包载香豆素-6的PEO-(hb-PG)-g-PCL杂臂聚合物胶束的体外评价, 细胞摄取以及跨膜转运

doi:10.5246/jcps.2013.03.036

包载香豆素-6的PEO-(hb-PG)-g-PCL杂臂聚合物胶束的体外评价, 细胞摄取以及跨膜转运

张小飞, 崔征, 张孝进, 何冰, 王学清, 张华, 钟振林, 张强^*

1. 北京大学医学部天然药物及仿生药物国家重点实验室; 药学院药剂学系, 北京 100191
2. 武汉大学化学与分子科学学院生物医用高分子材料教育部重点实验室, 湖北武汉 430072

收稿日期:2012-09-12 修回日期:2013-01-09 出版日期:2013-05-08 发布日期:2013-05-08
通讯作者: 张强*

Characteristics, cellular uptake and transepithelial transport of coumarin-6 loaded PEO-(hb-PG)-g-PCL miktoarm copolymer micelles

Xiaofei Zhang, Zheng Cui, Xiaojin Zhang, Bing He, Xueqing Wang, Hua Zhang, Zhenlin Zhong, Qiang Zhang^*

1. State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
2. Key Laboratory of Biomedical Polymers of Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, China

Received:2012-09-12 Revised:2013-01-09 Online:2013-05-08 Published:2013-05-08
Contact: Qiang Zhang*

摘要/Abstract

摘要：

当今聚合技术的发展为合成各种非线形两亲性聚合物提供了手段, 对于包载模型药物的杂臂聚合物胶束的摄取和跨膜转运却鲜有报道。本文对两种不同分子量的PEO-(hb-PG)-g-PCL杂臂聚合物胶束的物理性质和Caco-2细胞对其包载的香豆素-6 (C6) 的摄取量进行了比较, 随后选择了PEO₁₁₃-(hb-PG)₁₅-g-PCL₂₂聚合物胶束来研究PMs-C6在Caco-2单层的摄取和转运。细胞摄取和跨膜转运试验发现, 对于Caco-2细胞单层, PMs是很好的摄取和跨膜转运促进剂。对内吞通路的研究发现, PMs-C6的摄取是通过小窝蛋白介导的内吞途径而非网格蛋白介导的内吞途径进行的。本文中制备的PEO-(hb-PG)-g-PCL杂臂聚合物胶束有较小的临界胶束浓度, 对Caco-2细胞无显著细胞毒性, 以及强大的增加Caco-2细胞单层对疏水性荧光探针C6摄取的作用提示很有潜力用于口服药物递送。

关键词: 杂臂聚合物胶束, Caco-2, 细胞摄取, 内吞

Abstract:

Recently, advances in synthetic methodologies have provided efficient routes to generate nonlinear amphiphilic polymers. However, the uptake and transport of model-drug loaded novel miktoarm copolymer micelles have not been extensively studied. In this study, a comparison of the characteristics of two types of PEO-(hb-PG)-g-PCL micelles and the uptake of these two micelles loaded with coumarin-6 (C6) on Caco-2 cellular monolayers was carried out for the first time. PEO₁₁₃-(hb-PG)₁₅-g-PCL₂₂micelles (PMs) were then chosen as the vehicle to study the uptake and transport of PMs-C6 across Caco-2 cellular monolayers. In the cellular uptake and transport study, PMs were found to significantly enhance the uptake and transepithelial transport for C6. Mechanism studies further revealed that caveolin-mediated endocytosis pathway, rather than clathrin-mediated pathway, may play an important role in the uptake of PMs-C6. Thus, the novel PEO-(hb-PG)-g-PCL micelles prepared here might have the potential to be used for oral drug delivery due to its advantages in low critical micelle concentration, low cytotoxicity and significant facilitation of the uptake and transport of C6 on Caco-2 cellular monolayers.

Key words: Miktoarm copolymer micelles, Caco-2, Uptake, Endocytosis

中图分类号:

R943

Supporting:

Foundation items: National Nature Science Foundation (Grant No. 81130059), National Basic Research Program of China (Grant No. 2009CB930300) and Innovation Team of Ministry of Education (Grant No. BMU20110263).
^*Corresponding author. Tel.: 86-10-82802791

张小飞, 崔征, 张孝进, 何冰, 王学清, 张华, 钟振林, 张强^*. 包载香豆素-6的PEO-(hb-PG)-g-PCL杂臂聚合物胶束的体外评价, 细胞摄取以及跨膜转运[J]. , DOI: 10.5246/jcps.2013.03.036.

Xiaofei Zhang, Zheng Cui, Xiaojin Zhang, Bing He, Xueqing Wang, Hua Zhang, Zhenlin Zhong, Qiang Zhang^*. Characteristics, cellular uptake and transepithelial transport of coumarin-6 loaded PEO-(hb-PG)-g-PCL miktoarm copolymer micelles[J]. , DOI: 10.5246/jcps.2013.03.036.

参考文献

[1] Sadekar, S.; Ghandehari, H. Adv. Drug Deliver. Rev. 2012, 64, 571-588.
[2] Gaucher, G.; Satturwar, P.; Jones, M.C.; Furtos, A.; Leroux, J.C. Eur. J. Pharm. Biopharm. 2010, 76, 147-158.
[3] Sweet, D.M.; Kolhatkar, R.B.; Ray, A.; Swaan, P.; Ghandehari, H. J. Control. Release. 2009, 138, 78-85.
[4] Wang, Y.; Grayson, S.M. Adv. Drug Deliver. Rev. 2012, 64, 852-865.
[5] Tian, H. Biomaterials. 2007, 28, 2899-2907.
[6] Miao, Q. Biomaterials. 2010, 31, 7364-7375.
[7] Cartiera, M.S.; Johnson, K.M.; Rajendran, V.; Caplan, M.J.; Saltzman, W.M. Biomaterials. 2009, 30, 2790-2798.
[8] Chiu, Y.L. J. Control. Release. 2010, 146, 152-159.
[9] Chen, K.J.; Chiu, Y.L.; Chen, Y.M.; Ho, Y.C; Sung, H.W. Biomaterials. 2011, 32, 2586-2592.
[10] Siew, A. Mol. Pharmaceut. 2011, 9, 14-28.
[11] Yuan, H.; Lu, L.J.; Du, Y.Z.; Hu, F.Q. Mol. Pharmaceut. 2010, 8, 225-238.
[12] Zhang, X.; Cheng, J.; Wang, Q.; Zhong, Z.; Zhuo, R. Macromolecules. 2010, 43, 6671-6677.
[13] Rivolta, I. J. Physiol. Pharmacol. 2011, 62, 45-53.
[14] Kitchens, K.M.; Kolhatkar, R.B.; Swaan, P.W.; Ghandehari, H. Mol. Pharmaceut. 2008, 5, 364-369.
[15] Mo, R. Biomaterials. 2011, 32, 4609-4620.
[16] Zheng, N. Mol. Pharmaceut. 2012, 9, 1175-1188.
[17] Sun, H. Biomaterials. 2009, 30, 6358-6366.
[18] Zhang, Y. Biomaterials. 2012, 33, 679-691.
[19] Wu, Y. Mol. Pharmaceut. 2011, 8, 1662-1668.
[20] Zhao, S. J. Control. Release. 2012, 158, 413-423.
[21] Goldberg, D.; Ghandehari, H.; Swaan, P. Pharm. Res. 2010, 27, 1547-1557.
[22] Sato, K.; Nagai, J.; Mitsui, N.; Ryoko, Y.; Takano, M. Life Sci. 2009, 85, 800-807.
[23] Chen, H. Proc. Natl. Acad. Sci. 2008, 105, 6596-6601.
[24] Rosenbaum, A.I.; Zhang, G.; Warren, J.D.; Maxfield, F.R. Proc. Natl. Acad. Sci. USA. 2010, 107, 5477-5482.
[25] Sigismund, S. Proc. Natl. Acad. Sci. USA. 2005, 102, 2760-2765.