Nanoscaled Poly(l-glutamic acid)/Doxorubicin-Amphiphile Complex as pH-responsive Drug Delivery System for Effective Treatment of Nonsmall Cell Lung Cancer

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• 作者：Mingqiang Li ; Wantong Song ; Zhaohui Tang ; Shixian Lv ; Lin Lin ; Hai Sun ; Quanshun Li ; Yan Yang ; Hua Hong ; Xuesi Chen
• 刊名：ACS Applied Materials & Interfaces
• 出版年：2013
• 出版时间：March 13, 2013
• 年：2013
• 卷：5
• 期：5
• 页码：1781-1792
• 全文大小：763K
• 年卷期：v.5,no.5(March 13, 2013)
• ISSN：1944-8252

文摘

Nonsmall cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Herein, we develop a polypeptide-based block ionomer complex formed by anionic methoxy poly(ethylene glycol)-b-poly(l-glutamic acid) (mPEG-b-PLG) and cationic anticancer drug doxorubicin hydrochloride (DOX路HCl) for NSCLC treatment. This complex spontaneously self-assembled into spherical nanoparticles (NPs) in aqueous solutions via electrostatic interaction and hydrophobic stack, with a high loading efficiency (almost 100%) and negative surface charge. DOX路HCl release from the drug-loaded micellar nanoparticles (mPEG-b-PLG-DOX路HCl) was slow at physiological pH, but obviously increased at the acidic pH mimicking the endosomal/lysosomal environment. In vitro cytotoxicity and hemolysis assays demonstrated that the block copolypeptide was cytocompatible and hemocompatible, and the presence of copolypeptide carrier could reduce the hemolysis ratio of DOX路HCl significantly. Cellular uptake and cytotoxicity studies suggested that mPEG-b-PLG-DOX路HCl was taken up by A549 cells via endocytosis, with a slightly slower cellular internalization and lower cytotoxicity compared with free DOX路HCl. The pharmacokinetics study in rats showed that DOX路HCl-loaded micellar NPs significantly prolonged the blood circulation time. Moreover, mPEG-b-PLG-DOX路HCl exhibited enhanced therapeutic efficacy, increased apoptosis in tumor tissues, and reduced systemic toxicity in nude mice bearing A549 lung cancer xenograft compared with free DOX路HCl, which were further confirmed by histological and immunohistochemical analyses. The results demonstrated that mPEG-b-PLG was a promising vector to deliver DOX路HCl into tumors and achieve improved pharmacokinetics, biodistribution and efficacy of DOX路HCl with reduced toxicity. These features strongly supported the interest of developing mPEG-b-PLG-DOX路HCl as a valid therapeutic modality in the therapy of human NSCLC and other solid tumors.

Keywords:

poly(l-glutamic acid); doxorubicin hydrochloride; electrostatic interaction; pH-responsive; nonsmall cell lung cancer; antitumor