通过隐形纳米脂质体共递送阿霉素和 PSC 833（伐昔洛韦），有效克服多药耐药性。

Co-delivery of doxorubicin and PSC 833 (Valspodar) by stealth nanoliposomes for efficient overcoming of multidrug resistance.

机构信息

Pharmaceutical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

出版信息

J Pharm Pharm Sci. 2012;15(4):568-82. doi: 10.18433/j3sc7j.

DOI:10.18433/j3sc7j

PMID:23106959

Abstract

PURPOSE

This study was aimed at developing co-encapsulated stealth nanoliposomes containing PSC 833, an efficient MDR modulator, and doxorubicin (DOX) in order to increase the effectiveness and decrease adverse effects of the anticancer drug.

METHODS

In attempt to increase the encapsulation efficiency of drugs, different methods for liposome preparation were tested and the effect of different parameters such as drug to lipid molar ratio, cholesterol mole percent and lipid compositions, were investigated. The final product with a lipid composition of EPC:DSPE-PEG2000:Chol (60:5:30 %mol) was prepared by thin layer film hydration method. After preparation of empty liposomes, DOX and PSC 833 were loaded using ammonium sulfate gradient and remote film loading methods, respectively. Physical characteristics of optimized liposomes (DOX/PSC-L) such as particle size, zeta potential, encapsulation efficiency, in-vitro drugs release and stability were evaluated. Furthermore, in vitro cytotoxicity study of various liposomal formulations as well as drugs, solutions against resistant human breast cancer cell line, T47D/TAMR-6, was evaluated using MTT assay.

RESULTS

The best formulation showed a narrow size distribution with average diameter of 91.3 ± 0.2 nm with zeta potential of -6 ± 1.2, the encapsulation efficiency for DOX and PSC 833 were more than 95% and 65.5%, respectively. In DOX-resistant T47D/TAMR-6 cells, dual-agent stealth liposomes showed significantly greater cytotoxicity (P < 0.05) than free DOX and liposomal DOX plus free PSC 833 treatments.

CONCLUSIONS

Co-encapsulation of DOX and PSC 833 presents a promising anticancer formulation, capable of effective reversal of drug resistance, and should be explored further in therapeutic studies with animal tumor xenograft models. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

摘要

目的

本研究旨在开发载有 PSC 833（一种有效的多药耐药调节剂）和阿霉素（DOX）的共包封隐形纳米脂质体，以提高抗癌药物的疗效并降低其不良反应。

方法

为了提高药物的包封效率，尝试了不同的脂质体制备方法，并考察了药物与脂质摩尔比、胆固醇摩尔百分比和脂质组成等不同参数的影响。最终产品的脂质组成为 EPC：DSPE-PEG2000：Chol（60：5：30%mol），采用薄膜水化法制备。制备空白脂质体后，分别采用硫酸铵梯度法和远程薄膜加载法装载 DOX 和 PSC 833。对优化后的脂质体（DOX/PSC-L）的物理特性（如粒径、Zeta 电位、包封效率、体外药物释放和稳定性）进行评价。此外，采用 MTT 法评价各种脂质体制剂以及药物、溶液对耐药人乳腺癌细胞系 T47D/TAMR-6 的体外细胞毒性。

结果

最佳制剂粒径分布较窄，平均直径为 91.3±0.2nm，Zeta 电位为-6±1.2，DOX 和 PSC 833 的包封效率均超过 95%和 65.5%。在 DOX 耐药的 T47D/TAMR-6 细胞中，双药隐形脂质体的细胞毒性明显高于游离 DOX 及载药脂质体联合游离 PSC 833（P<0.05）。