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

MRI 监测索拉非尼洗脱微球向肝脏肿瘤的递送

基本信息

批准号：
9195072
负责人：
Andrew Christian Larson
金额：
$ 44.93万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9195072
关键词：
90Y Address Adoption Adverse effects Alternative Therapies Angiogenesis Inhibition BAY 54-9085 Biodistribution Biomedical Engineering Blood Vessels Catheters Cell Proliferation Chemical Engineering Chemoembolization Contrast Media Devices Diarrhea Dose Drug Carriers Drug Delivery Systems Emulsions Encapsulated Exanthema FDA approved Hypertension Image Individual Infusion procedures Injection of therapeutic agent Intervention KDR gene Kinetics Label Lead Liver neoplasms Liver parenchyma Magnetic Resonance Imaging Malignant neoplasm of liver Measurement Membrane Methods Microspheres Mitogen-Activated Protein Kinases Modeling Monitor ORALIT Oral Oryctolagus cuniculus Outcome Palliative Care Palmar-plantar erythrodysesthesia syndrome Pathway interactions Patients Pharmaceutical Preparations Platelet-Derived Growth Factor Receptor Polymers Prediction of Response to Therapy Primary carcinoma of the liver cells Process Property Radioembolization Radiology Specialty Severities Solvents Techniques Therapeutic Embolization Tissues Toxic effect Treatment Efficacy Treatment Protocols Unresectable angiogenesis biocompatible polymer evaporation feeding ferrofluid follow-up image guided image visualization imaging approach imaging modality imaging properties in vivo inhibitor/antagonist intrahepatic iron oxide nanoparticle non-invasive imaging novel strategies oncology poly(D,L-lactide-co-glycolide)pre-clinical predicting response public health relevance response systemic toxicity tablet formulation targeted imaging therapy outcome trait treatment response tumor tumor growth tumor specificity tumor vascular supply vascular bed

90Y Address Adoption Adverse effects Alternative Therapies Angiogenesis Inhibition BAY 54-9085 Biodistribution Biomedical Engineering Blood Vessels Catheters Cell Proliferation Chemical Engineering Chemoembolization Contrast Media Devices Diarrhea Dose Drug Carriers Drug Delivery Systems Emulsions Encapsulated Exanthema FDA approved Hypertension Image Individual Infusion procedures Injection of therapeutic agent Intervention KDR gene Kinetics Label Lead Liver neoplasms Liver parenchyma Magnetic Resonance Imaging Malignant neoplasm of liver Measurement Membrane Methods Microspheres Mitogen-Activated Protein Kinases Modeling Monitor ORALIT Oral Oryctolagus cuniculus Outcome Palliative Care Palmar-plantar erythrodysesthesia syndrome Pathway interactions Patients Pharmaceutical Preparations Platelet-Derived Growth Factor Receptor Polymers Prediction of Response to Therapy Primary carcinoma of the liver cells Process Property Radioembolization Radiology Specialty Severities Solvents Techniques Therapeutic Embolization Tissues Toxic effect Treatment Efficacy Treatment Protocols Unresectable angiogenesis biocompatible polymer evaporation feeding ferrofluid follow-up image guided image visualization imaging approach imaging modality imaging properties in vivo inhibitor/antagonist intrahepatic iron oxide nanoparticle non-invasive imaging novel strategies oncology poly(D,L-lactide-co-glycolide)pre-clinical predicting response public health relevance response systemic toxicity tablet formulation targeted imaging therapy outcome trait treatment response tumor tumor growth tumor specificity tumor vascular supply vascular bed

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项目摘要

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.

描述（由申请人提供）：索拉非尼是一种有效的多激酶抑制剂，用于治疗无法切除的肝细胞癌（HCC）患者。但是，全身暴露会导致严重的毒性。索拉非尼剂量通常必须减少或完全停止。微球药物输送平台提供了显着提高索拉非尼治疗HCC功效的潜力，同时通过针对性的图像引导的经导管递送减少系统性暴露。对索拉非尼洗脱微球递送的成像的定量方法对于允许早期预测反应至关重要，从而促使根据需要调整对治疗方案的调整（其他输注或采用替代疗法）。在这个临床前项目中，我们试图开发一种强大的新方法，用于将索拉非尼转向肝肿瘤的导管指导输送。我们将在建立良好的肝癌VX-2兔模型中解决以下特定目标：AIM 1：表征Poly（D，L-甲状腺素-CO-glycolide）（PLG）微球制造方法之间的关系，Sorafenib和对比剂载体载荷，尺寸分布，释放动力学和MRI特性。 AIM 2：优化对SPIO标记的索拉非尼PLG微球的体内MRI方法，并验证这些方法是否可以准确地量化经导管向肝肿瘤的递送。 AIM 3：验证索拉非尼洗脱微球抑制血管生成和肿瘤生长，比较了用索拉非尼洗脱微球治疗的肝肿瘤的结局，平淡的栓塞和索拉非尼化学栓塞（无微粒封装的药物输注），并最终比较了对跨科学微球递送到激烈的治疗反应的MRI测量。