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

• Published in: Pharmaceutics Vol. 11; no. 6; p. 261
• Main Authors: Egorova, Anna A, Shtykalova, Sofia V, Maretina, Marianna A, Sokolov, Dmitry I, Selkov, Sergei A, Baranov, Vladislav S, Kiselev, Anton V
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06.06.2019; MDPI
• Subjects: Angiogenesis; Apoptosis; Cytotoxicity; endoglin; endothelial cells; Endothelium; Gene expression; gene silencing; Growth factors; Hypoxia; Kinases; Ligands; migration; Mutation; peptide; Peptides; Prenatal development; proliferation; siRNA delivery; Tumors; VEGFA; VEGFR1; United States > US; Finland; Russia; endothelial cells; peptide; VEGFR1; proliferation; angiogenesis; gene silencing; migration; siRNA delivery; endoglin; VEGFA
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics11060261

Angiogenesis is a process of new blood vessel formation, which plays a significant role in carcinogenesis and the development of diseases associated with pathological neovascularization. An important role in the regulation of angiogenesis belongs to several key pathways such as VEGF-pathways, TGF-β-pathways, and some others. Introduction of small interfering RNA (siRNA) against genes of pro-angogenic factors is a promising strategy for the therapeutic suppression of angiogenesis. These siRNA molecules need to be specifically delivered into endothelial cells, and non-viral carriers modified with cellular receptor ligands can be proposed as perspective delivery systems for anti-angiogenic therapy purposes. Here we used modular peptide carrier L1, containing a ligand for the CXCR4 receptor, for the delivery of siRNAs targeting expression of VEGFA, VEGFR1 and endoglin genes. Transfection properties of siRNA/L1 polyplexes were studied in CXCR4-positive breast cancer cells MDA-MB-231 and endothelial cells EA.Hy926. We have demonstrated the efficient down-regulation of endothelial cells migration and proliferation by anti-VEGFA, anti-VEGFR1, and anti-endoglin siRNA-induced silencing. It was found that the efficiency of anti-angiogenic treatment can be synergistically improved via the combinatorial delivery of anti-VEGFA and anti-VEGFR1 siRNAs. Thus, this approach can be useful for the development of therapeutic angiogenesis inhibition.