MRI-Monitored Delivery of Sorafenib-Eluting Microspheres to Liver Tumors

描述(申请人提供)：索拉非尼是一种有效的多激酶抑制剂，用于治疗不能切除的肝细胞癌(HCC)。然而，全身暴露可能会导致严重的毒性。索拉非尼的剂量经常必须减少或完全停止给药。微球药物输送平台有可能显著提高索拉非尼治疗肝细胞癌的疗效，同时通过定向图像引导经导管输送减少全身暴露。对索拉非尼洗脱微球进行成像的定量方法可能对及早预测疗效至关重要，从而促使根据需要调整治疗方案(补充输液或采用替代疗法)。在这个临床前项目中，我们寻求开发一种强大的新方法，用于图像引导的导管定向给药，将索拉非尼输送到肝脏肿瘤。目的1：研究聚(D，L-丙交酯-乙交酯共聚物)微球的制备方法、索拉非尼与造影剂载量、粒径分布、释放动力学和磁共振成像特性之间的关系。目的：优化SPIO标记的索拉非尼洗脱PLG微球的体内磁共振成像方法，并验证这些方法可以准确地定量肝肿瘤的导管给药。目的3：验证索拉非尼洗脱微球抑制 这项研究旨在评估血管生成和肿瘤生长之间的关系，比较索拉非尼洗脱微球、普通栓塞术和索拉非尼化学栓塞术(未包裹微球的药物输注)治疗肝脏肿瘤的结果，最后将经导管微球释放的MRI测量结果与引发的治疗反应进行比较。

DESCRIPTION (provided by applicant): Sorafenib is a potent multi-kinase inhibitor for the treatment of patients with unresectable hepatocellular carcinoma (HCC). However, systemic exposures can lead to severe toxicities. Sorafenib dose often must be reduced or administration discontinued altogether. Microsphere drug delivery platforms offer the potential to significantly increase the efficacy of sorafenib therapy for HCC while reducing systemic exposures via targeted image-guided transcatheter delivery. Quantitative approaches for imaging sorafenib-eluting microsphere delivery may be critical to permit early prediction of response thus prompting adjustments to treatment regimens as needed (additional infusions or adoption of alternative therapies). During this pre-clinical project we seek to develop a powerful new approach for image-guided catheter-directed delivery of sorafenib to liver tumors. We will address the following Specific Aims in a well-established VX-2 rabbit model of liver cancer: Aim 1: Characterize the relationship between poly(D,L-lactide-co-glycolide) (PLG) microsphere fabrication methods, sorafenib and contrast agent loading, size distribution, release kinetics, and MRI properties. Aim 2: Optimize methods for in vivo MRI of SPIO-labeled sorafenib-eluting PLG microspheres and validate that these methods permit accurate quantification of transcatheter delivery to liver tumors. Aim 3: Validate that sorafenib-eluting microspheres inhibit angiogenesis and tumor growth, compare outcomes in liver tumors treated with sorafenib-eluting microspheres, bland embolization, and sorafenib chemo- embolization (drug infusion without microsphere encapsulation), and finally compare MRI measurements of transcatheter microsphere delivery to the elicited therapeutic responses.