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Synergistic Anti-Angiogenic Effects Using Peptide-Based Combinatorial Delivery of siRNAs Targeting VEGFA, VEGFR1, and

Anna A Egorova1, Sofia V Shtykalova2, Marianna A Maretina3

  • 1D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 Saint-Petersburg, Russia. egorova_anna@yahoo.com.

Pharmaceutics
|June 9, 2019
PubMed

Insights

Targeted delivery of anti-angiogenic small interfering RNA (siRNA) using a peptide carrier (L1) effectively inhibits cancer cell growth. Combining siRNA targeting VEGFA and VEGFR1 enhances therapeutic outcomes for angiogenesis inhibition.

Area of Science:

  • Biomedical Engineering
  • Molecular Biology
  • Cancer Research

Background:

  • Angiogenesis, the formation of new blood vessels, is crucial for cancer progression and pathological neovascularization.
  • Key regulatory pathways include VEGF and TGF-β, making them targets for anti-angiogenic therapies.
  • Small interfering RNA (siRNA) offers a promising strategy to suppress pro-angiogenic factors, but effective delivery is essential.

Purpose of the Study:

  • To develop and evaluate a non-viral peptide carrier (L1) for targeted delivery of anti-angiogenic siRNAs to endothelial cells.
  • To investigate the efficacy of L1-mediated siRNA delivery in silencing VEGFA, VEGFR1, and endoglin gene expression.
  • To assess the potential for synergistic effects through combinatorial siRNA delivery.

Main Methods:

  • Utilized a modular peptide carrier (L1) functionalized with a CXCR4 receptor ligand for targeted delivery.
  • Formulated siRNA/L1 polyplexes for transfection into CXCR4-positive breast cancer cells (MDA-MB-231) and endothelial cells (EA.Hy926).
  • Assessed the down-regulation of endothelial cell migration and proliferation post-transfection with anti-VEGFA, anti-VEGFR1, and anti-endoglin siRNAs.

Main Results:

  • Demonstrated efficient down-regulation of endothelial cell migration and proliferation via siRNA-induced gene silencing.
  • Confirmed successful transfection and gene silencing in both cancer and endothelial cell lines.
  • Showed that combinatorial delivery of anti-VEGFA and anti-VEGFR1 siRNAs synergistically enhanced anti-angiogenic treatment efficacy.

Conclusions:

  • The L1 peptide carrier facilitates effective delivery of anti-angiogenic siRNAs into target cells.
  • Targeted siRNA delivery demonstrates significant potential for inhibiting pathological angiogenesis.
  • Combinatorial siRNA therapy presents a promising strategy for enhanced therapeutic outcomes in angiogenesis inhibition.
Keywords:
VEGFAVEGFR1angiogenesisendoglinendothelial cellsgene silencingmigrationpeptideproliferationsiRNA delivery

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