Tat-TOS, 磷脂酶D抑制剂和阿霉素的多组分脂质体递送系统的制备及体内外评价

doi:10.5246/jcps.2018.05.034

中国药学(英文版) ›› 2018, Vol. 27 ›› Issue (5): 332-341.DOI: 10.5246/jcps.2018.05.034

Tat-TOS, 磷脂酶D抑制剂和阿霉素的多组分脂质体递送系统的制备及体内外评价

宋茂远, 张媛媛, 张文茜, 彭光华, 王佳星, 殷梦雅, 李佳佳, 刘雅婕, 李馨儒^*

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:2018-02-12 修回日期:2018-03-15 出版日期:2018-05-31 发布日期:2018-04-10
通讯作者: Tel.: +86-010-82801508, E-mail: ll@bjmu.edu.cn
基金资助:
The National Natural Science Foundation of China (Grant No. 81541085).

Preparation, characterization and evaluation of multi-component-loaded liposomes containing Tat-TOS, phospholipase D inhibitor and doxorubicin

Maoyuan Song, Yuanyuan Zhang, Wenxi Zhang, Guanghua Peng, Jiaxing Wang, Mengya Yin, Jiajia Li, Yajie Liu, Xinru Li^*

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

Received:2018-02-12 Revised:2018-03-15 Online:2018-05-31 Published:2018-04-10
Contact: Tel.: +86-010-82801508, E-mail: ll@bjmu.edu.cn
Supported by:
The National Natural Science Foundation of China (Grant No. 81541085).

摘要/Abstract

摘要：

本研究的目的是将α-维生素E琥珀酸酯的偶联物Tat-TOS与磷脂酶D抑制剂FIPI以及抗肿瘤药阿霉素共同包载于脂质体递送系统中, 用于抗肿瘤转移。首先采用固相合成法合成了Tat-TOS, 并对其进行结构确证, 用诱导凋亡法考察了游离Tat-TOS和Tat-脂质体的体外诱导细胞凋亡的能力, 并评价了表面修饰了Tat-TOS脂质体的肺部靶向特性, 采用薄膜分散法结合pH梯度法与后插入法制备了修饰有Tat-TOS的载FIPI和阿霉素的多组分脂质体, 并进行理化性质测定, 最后评价了细胞对该制剂的体外摄取能力。研究结果表明, 所制备脂质体具备粒径分布均一, 粒径小的特点, FIPI和DOX的包封率均超过85%, 无论是游离还是脂质体包载的Tat-TOS均能显著提高诱导肿瘤细胞凋亡的能力, 表面修饰了Tat-TOS的脂质体具有明显聚集于健康肺组织和肿瘤转移肺组织, 多组分脂质体具有最强的细胞摄取能力, 预示该脂质体制剂具有更强的体外抗转移功效。

关键词: 阿霉素, FIPI, 脂质体, α-维生素E琥珀酸酯, Tat

Abstract:

In the present study, we aimed to co-load the α-TOS conjugate Tat-TOS with the phospholipase D inhibitor FIPI and the antitumor drug doxorubicin (DOX) in a liposome delivery system for antitumor metastasis. Firstly, Tat-TOS was synthesized by solid-phase synthesis, and its structure was confirmed. The ability of free and liposomal Tat-TOS to induce apoptosis in vitro was evaluated by flow cytometry. Biodistribution of Tat-TOS-loaded liposomes was investigated by a molecular imaging system. Multi-component-loaded liposomes modified with Tat-TOS containing FIPI and DOX was prepared by thin film dispersion method in combination with pH gradient method and post-insertion method. Physicochemical properties were determined, and the in vitro uptake ability of the formulations was evaluated. The results showed that the prepared liposomes were characterized by a uniform particle size distribution and small particle size. The encapsulation efficiency of FIPI and DOX exceeded 85%. Both free and liposomal Tat-TOS significantly improved the activity of inducing apoptosis of tumor cells. The liposomes modified with Tat-TOS were apparently accumulated in normal lung tissue and tumor metastasized lung. Multi-component-loaded liposomes exhibited the strongest cell uptake capacity, suggesting a stronger anti-metastatic effect and anti-tumor activity in vivo.

Key words: Doxorubicin, FIPI, Liposomes, α-TOS, Tat

中图分类号:

R943

Supporting:

宋茂远, 张媛媛, 张文茜, 彭光华, 王佳星, 殷梦雅, 李佳佳, 刘雅婕, 李馨儒. Tat-TOS, 磷脂酶D抑制剂和阿霉素的多组分脂质体递送系统的制备及体内外评价[J]. 中国药学(英文版), 2018, 27(5): 332-341.

Maoyuan Song, Yuanyuan Zhang, Wenxi Zhang, Guanghua Peng, Jiaxing Wang, Mengya Yin, Jiajia Li, Yajie Liu, Xinru Li. Preparation, characterization and evaluation of multi-component-loaded liposomes containing Tat-TOS, phospholipase D inhibitor and doxorubicin[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(5): 332-341.

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Tat-TOS, 磷脂酶D抑制剂和阿霉素的多组分脂质体递送系统的制备及体内外评价

Preparation, characterization and evaluation of multi-component-loaded liposomes containing Tat-TOS, phospholipase D inhibitor and doxorubicin

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