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

Int J Nanomedicine. 2020 Aug 25:15:6451-6468. doi: 10.2147/IJN.S258906. eCollection 2020.

Abstract

Background: 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: MMP2 enzymes; dioscin; multi-functional liposomes; non-small cell lung cancer; tumor microenvironment; vinorelbine.

MeSH terms

  • A549 Cells
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Death / drug effects
  • Cell Movement / drug effects
  • Chickens
  • Endocytosis / drug effects
  • Epithelial-Mesenchymal Transition / drug effects
  • Humans
  • Hydrolysis
  • Liposomes
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / pathology
  • Phosphatidylethanolamines / chemistry
  • Polyethylene Glycols / chemistry
  • Tumor Microenvironment* / drug effects
  • Vinorelbine / pharmacology
  • Vinorelbine / therapeutic use

Substances

  • 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000)
  • Antineoplastic Agents
  • Liposomes
  • Phosphatidylethanolamines
  • Polyethylene Glycols
  • Vinorelbine