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

描述（由申请人提供）：索拉非尼是一种有效的多激酶抑制剂，用于治疗不可切除的肝细胞癌（HCC）。然而，全身接触可导致严重的毒性。通常必须减少索拉非尼剂量或完全停用。微球给药平台有可能显著提高索拉非尼治疗HCC的疗效，同时通过靶向图像引导的经导管给药减少全身暴露。sorafenib洗脱微球给药成像的定量方法可能是早期预测反应的关键，从而根据需要调整治疗方案（额外的输注或采用替代疗法）。在这个临床前项目中，我们寻求开发一种强大的新方法，用于图像引导导管定向输送索拉非尼到肝脏肿瘤。我们将在一个完善的VX-2兔肝癌模型中解决以下具体目标：目标1：表征聚（D， l-丙交酯-羟基乙酸酯）（PLG）微球制造方法，索拉非尼和造影剂负载，大小分布，释放动力学和MRI特性之间的关系。目的2：优化spio标记索拉非尼洗脱PLG微球的体内MRI方法，并验证这些方法可以准确定量经导管给肝肿瘤。目的3：验证索拉非尼洗脱微球抑制

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.