Abstract
Abstract Cationic polymers have received much attention as promising non-viral vectors for gene transfer. However, generating polymers that are stable and can systemically deliver large amounts of nucleic acids to specific disease sites continues to be a significant hurdle to non-viral vector success. Therefore, the purpose of this study was to develop a new biocompatible and biodegradable cationic polymer system for non-viral gene delivery of plasmid DNA. Poly-d/l Aspartate-Diethylenetriamine [Poly(d/l Asp-DET)] polymers were synthesized and used to complex plasmid DNA. Polymer/DNA polyplexes were further modified by covalent coupling with various polyethylene glycol (PEG) polymers. Polyplexes were characterized and evaluated for particle size, zeta potential and morphology by TEM. Plasmid DNA stability was assessed by challenging polyplexes with serum nucleases, and the efficacy of DNA delivery and gene expression was examined by performing transfection experiments on cancer cells. In vivo DNA tumor delivery and biodistribution was also investigated using tumor bearing nude mice. Poly(d/l Asp-DET) polymers were able to bind to plasmid DNA and formed polyplex particles the were amenable to surface coating with PEG. PEG-Polyplexes were approximately ∼70nm in diameter with neutral zeta potentials. TEM confirmed that the polyplexes were uniform in size. PEG-Polyplexes were also extremely stable and maintained the structural integrity of DNA following incubation in nucleases, and were also capable of transfecting HCT-116 and PC-3 culture cells with no cell toxicity. Tail vein administration of PEG-Polyplexes to tumor bearing nude mice did not reveal any observable toxicities. Moreover, improvements in PEG polymer chemistry increased nucleic acid accumulation in tumors while reducing DNA accumulation in other tissues including liver, kidney and spleen. Poly(d/l Asp-DET) cationic polymers show enormous potential as non-viral drug delivery agents. Further, the surface modification of polyplexes with PEG allowed for sustained systemic delivery of nucleic acids to tumors. The characterization of PEG-Poly(Asp-DET)/DNA polyplexes provides useful insights that can be used to the design vectors for targeted nucleic acid delivery. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5408. doi:10.1158/1538-7445.AM2011-5408
Published Version
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