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.