Sonic hedgehog intradermal gene therapy using a biodegradable poly(β-amino esters) nanoparticle to enhance wound healing

Abstract

Biodegradable cationic poly(β-amino esters) (PBAE) nanoparticles are promising tools for delivering genes into various types of cells and tissues. Specific end-modification of the PBAE terminal parts significantly improves the efficiency of gene delivery in vitro and in vivo, and reduces cytotoxicity. Here, we demonstrated that amine end-modified PBAE nanoparticles can be used for intradermal delivery of therapeutic genes for wound healing in an animal skin wound model. Sonic hedgehog (SHH), a prototypical morphogen with angiogenic potential, was applied as a therapeutic gene to regenerate skin tissue. Amine end-modified PBAEs showed higher gene transfection efficiency in vitro than the commercial reagent, Lipofectamine 2000. Intradermal delivery of the SHH gene using amine end-modified PBAEs was tested in a readout mouse model of SHH signaling. We evaluated its therapeutic efficacy in mice with full-thickness skin wounds. SHH gene therapy significantly increased the expression of the angiogenic growth factor, vascular endothelial growth factor, and the stromal cell-derived factor-1α chemokine within the wounded regions early after injection. Ultimately, wound closure was accelerated in mice receiving the PBAE/SHH gene therapy compared to mice receiving intradermal delivery of a control gene (β-galactosidase plasmid) by PBAE nanoparticles. Quantitative real-time polymerase chain reaction and histological analysis revealed that there were significant improvements in epidermis regeneration and blood vessel formation in the mice treated with PBAE/SHH nanoparticles. In conclusion, SHH intradermal gene therapy using biodegradable PBAE nanoparticles is a potential treatment to promote wound healing.