Department of Medicine 1, University Hospital Frankfurt, Frankfurt, Germany.
Department of Nuclear Medicine, University Hospital Frankfurt, Frankfurt, Germany.
Cancer Res. 2015 Aug 1;75(15):3147-54. doi: 10.1158/0008-5472.CAN-15-0395.
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.
iRGD 是整合素结合肽 RGD 的衍生物，它在几种临床前模型中选择性地增加了肿瘤组织对各种同时给予的物质的通透性。在这项研究中，我们使用已建立的肝癌（HCC）疾病小鼠模型，研究了 iRGD 提高索拉非尼和多柔比星治疗效果的能力。同时开发了一种对比增强 MRI 方法来评估 iRGD 在这种情况下的体内作用。我们发现，iRGD 将标记物质递送至 HCC 荷瘤小鼠的肿瘤中的效果提高了约三倍，而正常组织中没有平行增加。缺乏关键 CendR 模体的对照肽没有效果。同样，iRGD 也选择性地增加了 Gd-DTPA 增强 MRI 中肿瘤的信号强度。就抗肿瘤疗效而言，iRGD 联合给药显著增强了索拉非尼和多柔比星的单独抑制作用，而没有增加全身毒性。总的来说，我们的结果为 iRGD 联合给药作为 HCC 化疗治疗窗拓宽策略提供了临床前概念验证，Gd-DTPA 增强 MRI 是一种非侵入性、临床适用的方法，可识别 iRGD 反应性肿瘤。
