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

描述（由申请方提供）：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）患者。然而，全身暴露可导致严重毒性。索拉非尼剂量通常必须减少或完全停止给药。微球药物递送平台提供了显著提高索拉非尼治疗HCC的疗效的潜力，同时通过靶向图像引导的经导管递送降低全身暴露。索拉非尼洗脱微球给药成像的定量方法对于早期预测反应可能至关重要，从而促使根据需要调整治疗方案（额外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，用于图像引导的导管定向递送索拉非尼至肝肿瘤。我们将在成熟的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-共-乙交酯）（PLG）微球制造方法、索拉非尼和造影剂载量、尺寸分布、释放动力学和MRI特性之间的关系。目标二：优化SPIO标记的索拉非尼洗脱PLG微球的体内MRI方法，并验证这些方法允许经导管递送至肝肿瘤的准确定量。目的3：证实索拉非尼洗脱微球抑制 血管生成和肿瘤生长，比较用索拉非尼洗脱微球、温和栓塞和索拉非尼化疗栓塞（没有微球包封的药物输注）治疗的肝肿瘤的结果，最后比较经导管微球递送的MRI测量与引起的治疗反应。

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.