Tumor Microenvironmental Responsive Liposomes Simultaneously Encapsulating Biological and Chemotherapeutic Drugs for Enhancing Antitumor Efficacy of NSCLC

Abstract

Liang Kong,1 Shi-meng Zhang,2 Jia-hao Chu,3 Xin-ze Liu,1 Lu Zhang,1 Si-yu He,1 Si-min Yang,3 Rui-jun Ju,3 Xue-tao Li1 1School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, People’s Republic of China; 2Department of Neurology, Linyi People’s Hospital, Linyi 276003, People’s Republic of China; 3Department of Pharmaceutical Engineering, Beijing Institute of Petrochemical Technology, Beijing 102617, People’s Republic of ChinaCorrespondence: Xue-tao LiSchool of Pharmacy, Liaoning University of Traditional Chinese Medicine, Shengming 1 Road 77, Double D Port, Dalian 116600, People’s Republic of ChinaTel [phone]Fax [phone]Email [email protected] JuDepartment of Pharmaceutical Engineering, Beijing Institute of Petrochemical Technology, Qingyuan North Road 19, Beijing 102617, People’s Republic of ChinaTel [phone]Fax [phone]Email [email protected]: Non-small cell lung cancer (NSCLC) is one of the most lethal types of cancer with highly infiltrating. Chemotherapy is far from satisfactory, vasculogenic mimicry (VM) and angiogenesis results in invasion, migration and relapse.Purpose: The objective of this study was to construct a novel CPP (mmp) modified vinorelbine and dioscin liposomes by two new functional materials, DSPE-PEG2000-MAL and CPP-PVGLIG-PEG5000, to destroy VM channels, angiogenesis, EMT and inhibit invasion and migration.Methods and Results: The targeting liposomes could be enriched in tumor sites through passive targeting, and the positively charged CPP was exposed and enhanced active targeting via electrostatic adsorption after being hydrolyzed by MMP2 enzymes overexpressed in the tumor microenvironment. We found that CPP (mmp) modified vinorelbine and dioscin liposomes with the ideal physicochemical properties and exhibited enhanced cellular uptake. In vitro and in vivo results showed that CPP (mmp) modified vinorelbine and dioscin liposomes could inhibit migration and invasion of A549 cells, destroy VM channels formation and angiogenesis, and block the EMT process. Pharmacodynamic studies showed that the targeting liposomes had obvious accumulations in tumor sites and magnificent antitumor efficiency.Conclusion: CPP (mmp) modified vinorelbine plus dioscin liposomes could provide a new strategy for NSCLC.Keywords: vinorelbine, dioscin, non-small cell lung cancer, multi-functional liposomes, tumor microenvironment, MMP2 enzymes

Keywords

• vinorelbine
• dioscin
• non-small cell lung cancer
• multi-functional liposomes
• tumor microenvironment
• mmp2 enzymes