PEGylation of Polypropylenimine Dendrimer with Alkylcarboxylate Chain Linkage to Improve DNA Delivery and Cytotoxicity.

Abstract

One of the major limitations of effective nonviral gene carriers is their potential high cytotoxicity. Conjugation of polyethylene glycol (PEG) to polymers is a common approach to decrease toxicity and improve biodistribution. The aim of this study was to evaluate the effect of PEGylation on generation 5 polypropylenimine (PPI) dendrimer by using PEG moieties or alkyl-PEG groups. Polymers were synthesized by grafting of 5 and 10 % primary amines of PPI to NH2-PEG-COOH or Br-(CH2)9-CO-NH-PEG-COOH through Amide bond formation or nucleophilic substitution, respectively. Transfection efficiency and cytotoxicity were analyzed after 4 and 24 h exposure of neuroblastoma cell line (Neuro-2a) with synthesized vectors. Among all of the PEG-PPI derivatives, 5 % PEG-conjugated G5 PPI with alkyl chain (PPI-alkyl-PEG 5 %) resulted in the most efficient gene expression. This vector also significantly decreased the in vitro cytotoxicity and sub-G1 peak in flow cytometry histogram after 24 h incubation. Our results indicate that modification of 5 % primary amines of G5 PPI with PEG using alkyl chain as linker produces a promising vector combining low cytotoxicity, appropriate biodegradability, and high gene transfection efficiency.