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iRGD tumor-penetrating peptide-modified oncolytic adenovirus shows enhanced tumor transduction, intratumoral dissemination and antitumor efficacy

Gene Therapy volume 21, pages 767–774 (2014)Cite this article

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Abstract

Endovenously administered oncolytic viruses extravasate and penetrate poorly into tumors. iRGD is a cyclic peptide that enhances tumor penetration when conjugated or coadministered with different types of molecules such as drugs, nanoparticles or phages. iRGD-mediated tumor penetration occurs in three steps: binding to αv-integrins on tumor vasculature or tumor cells, exposure by proteolysis of a C-terminal motif that binds to neuropilin-1 (NRP-1) and cell internalization. We have genetically inserted the iRGD peptide in the fiber C terminus of ICOVIR15K, an oncolytic tumor-retargeted adenovirus to increase its tumor penetration. In vitro, NRP-1 interaction improved binding and internalization of the virus in different cancer cells overexpressing integrins and NRP-1. However, such NRP-1-mediated internalization did not affect transduction or cytotoxicity. In vivo, iRGD did not change the normal organ transduction pattern, with liver and spleen as main targeted organs. In tumors, however, iRGD enhanced transduction and early adenovirus dissemination through the tumor mass leading to an improved antitumor efficacy.

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Acknowledgements

We thank Rafael Moreno and Helena Aguilar for their valuable technical assistance, Marta Gimenez-Alejandre for scientific discussion and Lauren Fleming for extensive revision of the manuscript. CPS was supported by a predoctoral fellowship (PFIS) granted by the ‘Instituto de Salud Carlos III’ FI08/00163. This work was supported by a BIO2011-30299-C02-01 grant from the ‘Ministerio de Educación y Ciencia’ of the Government of Spain (to RA) and a 2009SGR283 research grant from the ‘Generalitat de Catalunya’ (to RA).

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Authors and Affiliations

  1. Translational Research Laboratory, Institut Català d’Oncologia–Institut d’Investigació Biomèdica de Bellvitge (ICO-IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain

    C Puig-Saus, L A Rojas, E Laborda, A Figueras & R Alemany

  2. Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Barcelona, Spain

    E Laborda

  3. Nanotherapix, SL Parc Empresarial Can Sant Joan, Sant Cugat del Vallès, Barcelona, Spain

    R Alba

  4. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Barcelona, Spain

    C Fillat

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  1. C Puig-Saus
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Correspondence to R Alemany.

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Puig-Saus, C., Rojas, L., Laborda, E. et al. iRGD tumor-penetrating peptide-modified oncolytic adenovirus shows enhanced tumor transduction, intratumoral dissemination and antitumor efficacy. Gene Ther 21, 767–774 (2014). https://doi.org/10.1038/gt.2014.52

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