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Efficient delivery of angiostatin K1-5 into tumors following insertion of an NGR peptide into adenovirus capsid

Gene Therapy volume 16, pages 1405–1415 (2009)Cite this article

Abstract

Adenovirus (Ad)-mediated delivery of anti-angiogenic molecules into tumors constitutes an appealing approach for growth inhibition. However, lack of expression on tumors of Ad receptors leads to weak tumor transduction. Therefore, to provide Ad with a new entry pathway into tumors, an NGR peptide was inserted into either fiber (AdFNGR) or hexon (AdHNGR) capsid proteins. This strategy provided Ad with a very efficient entry pathway in both endothelial cells and tumor cells, with the highest efficacy observed for AdHNGR. Using pharmacological, biochemical and genetic approaches, AdHNGR and AdFNGR were shown to bind not only to CD13 receptor, but also to αvβ3 integrins. Both vectors were efficient tools to deliver angiostatin K1-5 cDNA into endothelial cells, thus leading to a dramatic inhibition of their proliferation and increased cell death. Although AdHNGR and Adwt were found to display similar gene transduction efficacy in Lewis lung carcinoma (LLC), pseudotyping AdHNGR with an Ad3-fiber unmasked the ability of NGR-peptide to target these tumors. As a result, delivery of angiostatin K1-5 cDNA into highly aggressive tumors translated into a stronger inhibition of their growth. Altogether, our results suggest that NGR-bearing Ad are valuable tools to realize the potential of this anti-angiogenic approach to anti-tumor therapy.

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Acknowledgements

We thank C Ransy for Ad titration, F Larbret and Y Lecluse for cell sorting, A Galaup for providing us with K1-5 plasmid. We are also very grateful to all the staff of the animal facilities for technical help and animal care. The work was funded by the CNRS and the Association pour la Recherche contre le Cancer (ARC) to KB. BJ and FV received fellowships from the Ministère de la Recherche et de la Technologie; BJ received other fellowships from the Société Française du Cancer and ARC; FV received other fellowships from the Association Française contre les Myopathies and the Société Française d’Hématologie.

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Authors and Affiliations

  1. CNRS UMR 8121, Vectorologie et Transfert de Gènes, Institut Gustave Roussy, Villejuif Cedex, France

    B Jullienne, F Vigant, E Muth, C Bouquet, M Perricaudet & K Benihoud

  2. Université Paris−Sud, Orsay Cedex, France

    B Jullienne, F Vigant, E Muth, M Perricaudet & K Benihoud

  3. NSERM U790, Hématopoïèse et cellules souches normales et pathologiques, Université Paris-Sud, Institut Gustave Roussy, Villejuif Cedex, France

    R Chaligné & S Giraudier

  4. Bioalliance, Paris, France

    C Bouquet

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  1. B Jullienne
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Correspondence to K Benihoud.

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Supplementary Information accompanies the paper on Gene Therapy website (http://www.nature.com/gt)

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Jullienne, B., Vigant, F., Muth, E. et al. Efficient delivery of angiostatin K1-5 into tumors following insertion of an NGR peptide into adenovirus capsid. Gene Ther 16, 1405–1415 (2009). https://doi.org/10.1038/gt.2009.97

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