酸敏感靶向的阿霉素聚酰胺-胺型树枝状高分子的抗肿瘤研究

doi:10.5246/jcps.2013.01.011

酸敏感靶向的阿霉素聚酰胺-胺型树枝状高分子的抗肿瘤研究

彭飞, 高鹏超, 王向涛, 胡新^*

1. 北京大学医学部药学院, 北京 100191
2. 中国医学科学院药用植物研究所, 北京 100094

收稿日期:2012-08-31 修回日期:2012-12-03 出版日期:2013-01-20 发布日期:2013-01-20
通讯作者: 胡新*

Acid sensitive doxorubicin-PAMAM with tumor targeting profile

Fei Peng, Pengchao Gao, Xiangtao Wang, Xin Hu^*

1. School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2. Chinese Academy of Medical Sciences and Peking Union Medical College, Institute of Medicinal Plant Development, Beijing 100094, China

Received:2012-08-31 Revised:2012-12-03 Online:2013-01-20 Published:2013-01-20
Contact: Xin Hu*

摘要/Abstract

摘要：

聚酰胺-胺型树枝状高分子是近年来新出现的一种表面有多官能团的药物载体。本研究中, 顺-4,7,10,13,16,19-二十二碳六烯酸 (DHA)和阿霉素 (DOX)共价连接到2.5代的PAMAM分子上。通过这种设计, 载体结构可以优化药物在血液中的循环, 药物和载体之间的酸敏感键可以优化药物的释放。体外实验结果表明, pH 4.5条件下阿霉素的12小时累积释放量约为pH 7.4条件下的两倍。这种酸敏感的药物释放可以提高药效。药动学研究表明, DHA-PAMAM-DOX能提高药物浓度-时间曲线下面积。在荷B16黑色素瘤小鼠模型中, 实验构建的DHA-PAMAM-DOX抑瘤效果优于同等剂量(5 mg/kg)的阿霉素溶液。研究表明DHA-PAMAM-DOX在肿瘤药物靶向给药方面有很好的发展前景。

关键词: 聚酰胺-胺型树枝状高分子, 阿霉素, 顺-4,7,10,13,16,19-二十二碳六烯酸, 抗肿瘤

Abstract:

Poly (amidoamine) dendrimers are emerging as versatile and derivatizable nano-scale drug delivery vehicles. In our study, cis-4,7,10,13,16,19-docosahexenoic acid and doxorubicin were conjugated to generation 2.5 PAMAM. The molecular architecture of the carrier was designed for optimized blood circulation and optimized drug release through the use of pH-sensitive hydrazone linkages. In vitro, DHA-PAMAM-DOX conjugates were able to release twice as much doxorubicin at pH 4.5 (lysosomal pH) as at pH 7.4, ensuring more pronounced antitumor activity. Upon intravenous administration to ICR mice, the DHA-PAMAM-DOX delivery systems resulted in more plasma exposure of doxorubicin than free doxorubicin solution. In efﬁcacy studies performed with B6D2F1 mice bearing B16 melanoma tumors, DHA-PAMAM-DOX was significantly more efficient in inhibiting tumor growth than free doxorubicin at the dose equivalent to 5 mg/kg doxorubicin. Our research provides evidence that DHA-PAMAM-DOX conjugates have the potential to enhance the effect of cancer therapy in the course of delivering anticancer drugs to their target sites.

Key words: PAMAM, Doxorubicin, Docosahexenoic acid, Antitumor treatment

中图分类号:

R969

Supporting:

Foundation item: China International Science and Technology Cooperation Program for Key Projects (Grant No. 2008DFA31070).
^*Corresponding author. Tel.: 86-10-82801708

彭飞, 高鹏超, 王向涛, 胡新^*. 酸敏感靶向的阿霉素聚酰胺-胺型树枝状高分子的抗肿瘤研究[J]. , DOI: 10.5246/jcps.2013.01.011.

Fei Peng, Pengchao Gao, Xiangtao Wang, Xin Hu^*. Acid sensitive doxorubicin-PAMAM with tumor targeting profile[J]. , DOI: 10.5246/jcps.2013.01.011.

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