增强抗肿瘤药物肿瘤靶向性递送的叶酸修饰的pH敏感聚合物胶束

doi:10.5246/jcps.2020.09.058

中国药学(英文版) ›› 2020, Vol. 29 ›› Issue (9): 626-636.DOI: 10.5246/jcps.2020.09.058

增强抗肿瘤药物肿瘤靶向性递送的叶酸修饰的pH敏感聚合物胶束

周楚杭, 胡新平, 刘琦, 王乐淇, 周远航, 靳尧, 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:2020-06-12 修回日期:2020-07-25 出版日期:2020-09-30 发布日期:2020-09-01
通讯作者: Tel.: +86-10-82801508, E-mail: yanliu@bjmu.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 81673366).

Enhanced tumor-targeted delivery of anticancer drugs by folic acid-conjugated pH-sensitive polymeric micelles

Chuhang Zhou, Xinping Hu, Qi Liu, Leqi Wang, Yuanhang Zhou, Yao Jin, 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:2020-06-12 Revised:2020-07-25 Online:2020-09-30 Published:2020-09-01
Contact: Tel.: +86-10-82801508, E-mail: yanliu@bjmu.edu.cn
Supported by:
National Natural Science Foundation of China (Grant No. 81673366).

摘要/Abstract

摘要：

为增强抗肿瘤药物的聚合物胶束的肿瘤靶向性递送, 本研究基于叶酸修饰的聚-(2-乙基-2-噁唑啉)-聚乳酸嵌段共聚物和聚-(2-乙基-2-噁唑啉)-聚乳酸嵌段共聚物, 设计并制备了肿瘤细胞表面过表达的叶酸受体的配体叶酸修饰的pH敏感的聚合物胶束, 用于包载抗肿瘤药物阿霉素。所制备的载阿霉素的聚合物胶束的粒径约为36 nm, 粒径分布较窄, 透射电镜观察胶束呈规则的球形, 并具有pH敏感的释药行为。此外, 体外的细胞摄取、细胞毒性以及荷瘤裸鼠体内的近红外荧光成像的结果均证明了所制备的聚合物胶束增强的肿瘤靶向性, 并归因于叶酸受体的介导和胶束pH敏感性的协同作用。因此, 靶向叶酸受体的pH敏感胶束在肿瘤靶向递送难溶药物方面具有一定的潜力。

关键词: pH敏感聚合物胶束, 叶酸受体靶向, 肿瘤靶向递送, 细胞摄取, 阿霉素

Abstract:

In order to enhance the targeted delivery of anticancer drugs by polymeric micelles, folic acid (FA), the ligand of folate receptor (FR) over-expressed in the most cancer cells, modified pH-sensitive polymeric micelles were designed and fabricated to encapsulate doxorubicin (DOX) by combination of pH-sensitive amphiphilic polymer poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) with FA-conjugated poly(2-ethyl-2-oxazoline)-poly(D,L-lactide). The prepared micelles were characterized to have about 36 nm in diameter with narrow distribution, well-defined spherical shape observed under TEM and pH-responsive drug release behavior. Moreover, the tumor targeting ability of the FA-modified pH-sensitive polymeric micelles was demonstrated by the cellular uptake, in vitro cytotoxicity to FR-positive KB cells and in vivo real time near-infrared fluorescence imaging in KB tumor-bearing nude mice. The efficient drug delivery by the micelles was ascribed to the synergistic effects of FR-mediated targeting and pH-triggered drug release. In conclusion, the designed FR-targeted pH-sensitive polymeric micelles might be of great potential in tumor targeted delivery of water-insoluble anticancer drugs.

Key words: pH-sensitive polymeric micelles, Folate receptor-targeted, Tumor-targeted delivery, Cell uptake, Doxorubicin

中图分类号:

R944

Supporting:

周楚杭, 胡新平, 刘琦, 王乐淇, 周远航, 靳尧, 刘艳. 增强抗肿瘤药物肿瘤靶向性递送的叶酸修饰的pH敏感聚合物胶束[J]. 中国药学(英文版), 2020, 29(9): 626-636.

Chuhang Zhou, Xinping Hu, Qi Liu, Leqi Wang, Yuanhang Zhou, Yao Jin, Yan Liu. Enhanced tumor-targeted delivery of anticancer drugs by folic acid-conjugated pH-sensitive polymeric micelles[J]. Journal of Chinese Pharmaceutical Sciences, 2020, 29(9): 626-636.

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增强抗肿瘤药物肿瘤靶向性递送的叶酸修饰的pH敏感聚合物胶束

Enhanced tumor-targeted delivery of anticancer drugs by folic acid-conjugated pH-sensitive polymeric micelles

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