Oncolytic Adenovirus Coated with Arginine Grafted and PEGylated PEI Polymer for Cancer Gene Therapy

Abstract

Adenovirus (Ad) vectors as a delivery vehicle has shown a great promise in cancer gene therapy, but its immunogenic safety concerns and coxsackievirus and adenovirus receptor (CAR) dependency have limited their use in virotherapy. To overcome these hurdles, we utilize the advantages of both viral and non-viral vectors to develop an intelligent hybrid vehicle by coating an Ad with double argininegrafted links to a polyethylene glycol(PEG)-Polyethyleneamine backbone (Ad/PPSA). We characterized the particle size and zeta potential of Ad/PPSA in a polymer concentration-dependent manner and observed an increase in size and development of a cationic charge of the overall Ad/PPSA complex. Ad/PPSA also showed a marked increase in transduction efficiency in both CAR negative and positive cells compared with naked Ad. Competition assay demonstrates that Ad/PPSA induces higher levels of transgene expression than naked Ad and is able to transduce cells independently of CAR. When oncolytic Ad was complexed with PPSA, through cancer-specific killing effect of oncolytic Ad was able to overcome the nonspecificity of polymer-mediated therapies. Furthermore, the oncolytic Ad/PPSA nanocomplex elicited a 2.24-fold greater antitumor efficacy than naked Ad, which was supported by immunohistochemical staining confirmation of the higher expression of Ad E1A in the MCF7 human tumor xenograft than those treated with naked Ad. Lastly, intravenous injection of Ad/PPSA significantly reduced the innate immune response in contrast with naked Ad, as evaluated by interleukin-6 cytokine release from serum collections. Taken together, this study demonstrates that the increased antitumor effect and improved target to both CAR negative and positive cells of Ad/PPSA makes it a promising tool for cancer gene therapy.