Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1016/j.jconrel.2010.10.011

Type

Journal article

Journal

J Control Release

Publication Date

10/03/2011

Volume

150

Pages

196 - 203

Keywords

Acrylamides, Adenoviridae, Animals, Antibodies, Monoclonal, Bacterial Proteins, Cell Line, Tumor, Cells, Cultured, E-Selectin, Endothelial Cells, Endothelium, Vascular, Female, Gene Transfer Techniques, Hep G2 Cells, Humans, Luciferases, Firefly, Membrane Glycoproteins, Mice, Mice, Nude, Neoplasms, P-Selectin, Platelet Endothelial Cell Adhesion Molecule-1, Selectins, Transduction, Genetic, Tumor Necrosis Factor-alpha, Umbilical Cord, Viral Load, Xenograft Model Antitumor Assays