Co-delivery of polymeric metformin and cisplatin by self-assembled core-membrane nanoparticles to treat non-small cell lung cancer
Co-delivery of polymeric metformin and cisplatin by self-assembled core-membrane nanoparticles to treat non-small cell lung cancer
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自组装核膜纳米粒子联合递送聚合二甲双胍和顺铂治疗非小细胞肺癌
DOI：
10.1016/j.jconrel.2016.11.005
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发表时间：
2016
影响因子：
10.8
通讯作者：
Huang Leaf
中科院分区：
文献类型：
--
作者：
Xiong Yang;Zhao Yi;Miao Lei;Lin C. Michael;Huang Leaf
临床上，顺铂（CDDP）和二甲双胍联合治疗是治疗非小细胞肺癌（NSCLC）的有效方法。这一成功归功于两种药物之间的协同作用。因此，我们假设CDDP和二甲双胍的共包封将避免CDDP的显著毒性，同时保持方案之间的协同作用。CDDP首先与聚谷氨酸（PGA）结合形成阴离子PGA-CDDP，后者与阳离子聚合二甲双胍（polymet）静电络合。然后用由DOTAP（2，3-二油酰氧基-丙基）-三甲基铵/胆固醇/DSPE-PEG-茴香酰胺氨乙基组成的阳离子脂质体稳定纳米尺寸的复合物。体外和体内实验均证实了Polymet和CDDP之间的协同作用。与游离CDDP相比，用纳米颗粒（NPs）递送的CDDP表现出显著增加的肿瘤蓄积，并通过NSCLC H460荷瘤小鼠的细胞凋亡抑制肿瘤生长，而无肾毒性。polymet与CDDP的协同作用表明，polymet-CDDP NP可以激活AMP激活的蛋白激酶α（AMPK α）途径并抑制哺乳动物靶向雷帕霉素（mTOR）活性，以增强生长抑制作用。总之，该平台是第一个成功地将polymet、聚合物二甲双胍和CDDP共负载到同一纳米颗粒中以成功治疗NSCLC的平台。
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. Bothin vitroandin vivoexperiments 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.