the designed OCTN2-targeted micelles might have a promising potential for oral delivery of poorly water-soluble drugs.

Key words: Carnitine, Organic cation transporter 2 (OCTN2), Polymeric micelles, In vitro release, Intestinal absorption

中图分类号:

R943

Supporting:

何楚瑜, 靳尧, 邓运强, 邹洋, 韩诗迪, 周楚杭, 周远航, 李馨儒, 周艳霞, 刘艳. 靶向小肠转运体的聚合物胶束的制备与表征[J]. 中国药学(英文版), 2018, 27(7): 490-497.

Chuyu He, Yao Jin, Yunqiang Deng, Yang Zou, Shidi Han, Chuhang Zhou, Yuanhang Zhou, Xinru Li, Yanxia Zhou, Yan Liu. Preparation and characterization of intestinal transporter-targeted polymeric micelles[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(7): 490-497.

参考文献

[1] Merisko-Liversidge, E.M.; Liversidge, G.G. Drug Nanoparticles: Formulating Poorly Water-Soluble Compounds. Toxicol. Pathol. 2008, 36, 43-48.

[2] Majumdar, S.; Mitra, A.K. Chemical Modification and Formulation Approaches to Elevated Drug Transport across Cell Membranes. Expert Opin. Drug Deliv. 2006, 3, 511-527.

[3] Aungst, B.J. Absorption Enhancers: Applications and Advances. AAPS J. 2012, 14, 10-18.

[4] Bromberg, L. Polymeric Micelles in Oral Chemotherapy. J. Controlled Release. 2008, 128, 99-112.

[5] Varma, M.V.; Ambler, C.M.; Ullah, M.; Rotter, C.J.; Sun, H.; Litchfield, J.; Fenner, K.S.; El-Kattan, A.F. Targeting Intestinal Transporters for Optimizing Oral Drug Absorption. Curr. Drug Metab. 2010, 11, 730-742.

[6] Incecayir, T.; Sun, J.; Tsume, Y.; Xu, H.; Gose, T.; Nakanishi, T.; Tamai, I.; Hilfinger, J.; Lipka, E.; Amidon, G.L. Carrier-Mediated Prodrug Uptake to Improve the Oral Bioavailability of Polar Drugs: An Application to an Oseltamivir Analogue. J. Pharm. Sci. 2016, 105, 925-934.

[7]. Coothankandaswamy, V.; Cao, S.; Xu, Y.; Prasad, P.D.; Singh, P.K.; Reynolds, C.P.; Yang, S.; Ogura, J.; Ganapathy, V.; Bhutia, Y.D. Amino Acid Transporter SLC6A14 is a Novel and Effective Drug Target for Pancreatic Cancer. Br. J. Pharmacol. 2016, 173, 3292-3306.

[8] Gao, Y.; Li, Y.; Li, Y.; Yuan, L.; Zhou, Y.; Li, J.; Zhao, L.; Zhang, C.; Li, X.; Liu, Y. PSMA-Mediated Endosome Escape-Accelerating Polymeric Micelles for Targeted Therapy of Prostate Cancer and the Real Time Tracing of Their Intracellular Trafficking. Nanoscale. 2015, 7, 597-612.

[9] Gagic, Z.; Ivkovic, B.; Srdic-Rajic, T.; Vucicevic, J.; Nikolic, K.; Agbaba, D. Synthesis of the Vitamin E Amino Acid Esters with an Enhanced Anticancer Activity and in Silico Screening for New Antineoplastic Drugs. Eur. J. Pharm. Sci. 2016, 88, 59-69.

[10] Zhu, X.; Wu, J.; Shan, W.; Zhou, Z.; Liu, M.; Huang, Y. Sub-50 nm Nanoparticles with Biomimetic Surfaces to Sequentially Overcome the Mucosal Diffusion Barrier and the Epithelial Absorption Barrier. Adv. Funct. Mater. 2016, 26, 2728-2738.

[11] Lee, K.T. The Identification and Determination of Nitrogenous Organic Bases with Ammonium Reineckate. J. Pharm. Pharmacol. 1960, 12, 666-676.
[12] Wang, D.; Zhou, Y.; Li, X.; Qu, X.; Deng, Y.; Wang, Z.; He, C.; Zou, Y.; Jin, Y.; Liu, Y. Mechanisms of pH-Sensitivity and Cellular Internalization of PEOz-b-PLA Micelles with Varied Hydrophilic/Hydrophobic Ratios and Intracellular Trafficking Routes and Fate of the Copolymer. ACS Appl. Mater. Interfaces. 2017, 9, 6916-6930.

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靶向小肠转运体的聚合物胶束的制备与表征

Preparation and characterization of intestinal transporter-targeted polymeric micelles

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