Song Xiao-Li, Ju Rui-Jun, Xiao Yao, Wang Xin, Liu Shuang, Fu Min, Liu Jing-Jing, Gu Li-Yan, Li Xue-Tao, Cheng Lan
School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian.
Department of Pharmaceutical Engineering, Beijing Institute of Petrochemical Technology, Beijing, China.
Int J Nanomedicine. 2017 Oct 11;12:7433-7451. doi: 10.2147/IJN.S141787. eCollection 2017.
Chemotherapy for aggressive non-small-cell lung cancer (NSCLC) usually results in a poor prognosis due to tumor metastasis, vasculogenic mimicry (VM) channels, limited killing of tumor cells, and severe systemic toxicity. Herein, we developed a kind of multifunctional targeting epirubicin liposomes to enhance antitumor efficacy for NSCLC. In the liposomes, octreotide was modified on liposomal surface for obtaining a receptor-mediated targeting effect, and honokiol was incorporated into the lipid bilayer for inhibiting tumor metastasis and eliminating VM channels. In vitro cellular assays showed that multifunctional targeting epirubicin liposomes not only exhibited the strongest cytotoxic effect on Lewis lung tumor cells but also showed the most efficient inhibition on VM channels. Action mechanism studies showed that multifunctional targeting epirubicin liposomes could downregulate PI3K, MMP-2, MMP-9, VE-Cadherin, and FAK and activate apoptotic enzyme caspase 3. In vivo results exhibited that multifunctional targeting epirubicin liposomes could accumulate selectively in tumor site and display an obvious antitumor efficacy. In addition, no significant toxicity of blood system and major organs was observed at a test dose. Therefore, multifunctional targeting epirubicin liposomes may provide a safe and efficient therapy strategy for NSCLC.
侵袭性非小细胞肺癌（NSCLC）的化疗通常预后较差，原因包括肿瘤转移、血管生成拟态（VM）通道、肿瘤细胞杀伤有限以及严重的全身毒性。在此，我们开发了一种多功能靶向表柔比星脂质体，以增强对NSCLC的抗肿瘤疗效。在脂质体中，奥曲肽修饰在脂质体表面以获得受体介导的靶向作用，厚朴酚被掺入脂质双层以抑制肿瘤转移并消除VM通道。体外细胞实验表明，多功能靶向表柔比星脂质体不仅对Lewis肺癌细胞表现出最强的细胞毒性作用，而且对VM通道显示出最有效的抑制作用。作用机制研究表明，多功能靶向表柔比星脂质体可下调PI3K、MMP-2、MMP-9、VE-钙黏蛋白和FAK，并激活凋亡酶caspase 3。体内结果显示，多功能靶向表柔比星脂质体可选择性地在肿瘤部位蓄积，并显示出明显的抗肿瘤疗效。此外，在测试剂量下未观察到血液系统和主要器官的明显毒性。因此，多功能靶向表柔比星脂质体可能为NSCLC提供一种安全有效的治疗策略。
