2. Academic Validation
  3. Improving Drug Penetrability with iRGD Leverages the Therapeutic Response to Sorafenib and Doxorubicin in Hepatocellular Carcinoma

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

  • Cancer Res. 2015 Aug 1;75(15):3147-54. doi: 10.1158/0008-5472.CAN-15-0395.
Christian Schmithals 1,  Verena Köberle 1,  Hüdayi Korkusuz 2,  Thomas Pleli 1,  Bianca Kakoschky 1,  Eduardo Alonso Augusto 1,  Ahmed Atef Ibrahim 3,  Jose M Arencibia 1,  Vida Vafaizadeh 4,  Bernd Groner 4,  Horst-Werner Korf 5,  Bernd Kronenberger 1,  Stefan Zeuzem 1,  Thomas J Vogl 6,  Oliver Waidmann 1,  Albrecht Piiper 7
Affiliations

Affiliations

  • 1 Department of Medicine 1, University Hospital Frankfurt, Frankfurt, Germany.
  • 2 Department of Nuclear Medicine, University Hospital Frankfurt, Frankfurt, Germany.
  • 3 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.
  • 4 Georg-Speyer Haus, Frankfurt am Main, Germany.
  • 5 Institute of Anatomy 2, University Hospital Frankfurt, Frankfurt, Germany.
  • 6 Department of Diagnostic and Interventional Radiology, University Hospital Frankfurt, Frankfurt, Germany.
  • 7 Department of Medicine 1, University Hospital Frankfurt, Frankfurt, Germany. piiper@med.uni-frankfurt.de.
PMID: 26239478 DOI: 10.1158/0008-5472.CAN-15-0395
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.

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