Antiangiogenic gene therapy

Abstract

Angiogenesis is one of the crucial steps in tumor development and progression, as the formation of a blood vessel network within the tumor enables the tumor to grow and allows tumor cells to enter the blood stream and form distant metastases. Signaling molecules consist mainly of soluble ligands and their receptors on endothelial cells, and the most representative activators are vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF/FGF2). Targeting of angiogenesis activators or the delivery of inhibitors by gene electrotransfer is a promising approach for cancer therapy. Gene electrotransfer is based on electroporation, a physical method, which causes a transient increase in cell membrane permeability due to the application of electric pulses and thus enables the transport of large molecules into cells. Gene electrotransfer was already used to deliver antiangiogenic plasmids or small interfering molecules (siRNA) into cells, targeting different molecular targets involved in angiogenesis, including VEGF pathway, TGF-β and endoglin pathway, integrins, FGF2, and others. Gene electrotransfer of plasmids encoding different antiangiogenic molecules has been proven to be safe, feasible, and effective. Various in vitro and in vivo studies demonstrated its great potential for further research. This approach could easily be implemented into everyday clinical practice. For ensuring safer gene electrotransfer in clinical practice, the use of tissue-specific plasmids, without antibiotic resistance gene, would be preferred.