title: Improving Drug Penetrability with iRGD Leverages the Therapeutic Response to Sorafenib and Doxorubicin in Hepatocellular Carcinoma.
abstract: iRGD is a derivative of the integrin-binding peptide RGD, which selectively increases the penetrability of tumor tissue to various coadministered substances in several preclinical models. In this study, we investigated the ability of iRGD to improve the delivery of sorafenib and doxorubicin therapy in hepatocellular carcinoma (HCC) using established mouse models of the disease. A contrast-enhanced MRI method was developed in parallel to assess the in vivo effects of iRGD in this setting. We found that iRGD improved the delivery of marker substances to the tumors of HCC-bearing mice about three-fold without a parallel increase in normal tissues. Control peptides lacking the critical CendR motif had no effect. Similarly, iRGD also selectively increased the signal intensity from tumors in Gd-DTPA-enhanced MRI. In terms of antitumor efficacy, iRGD coadministration significantly augmented the individual inhibitory effects of sorafenib and doxorubicin without increasing systemic toxicity. Overall, our results offered a preclinical proof of concept for the use of iRGD coadministration as a strategy to widen the therapeutic window for HCC chemotherapy, as monitored by Gd-DTPA-enhanced MRI as a noninvasive, clinically applicable method to identify iRGD-reactive tumors.
authors.affiliation: Department of Medicine 1, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schmithals
authors.affiliation: Department of Medicine 1, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Köberle
authors.affiliation: Department of Nuclear Medicine, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Hüdayi
authors.initials: H
authors.lastname: Korkusuz
authors.affiliation: Department of Medicine 1, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pleli
authors.affiliation: Department of Medicine 1, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Kakoschky
authors.affiliation: Department of Medicine 1, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Eduardo Alonso
authors.initials: EA
authors.lastname: Augusto
authors.affiliation: Department of Medicine 1, University Hospital Frankfurt, Frankfurt, Germany. The Immunology and Infectious Diseases Laboratory, Therapeutic Chemistry Department, The National Research Center, Dokki, Cairo, Egypt.
authors.forename: Ahmed Atef
authors.initials: AA
authors.lastname: Ibrahim
authors.affiliation: Department of Medicine 1, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Arencibia
authors.affiliation: Georg-Speyer Haus, Frankfurt am Main, Germany.
authors.forename: Vida
authors.initials: V
authors.lastname: Vafaizadeh
authors.affiliation: Georg-Speyer Haus, Frankfurt am Main, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Groner
authors.affiliation: Institute of Anatomy 2, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Horst-Werner
authors.initials: HW
authors.lastname: Korf
authors.affiliation: Department of Medicine 1, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kronenberger
authors.affiliation: Department of Medicine 1, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.affiliation: Department of Diagnostic and Interventional Radiology, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Vogl
authors.affiliation: Department of Medicine 1, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Waidmann
authors.affiliation: Department of Medicine 1, University Hospital Frankfurt, Frankfurt, Germany. piiper@med.uni-frankfurt.de.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Piiper
mesh_terms: D061605:Administration, Intravenous; D020816:Amino Acid Motifs; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D005070:Evans Blue / Q000008:administration & dosage; D019786:Gadolinium DTPA; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D008279:Magnetic Resonance Imaging; D008297:Male; D008819:Mice, Nude; D008822:Mice, Transgenic; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D000077157:Sorafenib; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; C569656:N-end cysteine peptide tumor-homing peptide; D009842:Oligopeptides; D010671:Phenylurea Compounds; D009536:Niacinamide; D005070:Evans Blue; D004317:Doxorubicin; D000077157:Sorafenib; D019786:Gadolinium DTPA