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J Control Release. 2011 Mar 10;150(2):196-203. doi: 10.1016/j.jconrel.2010.10.011. Epub 2010 Oct 18.

Targeting adenovirus gene delivery to activated tumour-associated vasculature via endothelial selectins.

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  • 1Department of Clinical Pharmacology, University of Oxford, Old Road Campus, Headington, Oxford OX3 7DQ, UK. houria.bachtarzi@clinpharm.ox.ac.uk

Abstract

Clinical experience with adenovirus vectors has highlighted the need for improved delivery and targeting. Tumour-associated endothelium offers an additional mechanism for enhanced viral uptake into tumours which is accessible for systemic gene delivery. Building on expertise in using polymer 'stealthed' viruses for targeting in vivo, adenovirus expressing luciferase (Adluc) was coated with an amino-reactive polymer based on poly [N-(2-hydroxypropyl) methacrylamide] to ablate normal infection pathways. Direct linkage of a monoclonal antibody against E-selectin (MHES) demonstrated E-selectin-specific transduction of tumour necrosis factor-α (TNF-α)-activated endothelial cells. A two-component targeting system using protein G was developed, to provide optimal antibody orientation. We report an enhancement in transduction of TNF-α-activated endothelium in vitro and ex vivo in a human umbilical vein cord model using the MHES antibody. Similarly a virus retargeted using a chimeric P-selectin Glycoprotein Ligand-1-Fc fusion (PSGL-1) protein showed better circulation kinetics and significant uptake into HepG2 xenografts following systemic administration in mice, with 36-fold higher genome copies, compared with non-modified virus. Immunohistochemistry staining of tumour sections from mice treated with PSGL-1-retargeted virus showed a co-localisation of firefly luciferase with CD31 suggesting selective endothelial targeting. Employment of optimal viral modification using protein G will enable exploration and comparison of alternative targeting ligands targeting tumour-associated endothelium.

Copyright © 2010 Elsevier B.V. All rights reserved.

PMID:
20965218
[PubMed - indexed for MEDLINE]
PMCID:
PMC3071491
Free PMC Article

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