PEG-b-PCL Copolymer Micelles with the Ability of pH-Controlled Negative-to-Positive Charge Reversal for Intracellular Delivery of Doxorubicin

详细信息    查看全文

• 作者：Hongzhang Deng ; Jinjian Liu ; Xuefei Zhao ; Yuming Zhang ; Jianfeng Liu ; Shuxin Xu ; Liandong Deng ; Anjie Dong ; Jianhua Zhang
• 刊名：Biomacromolecules
• 出版年：2014
• 出版时间：November 10, 2014
• 年：2014
• 卷：15
• 期：11
• 页码：4281-4292
• 全文大小：701K
• ISSN：1526-4602

文摘

The application of PEG-b-PCL micelles was dampened by their inherent low drug-loading capability and relatively poor cell uptake efficiency. In this study, a series of novel PEG-b-PCL copolymers methoxy poly(ethylene glycol)-b-poly(蔚-caprolactone-co-纬-dimethyl maleamidic acid -蔚-caprolactone) (mPEG-b-P(CL-co-DCL)) bearing different amounts of acid-labile 尾-carboxylic amides on the polyester moiety were synthesized. The chain structure and chemical composition of copolymers were characterized by ¹H NMR, Fourier transform infrared spectroscopy (FT-IR), and gel permeation chromatography (GPC). mPEG-b-P(CL-co-DCL) with critical micellar concentrations (CMCs) of 3.2鈥?.3 渭g/mL could self-assemble into stable micelles in water with diameters of 100 to 150 nm. Doxorubicin (DOX), a cationic hydrophobic drug, was successfully encapsulated into the polymer micelles, achieving a very high loading content due to electrostatic interaction. Then the stability, charge-conversional behavior, loading and release profiles, cellular uptake and in vitro cytotoxicity of free drug and drug-loaded micelles were evaluated. The 尾-carboxylic amides functionalized polymer micelles are negatively charged and stable in neutral solution but quickly become positively charged at pH 6.0, due to the hydrolysis of 尾-carboxylic amides in acidic conditions. The pH-triggered negative-to-positive charge reversal not only resulted in a very fast drug release in acidic conditions, but also effectively enhanced the cellular uptake by electrostatic absorptive endocytosis. The MTT assay demonstrated that mPEG-b-P(CL-co-DCL) micelles were biocompatible to HepG2 cells while DOX-loaded micelles showed significant cytotoxicity. In sum, the introduction of acid-labile 尾-carboxylic amides on the polyester block in mPEG-b-P(CL-co-DCL) exhibited great potentials for the modifications in the stability in blood circulation, drug solubilization, and release properties, as well as cell internalization and intracellular drug release.