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Extended plasma circulation time and decreased toxicity of polymer-coated adenovirus

Gene Therapy volume 11, pages 1256–1263 (2004)Cite this article

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.

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Acknowledgements

We are grateful to the Medical Research Council (SJH, VM), Cancer Research UK (KDF) and the National Translational Cancer Network (LWS) for financial support.

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Authors and Affiliations

  1. Hybrid Systems Ltd, Oxford BioBusiness Centre, Littlemore Park, Littlemore, Oxford, UK

    N K Green, C W Herbert & A B Hale

  2. Department of Clinical Pharmacology, University of Oxford, Radcliffe Infirmary, Woodstock Road, Oxford, UK

    S J Hale, K D Fisher & L W Seymour

  3. Cancer Research UK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, UK

    V Mautner

  4. Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA, USA

    R Harkins & T Hermiston

  5. Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovsky Square 2, Prague, 6, The Czech Republic

    K Ulbrich

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  1. N K Green
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  2. C W Herbert
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  4. A B Hale
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Green, N., Herbert, C., Hale, S. et al. Extended plasma circulation time and decreased toxicity of polymer-coated adenovirus. Gene Ther 11, 1256–1263 (2004). https://doi.org/10.1038/sj.gt.3302295

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