Kidney-Specific Peptide-Conjugated Poly(ester amine) for the Treatment of Kidney Fibrosis

Abstract

Kidney gene therapy using the hepatocyte growth factor (HGF) gene may offer new strategies for the treatment of chronic renal disease such as kidney fibrosis, because HGF has the potential to promote tubular repair and to inhibit tissue fibrosis. As a non-viral vector for gene delivery, polyethylenimine (PEI) exhibits high gene expression due to its buffering capacity with cytotoxicity, although its cytotoxicity depends on its molecular weight. In this study, to minimize the cytotoxicity of PEI with a high transfection efficiency, biodegradable poly(ester amine) (PEA) based on glycerol dimethacrylate (GDM) and low molecular weight PEI (LMW PEI) was synthesized and kidney targeting peptide was conjugated to the PEA (PEP-PEA) to give it kidney cell specificity. The PEP-PEA showed good physicochemical properties as a gene delivery carrier, such as DNA condensation ability, protection of the DNA in the complexes from enzyme degradation, and formation of nanosized complexes with spherical shapes. Higher transfection efficiency in 293T cells was achieved with the PEP-PEA than with the PEA and the PEI 25 kDa with lower cytotoxicity. Also, the HGF gene that was complexed with the PEP-PEA was specifically delivered to the obstructed kidney in the unilateral ureteral obstruction (UUO) model rats. The delivered HGF gene exhibited potency in recovering renal functions, which indicates the potential of the PEP-PEA as a safe and efficient carrier for the treatment of kidney fibrosis.