1. ¹Hybrid Systems Ltd, Oxford BioBusiness Centre, Littlemore Park, Littlemore, Oxford, UK
2. ²Department of Clinical Pharmacology, University of Oxford, Radcliffe Infirmary, Woodstock Road, Oxford, UK
3. ³Cancer Research UK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, UK
4. ⁴Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA, USA
5. ⁵Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovsky Square 2, Prague 6, The Czech Republic

Correspondence: Dr LW Seymour, Department of Clinical Pharmacology, University of Oxford, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK

Received 26 July 2003; Accepted 29 February 2004; Published online 24 June 2004.

Abstract

Systemic delivery of adenoviral vectors is a major goal in cancer gene therapy, but is currently prohibited by rapid hepatic uptake of virus following intravenous injection with levels of viable virus in the murine plasma typically falling to less than 0.1% after 30 min. We have used a surface-masking technique based on multivalent copolymers of poly(N-(2-hydroxypropyl)methacrylamide) to ablate all pathways of receptor-mediated infection, combined with dose modulation to achieve partial saturation of nonspecific uptake pathways. Polymer coating gave at least 100-fold decreased hepatic transgene expression at all doses and even high doses of coated virus (pc-virus) showed no weight loss or stimulation of serum transaminases. Low doses of virus and pc-virus (10⁹ viral particles (vp)/mouse) were mainly captured by the liver (assessed by quantitative PCR), although higher doses led to greater fractional persistence in the plasma (measured after 30 min). Coated virus at a dose of 6 10¹¹ vp/mouse showed nearly 50% plasma circulation, representing a 3.5-fold greater area under the concentration–time curve (0–30 min) compared to unmodified virus. Such an increase in the bioavailability of adenovirus, coupled with substantial decreases in toxicity and unwanted transgene expression is an important step towards producing systemically available tumour-targeted viruses.