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

• Published in: Gene therapy Vol. 16; no. 12; pp. 1405 - 1415
• Main Authors: Jullienne, B, Vigant, F, Muth, E, Chaligné, R, Bouquet, C, Giraudier, S, Perricaudet, M, Benihoud, K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2009; Nature Publishing Group
• Subjects: Adenoviridae - genetics; Adenovirus; Adenoviruses; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Angiogenesis; Angiostatin; Angiostatins - therapeutic use; Animals; Applied cell therapy and gene therapy; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Biotechnology; Capsid; Carcinoma, Lewis Lung; CD13 antigen; CD13 Antigens; Cell Biology; Cell death; Cell Line, Tumor; Cell proliferation; Cytokine Receptor gp130; Drug therapy; Endothelial Cells; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene Therapy; Gene Transfer Techniques; Genetic aspects; Genetic Therapy - methods; Genetic Vectors; Growth inhibition; Health. Pharmaceutical industry; Human Genetics; Humans; Industrial applications and implications. Economical aspects; Insertion; Integrins; Lung carcinoma; Medical sciences; Methods; Mice; Nanotechnology; Neoplasms - therapy; Oligopeptides; original-article; Peptides; Physiological aspects; Transduction, Genetic; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Tumor cells; Tumors; Viral proteins; France; capsid engineering; angiostatin; aminopeptidase N; integrin; adenovirus; Adenoviridae; Peptides; Enzyme; Aminopeptidases; Insertion; Virus; Peptidases; Integrin; Hydrolases; Tumor; Mutation; Capsid; Gene therapy; Vector; Membrane alanyl aminopeptidase
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2009.97

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.