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脂质体共递送长春瑞滨和顺铂聚合物胶束协同治疗非小细胞肺癌。

Synergistic Antitumor Efficacy Mediated by Liposomal Co-Delivery of Polymeric Micelles of Vinorelbine and Cisplatin in Non-Small Cell Lung Cancer.

机构信息

Department of Pharmaceutics, College of Pharmacy Sciences, Jilin University, Changchun, 130021, Jilin, People's Republic of China.

Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.

出版信息

Int J Nanomedicine. 2021 Mar 22;16:2357-2372. doi: 10.2147/IJN.S290263. eCollection 2021.

DOI:10.2147/IJN.S290263
PMID:33790554
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7997865/
Abstract

PURPOSE

Non-small cell lung cancer (NSCLC) is an aggressive tumor with high mortality and poor prognosis. In this study, we designed a liposome encapsulating polymeric micelles (PMs) loaded with vinorelbine (NVB) and cis-diamminedichloroplatinum (II) (cisplatin or CDDP) for the treatment of NSCLC.

MATERIALS AND METHODS

Sodium poly(α-l-glutamic acid)-graft-methoxy-polyethylene glycol (PLG-G-PEG) was used to prepare NVB-loaded NVB-PMs and CDDP-loaded CDDP-PMs that were co-encapsulated into liposomes by a reverse evaporation method, yielding NVB and CDDP co-delivery liposomes (CoNP-lips) composed of egg phosphatidyl lipid-80/cholesterol/DPPG/DSPE-mPEG at a molar ratio of 52:32:14:2. The CoNP-lips were characterized in terms of particle size, zeta potential, drug content, encapsulation efficiency, and structural properties. Drug release by the CoNP-lips as well as their stability and cytotoxicity was evaluated in vitro, and their antitumor efficacy was assessed in a mouse xenograft model of Lewis lung carcinoma cell-derived tumors.

RESULTS

CoNP-lips had a spherical shape with uniform size distribution; the average particle size was 162.97±9.06 nm, and the average zeta potential was -13.02±0.22 mV. In vitro cytotoxicity analysis and the combination index demonstrated that the CoNP-lips achieved a synergistic cytotoxic effect at an NVB:CDDP weight ratio of 2:1 in an NSCLC cell line. There was sustained release of both drugs from CoNP-lips. The pharmacokinetic analysis showed that CoNP-lips had a higher plasma half-life than NP solution, with 6.52- and 8.03-fold larger areas under the receiver operating characteristic curves of NVB and CDDP. CoNP-lips showed antitumor efficacy in tumor-bearing C57BL/6 mice and drug accumulation in tumors via the enhanced permeability and retention effect.

CONCLUSION

CoNP-lips are a promising formulation for targeted therapy in NSCLC.

摘要

目的

非小细胞肺癌（NSCLC）是一种侵袭性肿瘤，死亡率高，预后差。在本研究中，我们设计了一种包载长春瑞滨（NVB）和顺铂（CDDP）的脂质体包载聚合物胶束（PMs）用于治疗 NSCLC。

材料和方法

采用聚（α-谷氨酸-γ-聚乙二醇）接枝聚天冬氨酸（PLG-G-PEG）制备载 NVB 的 NVB-PMs 和载 CDDP 的 CDDP-PMs，然后采用逆相蒸发法将两者共包载到脂质体中，得到由蛋黄磷脂酰胆碱-80/胆固醇/二棕榈酰磷脂酰甘油（DPPG）/二硬脂酰基磷脂酰乙醇胺-聚乙二醇（DSPE-mPEG）以摩尔比 52:32:14:2 组成的 NVB 和 CDDP 共载脂质体（CoNP-lips）。对 CoNP-lips 的粒径、Zeta 电位、载药量、包封率和结构性质进行了表征。在体外评价了 CoNP-lips 的药物释放、稳定性和细胞毒性，并在 Lewis 肺癌细胞衍生肿瘤的小鼠异种移植模型中评估了其抗肿瘤疗效。

结果

CoNP-lips 呈球形，粒径分布均匀；平均粒径为 162.97±9.06nm，平均 Zeta 电位为-13.02±0.22mV。体外细胞毒性分析和组合指数表明，在 NSCLC 细胞系中，当 NVB:CDDP 重量比为 2:1 时，CoNP-lips 具有协同的细胞毒性作用。两种药物均能持续从 CoNP-lips 中释放。药代动力学分析表明，CoNP-lips 较 NP 溶液具有更高的血浆半衰期，NVB 和 CDDP 的受试者工作特征曲线下面积分别增大了 6.52 倍和 8.03 倍。CoNP-lips 在荷瘤 C57BL/6 小鼠中表现出抗肿瘤疗效，并通过增强的通透性和滞留效应使肿瘤内药物蓄积。

结论

CoNP-lips 是一种有前途的 NSCLC 靶向治疗制剂。

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