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

Abstract

Shuhang Wang,1 Jingxin Gou,2 Yue Wang,1 Xinyi Tan,2 Linxuan Zhao,1 Xiangqun Jin,1 Xing Tang2 1Department of Pharmaceutics, College of Pharmacy Sciences, Jilin University, Changchun, 130021, Jilin, People’s Republic of China; 2Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang, 110016, People’s Republic of ChinaCorrespondence: Xiangqun JinDepartment of Pharmaceutics, College of Pharmacy Sciences, Jilin University, Changchun, 130021, Jilin, People’s Republic of ChinaTel [phone]Fax [phone]Email [email protected]: 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-PEG5K) 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-mPEG2000 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.Keywords: cisplatin, vinorelbine, co-delivery liposomes, combination therapy, polymeric micelles, non-small cell lung cancer

Keywords

• cisplatin
• vinorelbine
• co-delivery liposomes
• combination therapy
• polymeric micelles
• non-small cell lung cancer