Chitosan-DNA nanoparticles delivered by intrabiliary infusion enhance liver-targeted gene delivery

Hui Dai^1,2,4, Xuan Jiang⁵, Geoffrey CY Tan¹, Yong Chen², Michael Torbenson³, Kam W Leong^1,4, Hai-Quan Mao^1,5
 

¹Tissue and Therapeutic Engineering lab, Division of Johns Hopkins in Singapore, Singapore; ²Department of Hepatobiliary Surgery, Xijing Hospital, the Fourth Military Medical University, Xian, P.R. China; ³Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; ⁴Department of Biomedical Engineering, Duke University, Durham, NC, USA; ⁵Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA

Abstract: The goal of this study was to examine the efficacy of liver-targeted gene delivery by chitosan-DNA nanoparticles through retrograde intrabiliary infusion (RII). The transfection efficiency of chitosan-DNA nanoparticles, as compared with PEI-DNA nanoparticles or naked DNA, was evaluated in Wistar rats by infusion into the common bile duct, portal vein, or tail vein. Chitosan-DNA nanoparticles administrated through the portal vein or tail vein did not produce detectable luciferase expression. In contrast, rats that received chitosan-DNA nanoparticles showed more than 500 times higher luciferase expression in the liver 3 days after RII; and transgene expression levels decreased gradually over 14 days. Luciferase expression in the kidney, lung, spleen, and heart was negligible compared with that in the liver. RII of chitosan-DNA nanoparticles did not yield significant toxicity and damage to the liver and biliary tree as evidenced by liver function analysis and histopathological examination. Luciferase expression by RII of PEI-DNA nanoparticles was 17-fold lower than that of chitosan-DNA nanoparticles on day 3, but it increased slightly over time. These results suggest that RII is a promising routine to achieve liver-targeted gene delivery by non-viral nanoparticles; and both gene carrier characteristics and mode of administration significantly influence gene delivery efficiency.

Keywords: nanoparticles, gene delivery, liver-targeted, chitosan, retrograde intrabiliary infusion