A galactose-functionalized dendritic siRNA-nanovector to potentiate hepatitis C inhibition in liver cells

Lakshminarayanan, Abirami and Reddy, Uma B and Raghav, Nallani and Ravi, Vijay Kumar and Kumar, Anuj and Maiti, Prabal K and Sood, AK and Jayaraman, N and Das, Saumitra (2015) A galactose-functionalized dendritic siRNA-nanovector to potentiate hepatitis C inhibition in liver cells. In: NANOSCALE, 7 (40). pp. 16921-16931.

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Abstract

A RNAi based antiviral strategy holds the promise to impede hepatitis C viral (HCV) infection overcoming the problem of emergence of drug resistant variants, usually encountered in the interferon free direct-acting antiviral therapy. Targeted delivery of siRNA helps minimize adverse `off-target' effects and maximize the efficacy of therapeutic response. Herein, we report the delivery of siRNA against the conserved 5'-untranslated region (UTR) of HCV RNA using a liver-targeted dendritic nano-vector functionalized with a galactopyranoside ligand (DG). Physico-chemical characterization revealed finer details of complexation of DG with siRNA, whereas molecular dynamic simulations demonstrated sugar moieties projecting ``out'' in the complex. Preferential delivery of siRNA to the liver was achieved through a highly specific ligand-receptor interaction between dendritic galactose and the asialoglycoprotein receptor. The siRNA-DG complex exhibited perinuclear localization in liver cells and co-localization with viral proteins. The histopathological studies showed the systemic tolerance and biocompatibility of DG. Further, whole body imaging and immunohistochemistry studies confirmed the preferential delivery of the nucleic acid to mice liver. Significant decrease in HCV RNA levels (up to 75%) was achieved in HCV subgenomic replicon and full length HCV-JFH1 infectious cell culture systems. The multidisciplinary approach provides the `proof of concept' for restricted delivery of therapeutic siRNAs using a target oriented dendritic nano-vector.

Item Type:	Journal Article
Publication:	NANOSCALE
Publisher:	ROYAL SOC CHEMISTRY
Additional Information:	Copy right for this article belongs to the ROYAL SOC CHEMISTRY, THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology Division of Chemical Sciences > Organic Chemistry Division of Physical & Mathematical Sciences > Physics
Date Deposited:	12 Nov 2015 05:14
Last Modified:	12 Nov 2015 05:14
URI:	http://eprints.iisc.ac.in/id/eprint/52743

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