title: CXCR4-targeted modular peptide carriers for efficient anti-VEGF siRNA delivery.
abstract: The application of small interfering RNA (siRNA) for specific gene inhibition is a promising strategy in gene therapy treatments. The efficient cellular delivery of therapeutic siRNA is a critical step in RNA interference (RNAi) application. Highly efficient siRNA carriers should be developed for specific cellular uptake, stable RNA-complexes formation and intracellular RNA release. To study these features, we evaluated modular peptide carriers bearing CXCR4 targeting ligand for their ability to condense siRNA, facilitate endosomal escape and VEGFA gene silencing in CXCR4-expressing endothelial and glioblastoma cells. Peptide carriers were shown to condense and protect siRNA from RNAse degradation. Various N/P ratios were used for physicochemical characterization to optimize siRNA/peptide complexes for in vitro studies. On average, cytotoxicity of siRNA-polyplexes depended on cell type and was not higher than that of PEI/siRNA complexes. VEGFA gene knockdown was significantly improved with CXCR4-targeted carriers in contrast to nontargeted peptides. siRNA delivery by means of ligandconjugated carriers resulted in 2.5-3-fold decrease of VEGF expression in glioblastoma cells and in 1.5-2-fold decrease of VEGF expression in endothelial cells. Delivery of siRNA/peptide complexes resulted in 2-6- fold decrease in VEGF protein yield and in significant inhibition of endothelial cells migration. The study shows that implication of peptide carriers modified with CXCR4 ligand is a promising approach to develop targeted siRNA delivery system into CXCR4-expressing cancer and endothelial cells.
authors: D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Mendeleevskaya Line, 3, Saint-Petersburg 199034, Russia.
authors: Anna
authors: A
authors: Egorova
authors: D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Mendeleevskaya Line, 3, Saint-Petersburg 199034, Russia.
authors: Anastasia
authors: A
authors: Shubina
authors: D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Mendeleevskaya Line, 3, Saint-Petersburg 199034, Russia.
authors: Dmitriy
authors: D
authors: Sokolov
authors: D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Mendeleevskaya Line, 3, Saint-Petersburg 199034, Russia.
authors: Sergey
authors: S
authors: Selkov
authors: D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Mendeleevskaya Line, 3, Saint-Petersburg 199034, Russia.
authors: Vladislav
authors: V
authors: Baranov
authors: D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Mendeleevskaya Line, 3, Saint-Petersburg 199034, Russia. Electronic address: ankiselev@yahoo.co.uk.
authors: Anton
authors: A
authors: Kiselev
mesh_terms: D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D055785:Gene Knockdown Techniques / Q000379:methods; D020868:Gene Silencing / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008024:Ligands; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry*; D034622:RNA Interference / Q000187:drug effects; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C527276:CXCR4 protein, human; D004337:Drug Carriers; D008024:Ligands; D010455:Peptides; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A
keywords: CXCR4; Cross-linking peptides; Endothelium; Glioblastoma; VEGF; siRNA