title: 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.
authors.affiliation: Translational Research Laboratory, Institut Català d'Oncologia-Institut d'Investigació Biomèdica de Bellvitge (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Puig-Saus
authors.affiliation: Translational Research Laboratory, Institut Català d'Oncologia-Institut d'Investigació Biomèdica de Bellvitge (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: L A
authors.initials: LA
authors.lastname: Rojas
authors.affiliation: 1] Translational Research Laboratory, Institut Català d'Oncologia-Institut d'Investigació Biomèdica de Bellvitge (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain [2] Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Laborda
authors.affiliation: Translational Research Laboratory, Institut Català d'Oncologia-Institut d'Investigació Biomèdica de Bellvitge (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Figueras
authors.affiliation: Nanotherapix, SL Parc Empresarial Can Sant Joan, Sant Cugat del Vallès, Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Alba
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Fillat
authors.affiliation: Translational Research Laboratory, Institut Català d'Oncologia-Institut d'Investigació Biomèdica de Bellvitge (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Alemany
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D039942:Neuropilin-1 / Q000378:metabolism; D009842:Oligopeptides / Q000627:therapeutic use*; D050130:Oncolytic Virotherapy / Q000379:methods*; D053586:Virus Internalization; D023041:Xenograft Model Antitumor Assays
chemical_list: C569656:N-end cysteine peptide tumor-homing peptide; D009842:Oligopeptides; D039942:Neuropilin-1