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

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

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-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; co-delivery liposomes; combination therapy; non-small cell lung cancer; polymeric micelles; vinorelbine.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cisplatin / administration & dosage
  • Cisplatin / pharmacokinetics
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use*
  • Drug Delivery Systems*
  • Drug Liberation
  • Humans
  • Liposomes
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Micelles*
  • Nanoparticles / ultrastructure
  • Particle Size
  • Polyethylene Glycols / chemistry
  • Polymers / chemistry*
  • Rats
  • Rats, Sprague-Dawley
  • Tissue Distribution
  • Vinorelbine / pharmacokinetics
  • Vinorelbine / pharmacology
  • Vinorelbine / therapeutic use*

Substances

  • Antineoplastic Agents
  • Liposomes
  • Micelles
  • Polymers
  • Polyethylene Glycols
  • monomethoxypolyethylene glycol
  • Cisplatin
  • Vinorelbine

Grants and funding

This work was supported by a grant from National Mega-project for Innovative Drugs of China (no. 2019ZX09721001).