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Targeted delivery of Bcl-2 conversion gene by MPEG-PCL-PEI-FA cationic copolymer to combat therapeutic resistant

Zibiao Li1, Xuan Liu2, Xiaohong Chen2

  • 1Institute of Materials Research and Engineering, A*STAR (Agency for Science, Technology and Research), 2 Fusionopolis Way, Innovis, #08-03, Singapore 138634, Singapore..

Materials Science & Engineering. C, Materials for Biological Applications
|May 10, 2017
PubMed

Insights

Researchers developed a novel copolymer carrier for gene therapy, effectively delivering the Nur77 gene to combat drug-resistant cancers. This new system shows promise for treating cancers with high Bcl-2 protein expression.

Area of Science:

  • Biomaterials Science
  • Cancer Gene Therapy
  • Nanotechnology

Background:

  • Deregulation of anti-apoptotic Bcl-2 protein is a hallmark of therapeutic resistance in human cancers.
  • Nuclear receptor Nur77 can be engineered to induce apoptosis in cancer cells via an "enemy to friend" strategy.
  • Safe and effective gene delivery systems for targeting resistant cancers remain a significant challenge.

Purpose of the Study:

  • To design and evaluate a novel amphiphilic cationic copolymer (MPEG-PCL-PEI-FA) for efficient Nur77 gene delivery.
  • To target folate receptor (FR)-overexpressing and therapeutic-resistant HeLa/Bcl-2 cancer cells.
  • To assess the copolymer's efficacy, toxicity, and targeting ability in combating resistant cancers.

Main Methods:

  • Synthesis of an amphiphilic cationic copolymer: MPEG-PCL-PEI-FA, incorporating biocompatible, biodegradable, and targeting moieties.
  • Utilizing the copolymer as a gene carrier for the Nur77 gene.
  • Evaluating gene transfection efficiency, cytotoxicity, and anti-cancer activity against HeLa/Bcl-2 cells.
  • Comparing the copolymer's performance against the gold standard non-viral gene carrier, PEI (25kDa).

Main Results:

  • The MPEG-PCL-PEI-FA copolymer demonstrated significantly lower toxicity and higher gene transfection efficiency compared to PEI (25kDa).
  • The copolymer, facilitated by its "enemy to friend" strategy and FA targeting, effectively inhibited the growth of therapeutic-resistant HeLa/Bcl-2 cancer cells.
  • Micelle formation by the copolymer likely stabilized polyplexes, enhancing gene transfection capabilities.

Conclusions:

  • Cationic amphiphilic MPEG-PCL-PEI-FA copolymers represent a promising platform for gene delivery to therapeutic-resistant cancers.
  • This approach effectively targets cancer cells with high Bcl-2 protein expression and folate receptor overexpression.
  • The findings encourage further development of polymeric platforms for overcoming drug resistance in tumors.
Keywords:
Bcl-2Cancer therapyGene deliveryNon-viral gene carrier

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