title: 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.
authors.affiliation: Department of Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors.forename: Hyun-Ji
authors.initials: HJ
authors.lastname: Park
authors.forename: Joan
authors.initials: J
authors.lastname: Lee
authors.forename: Mun-Jung
authors.initials: MJ
authors.lastname: Kim
authors.forename: Taek Jin
authors.initials: TJ
authors.lastname: Kang
authors.forename: Yongsu
authors.initials: Y
authors.lastname: Jeong
authors.forename: Soong Ho
authors.initials: SH
authors.lastname: Um
authors.forename: Seung-Woo
authors.initials: SW
authors.lastname: Cho
mesh_terms: D000818:Animals; D001673:Biodegradation, Environmental; D002412:Cations / Q000737:chemistry; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D053823:Hedgehog Proteins / Q000235:genetics / Q000627:therapeutic use*; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D023421:Models, Animal; D053758:Nanoparticles / Q000737:chemistry*; D010957:Plasmids; D011108:Polymers / Q000737:chemistry*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects / Q000293:injuries; D014162:Transfection; D042442:Vascular Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D002412:Cations; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D053823:Hedgehog Proteins; D011108:Polymers; D042442:Vascular Endothelial Growth Factors; C507253:poly(beta-amino ester); D001616:beta-Galactosidase