Nanoscaled poly(L-glutamic acid)/doxorubicin-amphiphile complex as pH-responsive drug delivery system for effective treatment of nonsmall cell lung cancer.

Abstract

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·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·HCl release from the drug-loaded micellar nanoparticles (mPEG-b-PLG-DOX·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·HCl significantly. Cellular uptake and cytotoxicity studies suggested that mPEG-b-PLG-DOX·HCl was taken up by A549 cells via endocytosis, with a slightly slower cellular internalization and lower cytotoxicity compared with free DOX·HCl. The pharmacokinetics study in rats showed that DOX·HCl-loaded micellar NPs significantly prolonged the blood circulation time. Moreover, mPEG-b-PLG-DOX·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·HCl, which were further confirmed by histological and immunohistochemical analyses. The results demonstrated that mPEG-b-PLG was a promising vector to deliver DOX·HCl into tumors and achieve improved pharmacokinetics, biodistribution and efficacy of DOX·HCl with reduced toxicity. These features strongly supported the interest of developing mPEG-b-PLG-DOX·HCl as a valid therapeutic modality in the therapy of human NSCLC and other solid tumors.

• Authors: Mingqiang Li, Wantong Song, Zhaohui Tang, Shixian Lv, Lin Lin, Hai Sun, Quanshun Li, Yan Yang, Hua Hong, Xuesi Chen
• Journal: ACS applied materials & interfaces (ACS Appl Mater Interfaces) Vol. 5 Issue 5 Pg. 1781-92 (Mar 13 2013) ISSN: 1944-8252 [Electronic] United States
• PMID: 23410916 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Drug Carriers
• Surface-Active Agents
• Polyglutamic Acid
• Doxorubicin

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (chemistry, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy)
• Doxorubicin (chemistry, therapeutic use)
• Drug Carriers (chemistry)
• Drug Delivery Systems (instrumentation, methods)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Polyglutamic Acid (chemistry)
• Rats
• Rats, Sprague-Dawley
• Surface-Active Agents (chemistry)