Improving Drug Penetrability with iRGD Leverages the Therapeutic Response to Sorafenib and Doxorubicin in Hepatocellular Carcinoma
| Autor: | Christian Schmithals, Ahmed Atef Ibrahim, Stefan Zeuzem, Verena Köberle, Albrecht Piiper, Jose M. Arencibia, Thomas J. Vogl, Bianca Kakoschky, Vida Vafaizadeh, Bernd Kronenberger, Oliver Waidmann, Bernd Groner, Horst-Werner Korf, Eduardo Alonso Augusto, Thomas Pleli, H. Korkusuz |
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| Rok vydání: | 2015 |
| Předmět: |
Gadolinium DTPA
Male Niacinamide Drug Sorafenib Cancer Research Carcinoma Hepatocellular media_common.quotation_subject medicine.medical_treatment Amino Acid Motifs Normal tissue Mice Nude Antineoplastic Agents Mice Transgenic Pharmacology Drug Delivery Systems In vivo Antineoplastic Combined Chemotherapy Protocols medicine Carcinoma Animals Humans Tissue Distribution Doxorubicin media_common Chemotherapy business.industry Phenylurea Compounds Liver Neoplasms Hep G2 Cells medicine.disease Magnetic Resonance Imaging Oncology Hepatocellular carcinoma Administration Intravenous business Oligopeptides Evans Blue medicine.drug |
| Zdroj: | Cancer Research. 75:3147-3154 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-15-0395 |
| Popis: | 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. Cancer Res; 75(15); 3147–54. ©2015 AACR. |
| Databáze: | OpenAIRE |
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