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Systemic study of solvent-assisted active loading of gambogic acid into liposomes and its formulation optimization for improved delivery
Biomaterials ( IF 14.0 ) Pub Date : 2018-03-03 , DOI: 10.1016/j.biomaterials.2018.03.004
Wei-Lun Tang , Wei-Hsin Tang , Andras Szeitz , Jayesh Kulkarni , Pieter Cullis , Shyh-Dar Li

The solvent-assisted active loading technology (SALT) was developed for encapsulating a water insoluble weak base into the liposomal core in the presence of 5% DMSO. In this study, we further examined the effect of various water miscible solvents in promoting active loading of other types of drugs into liposomes. To achieve complete drug loading, the amount of solvent required must result in complete drug solubilization and membrane permeability enhancement, but must be below the threshold that induces liposomal aggregation or causes bilayer disruption. We then used the SALT to load gambogic acid (GA, an insoluble model drug that shows promising anticancer effect) into liposomes, and optimized the loading gradient and lipid composition to prepare a stable formulation (Lipo-GA) that displayed >95% drug retention after incubation with serum for 3 days. Lipo-GA contained a high drug-to-lipid ratio of 1/5 (w/w) with a mean particle size of ∼75 nm. It also displayed a prolonged circulation half-life (1.5 h vs. 18.6 h) and enhanced antitumor activity in two syngeneic mice models compared to free GA. Particularly, complete tumor regression was observed in the EMT6 tumor model for 14 d with significant inhibition of multiple oncogenes including HIF-1α, VEGF, STAT3, BCL-2, and NF-κB.



中文翻译:

溶剂辅助将藤黄酸有效负载到脂质体中的系统研究及其优化制剂以改善递送

开发了溶剂辅助的主动加载技术(SALT),用于在5%DMSO存在下将水不溶性弱碱包裹到脂质体核心中。在这项研究中,我们进一步检查了各种与水混溶的溶剂在促进其他类型药物向脂质体中的有效负载方面的作用。为了实现完全的药物负载,所需的溶剂量必须导致完全的药物溶解和膜通透性增强,但必须低于引起脂质体聚集或引起双层破坏的阈值。然后,我们使用SALT将藤黄酸(GA,一种显示出有希望的抗癌作用的不溶性模型药物)加载到脂质体中,并优化了加载梯度和脂质组成,以制备出稳定的制剂(Lipo-GA),该制剂可显示> 与血清孵育3天后,药物保留率达到95%。Lipo-GA的药物与脂质比率高达1/5(w / w),平均粒径约为75 nm。与游离GA相比,它在两个同系小鼠模型中还显示出延长的循环半衰期(1.5小时vs. 18.6小时)和增强的抗肿瘤活性。特别地,在EMT6肿瘤模型中观察到了14天的完全肿瘤消退,并且显着抑制了多种癌基因,包括HIF-1α,VEGF,STAT3,BCL-2和NF-κB。

更新日期:2018-03-06
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