双重pH敏感的聚合物-阿霉素偶联物胶束的制备与表征

doi:10.5246/jcps.2018.08.054

中国药学(英文版) ›› 2018, Vol. 27 ›› Issue (8): 530-539.DOI: 10.5246/jcps.2018.08.054

双重pH敏感的聚合物-阿霉素偶联物胶束的制备与表征

邹洋, 靳尧, 周远航, 何楚瑜, 邓运强, 韩诗迪, 周楚杭, 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:2018-04-21 修回日期:2018-06-16 出版日期:2018-09-04 发布日期:2018-07-05
通讯作者: Tel.: +86-010-82801508, E-mail: yanliu@bjmu.edu.cn
基金资助:
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 dual pH-sensitive polymer-doxorubicin conjugate micelles

Yang Zou, Yao Jin, Yuanhang Zhou, Chuyu He, Yunqiang Deng, Shidi Han, Chuhang 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:2018-04-21 Revised:2018-06-16 Online:2018-09-04 Published:2018-07-05
Contact: Tel.: +86-010-82801508, E-mail: yanliu@bjmu.edu.cn
Supported by:
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：

为了有效抑制肿瘤生长并降低抗肿瘤药物的毒副作用, 本研究设计并构建了基于阿霉素(DOX)与聚(2-乙基-2-噁唑啉)-聚乳酸(PEOz-PLA)偶联物(PEOz-PLA-imi-DOX)的双重pH敏感聚合物胶束。成功合成了DOX与pH敏感的PEOz-PLA经酸敏感的安息香亚胺键偶联的PEOz-PLA-imi-DOX, 并用¹H NMR和薄层色谱进行了确证, 芘荧光探针法测定其临界胶束浓度为(14.84±3.85) mg/L。由PEOz-PLA-imi-DOX经薄膜水化法制备的偶联物胶束(PP-DOX-PM)的粒径约为21 nm, 载药量为1.67%。体外释放实验表明, PP-DOX-PM具有随着pH的降低而释放逐渐加快的pH依赖性释放行为, 说明该胶束能识别正常生理环境和胞内的pH差异, 预示该胶束具有胞内快速释药的特征。此外, PP-DOX-PM保持了DOX对MDA-MB-231细胞的毒性。因此, PP-DOX-PM胶束在抗肿瘤方面具有潜在的优势。

关键词: 阿霉素, 安息香亚胺键, 聚合物-药物偶联物, pH敏感聚合物胶束, 体外释放

Abstract:

In the present study, we designed and fabricated pH-sensitive polymeric micelles based on the conjugate of poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) (PEOz-PLA) with doxorubicin (PEOz-PLA-imi-DOX) to efficiently inhibit tumor cell growth. Hence, PEOz-PLA-imi-DOX was successfully synthesized by connecting DOX to the hydrophobic end of pH-sensitive PEOz-PLAvia acid cleavable benzoic imine linker and characterized by ¹H NMR spectrum and thin layer chromatography. The critical micelle concentration of PEOz-PLA-imi-DOX was determined to be (14.84±3.85) mg/L. The conjugate micelles (denoted as PP-DOX-PM) formed by PEOz-PLA-imi-DOX using film-hydration method were characterized to have a nano-scaled size of about 21 nm in diameter, and the drug loading content was 1.67%. PP-DOX-PM showed pH-dependent drug release behavior with gradually accelerated release of DOX with decrease of pH value, illustrating the micelles’ distinguishing feature of endo/lysosomal pH from physiological pH by accelerating drug release. As anticipated, PP-DOX-PM maintained the cytotoxicity of DOX against MDA-MB-231 cells. Collectively, PP-DOX-PM might have great potential for effective suppression of tumor growth.

Key words: Doxorubicin, Acid-cleavable imine, Polymer-drug conjugate, pH-sensitive polymeric micelles, In vitro release

中图分类号:

R944

Supporting:

邹洋, 靳尧, 周远航, 何楚瑜, 邓运强, 韩诗迪, 周楚杭, 李馨儒, 周艳霞, 刘艳. 双重pH敏感的聚合物-阿霉素偶联物胶束的制备与表征[J]. 中国药学(英文版), 2018, 27(8): 530-539.

Yang Zou, Yao Jin, Yuanhang Zhou, Chuyu He, Yunqiang Deng, Shidi Han, Chuhang Zhou, Xinru Li, Yanxia Zhou, Yan Liu. Preparation and characterization of dual pH-sensitive polymer-doxorubicin conjugate micelles[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(8): 530-539.

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双重pH敏感的聚合物-阿霉素偶联物胶束的制备与表征

Preparation and characterization of dual pH-sensitive polymer-doxorubicin conjugate micelles

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