Bioreducible Polymer Micelles Based on Acid-Degradable Poly(ethylene glycol)-poly(amino ketal) Enhance the Stromal Cell-Derived Factor-1 Gene Transfection Efficacy and Therapeutic Angiogenesis of Human Adipose-Derived Stem Cells

Abstract

Adipose-derived stem cells (ADSCs) have the potential to treat ischemic diseases. In general, ADSCs facilitate angiogenesis by secreting various pro-angiogenic growth factors. However, transplanted ADSCs have a low therapeutic efficacy in ischemic tissues due to their poor engraftment and low viability. Stromal cell-derived factor-1 (SDF-1) improves the survival rate of stem cells transplanted into ischemic regions. In this study, we developed acid-degradable poly(ethylene glycol)-poly(amino ketal) (PEG-PAK)-based micelles for efficient intracellular delivery of SDF-1 plasmid DNA. The SDF-1 gene was successfully delivered into human ADSCs (hADSCs) using PEG-PAK micelles. Transfection of SDF-1 increased SDF-1, vascular endothelial growth factor, and basic fibroblast growth factor gene expression and decreased apoptotic activity in hADSCs cultured under hypoxic conditions in comparison with conventional gene transfection using polyethylenimine. SDF-1-transfected hADSCs also showed significantly increased SDF-1 and VEGF expression together with reduced apoptotic activity at 4 weeks after transplantation into mouse ischemic hindlimbs. Consequently, these cells improved angiogenesis in ischemic hindlimb regions. These PEG-PAK micelles may lead to the development of a novel therapeutic modality for ischemic diseases based on an acid-degradable polymer specialized for gene delivery.