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

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.

Viral and Other Cell-Penetrating Peptides as Vectors of Therapeutic Agents in Medicine

“…Peptide/protein and nucleic acids were delivered into the cells, both in vitro and in vivo, respectively (Morris et al, 2008). Since that time, the new CPP-based carrier-cargo complexes have been under intensive development (Jafari et al, 2013;Montrose et al, 2013;Puig-Saus et al, 2014).…”

Improving Drug Penetrability with iRGD Leverages the Therapeutic Response to Sorafenib and Doxorubicin in Hepatocellular Carcinoma

“…This results in the generation of CRGDK/R, which dissociates from the integrins and binds to neuropilin-1 (NRP1), thereby activating an endocytic bulk transport pathway through the tumor tissue (8)(9)(10)(11). The increased tumor delivery of iRGDconjugated payloads has been shown in different experimental tumor models by other independent studies (12,13) and translates into a higher therapeutic efficacy (4,5).…”

In vivo tumor gene delivery using novel peptideticles: pH‐responsive and ligand targeted core–shell nanoassembly

“…As revealed by fluorescence analysis, the iRGD targeted peptideticles attach to HUVEC cells through specific interaction between RGD motif and αv integrin(Fig. a ) . This selective targeting strategy ensures the preferentially migration of the peptideticles toward tumor vessels, extravasation to tumor tissue and thereby its accumulation at tumor perivascular that increases their local concentration .…”