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

Tissue and Therapeutic Engineering Lab, Division of Johns Hopkins in Singapore, Singapore.
International Journal of Nanomedicine (Impact Factor: 4.38). 02/2006; 1(4):507-22. DOI: 10.2147/nano.2006.1.4.507
Source: PubMed


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.

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    • "Although the therapeutic strategy aimed at selective enrichment of the therapeutic at the fibrotic foci, the acute changes in hepatic sinusoids during fibrosis pose the risks of obstruction of the sinusoids and increased portal hypertension (DeLeve, 2007). When compared to portal vein infusion, retrograde intrabiliary infusion has several advantages , such as reducing contact with Kupffer cells, increased delivery to the liver, and significant increases in the transgene expression (Otsuka et al., 2000; Dai et al., 2006). To circumvent the damaged hepatic microvasculature and increase the delivery efficacy to the fibrotic liver, we administered the HSC-targeted therapeutic complexes through retrograde intrabiliary infusion. "
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    ABSTRACT: Liver fibrosis generates fibrotic foci with abundant activated hepatic stellate cells and excessive collagen deposition juxtaposed with healthy regions. Targeted delivery of anti-fibrotic therapeutics to hepatic stellate cells (HSCs) might improve treatment outcomes and reduce adverse effects on healthy tissue. We delivered the hepatocyte growth factor (HGF) gene specifically to activated hepatic stellate cells in fibrotic liver using vitamin A-coupled liposomes by retrograde intrabiliary infusion to bypass capillarized hepatic sinusoids. The anti-fibrotic effects of DsRed2-HGF vector encapsulated within vitamin A-coupled liposomes were validated by decreases in fibrotic markers in vitro. Fibrotic cultures transfected with the targeted transgene showed a significant decrease in fibrotic markers such as transforming growth factor-beta1. In rats, dimethylnitrosamine-induced liver fibrosis is manifested by an increase in collagen deposition and severe defenestration of sinusoidal endothelial cells. The HSC-targeted transgene, administered via retrograde intrabiliary infusion in fibrotic rats, successfully reduced liver fibrosis markers alpha-smooth muscle actin and collagen, accompanied by an increase in the expression of DsRed2-HGF near the fibrotic foci. Thus targeted delivery of HGF gene to hepatic stellate cells increased the transgene expression at the fibrotic foci and strongly enhanced its anti-fibrotic effects.
    Full-text · Article · Mar 2013 · Human gene therapy
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    • "We also determined that ceria induced dose-dependent activation of Kupffer cells with subsequent nanoceria uptake into hepatocytes (Yokel et al., 2009). Kupffer cells residing along the hepatic sinusoidal lining are known to be the first macrophages to contact xenobiotic materials, such as an infusion of nanoceria, entering the liver from the hepatic portal vein (Dai et al., 2006; Sadauskas et al., 2009; Zhang et al., 2005). Additionally, the liver is known to be a major immunological organ affecting systemic responses in animals in response to xenobiotics, in part because of the abundance of mononuclear phagocytes (Si-Tayeb et al., 2010). "
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    ABSTRACT: Beyond the traditional use of ceria as an abrasive, the scope of nanoceria applications now extends into fuel cell manufacturing, diesel fuel additives, and for therapeutic intervention as a putative antioxidant. However, the biological effects of nanoceria exposure have yet to be fully defined, which gave us the impetus to examine its systemic biodistribution and biological responses. An extensively characterized nanoceria (5 nm) dispersion was vascularly infused into rats, which were terminated 1 h, 20 h or 30 days later. Light and electron microscopic tissue characterization was conducted and hepatic oxidative stress parameters determined. We observed acute ceria nanoparticle sequestration by Kupffer cells with subsequent bioretention in parenchymal cells as well. The internalized ceria nanoparticles appeared as spherical agglomerates of varying dimension without specific organelle penetration. In hepatocytes, the agglomerated nanoceria frequently localized to the plasma membrane facing bile canaliculi. Hepatic stellate cells also sequestered nanoceria. Within the sinusoids, sustained nanoceria bioretention was associated with granuloma formations comprised of Kupffer cells and intermingling CD3⁺ T cells. A statistically significant elevation of serum aspartate aminotransferase (AST) level was seen at 1 and 20 h, but subsided by 30 days after ceria administration. Further, elevated apoptosis was observed on day 30. These findings, together with increased hepatic protein carbonyl levels on day 30, indicate ceria-induced hepatic injury and oxidative stress, respectively. Such observations suggest a single vascular infusion of nanoceria can lead to persistent hepatic retention of particles with possible implications for occupational and therapeutic exposures.
    Full-text · Article · Feb 2012 · Toxicology and Applied Pharmacology
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    • "Those findings indicated that PEI- DNA nanoparticles may induce a higher level of KC activation, and thus lead to stronger inhibition of transfection efficiency in the liver, compared with the other two groups. In addition, we found that, unlike that in untreated rats, the transfection efficiency of these carriers after KC removal correlated well with that in primary hepatocyte culture (Dai et al., 2006). The method for transient depletion of KCs is an attractive approach for potential clinical application. "
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    ABSTRACT: In this report, we have demonstrated that by temporarily removing Kupffer cells (KCs), the transgene expression levels mediated by retrograde intrabiliary infusion (RII) of plasmid DNA, polyethylenimine-DNA, and chitosan nanoparticles were enhanced by 1,927-, 131-, and 23,450-fold, respectively, in comparison with the respective groups without KC removal. KC removal also led to significantly prolonged transgene expression in the liver that received all three carriers. This increased transgene expression was correlated with significantly reduced serum tumor necrosis factor-α level as an indicator for KC activation. These results suggest that KC activation is a significant contributing factor to the lowered transgene expression by polycation-DNA nanoparticles delivered by RII. More importantly, the combination of RII and transient removal of KCs may be adopted as an effective approach to achieving high and persistent transgene expression in the liver mediated by nonviral nanoparticles.
    Full-text · Article · Nov 2010 · Human gene therapy
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