Co-delivery of polymeric metformin and cisplatin by self-assembled core-membrane nanoparticles to treat non-small cell lung cancer

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• 作者：Yang Xiong^a ; ^b ; Yi Zhao^a ; Lei Miao^a ; C. Michael Lin^a ; Leaf Huang^a ; ^{leafh@email.unc.edu}
• 关键词：NSCLC ; non-small cell lung cancer ; CDDP ; cisplatin ; polymet ; polymeric metformin ; AMPK ; AMP-activated protein kinase ; mTOR ; mammalian target of rapamycin ; ERCC1 ; excision repair cross-complementation group 1 ; IV ; intravenous ; PK ; pharmacokinetic ; NPs ; nanoparticles ; RES ; reticuloendothelial system ; PGA ; polyglutamic acid ; PEI ; polyethylenimine ; EDC ; ethylene dichloride ; NHS ; N-hydroxysuccinimide ; MTT ; 3-[4.5-dimethylthiazol-2-yl]-2.5-diphenyltetrazolium bromide ; DAPI ; 4&prime ; 6-diamidino-2-phen
• 刊名：Journal of Controlled Release
• 出版年：2016
• 出版时间：28 December 2016
• 年：2016
• 卷：244
• 期：part_PA
• 页码：63-73
• 全文大小：1222 K
• 卷排序：244

文摘

Clinically, combined therapy of cisplatin (CDDP) and metformin is an effective treatment for non-small cell lung cancer (NSCLC). The success is attributed to synergistic effects between the two drugs. Therefore, we hypothesize that co-encapsulation of CDDP and metformin will avoid the prominent toxicity of CDDP while maintaining the synergy between the regimens. CDDP was first conjugated to polyglutamic acid (PGA) to form anionic PGA-CDDP which was electrostatically complexed with the cationic polymeric metformin (polymet). The nano-sized complex was then stabilized with cationic liposomes composed of DOTAP (2, 3-Dioleoyloxy-propyl)-trimethylammonium/Cholesterol/DSPE-PEG-anisamide aminoethyl. Both in vitro and in vivo experiments confirmed the synergy between polymet and CDDP. CDDP delivered with nanoparticles (NPs) exhibited significantly increased tumor accumulation over free CDDP and suppressed tumor growth through apoptosis in NSCLC H460 tumor-bearing mice without nephrotoxicity. The synergistic effect of polymet alongside CDDP demonstrates that polymet-CDDP NPs can activate the AMP-activated protein kinase α (AMPKα) pathway and inhibit mammalian target rapamycin (mTOR) activity to enhance growth suppression. In all, this platform is the first to successfully co-load polymet, a polymeric metformin, and CDDP into the same nanoparticle for successful treatment of NSCLC.