Enabling high dose regional chemotherapy while minimizing systemic toxicity

实现高剂量局部化疗，同时最大限度地减少全身毒性

• 批准号: 8004768
• 负责人: SHAKER A MOUSA
• 金额: $ 15.93万
• 依托单位: VASCULAR VISION PHARMACEUTICALS COMPANY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-16 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8004768
• 关键词: Adverse effects; Antineoplastic Agents; Biocompatible; Blood; Blood Chemical Analysis; Blood Vessels; Blood coagulation; Body Regions; Cancer Patient; Carbon; Cattle; Cellulose; Charcoal; Clinical; Clinical Research; Coagulation Process; Disorder by Site; Dose; Doxorubicin; Drug Delivery Systems; Excision; Exhibits; Filtration; Heparin; Hepatic; Legal patent; Localized Malignant Neoplasm; Malignant neoplasm of liver; Measures; Patients; Perfusion; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase II Clinical Trials; Platelet Activation; Polymethyl Methacrylate; Quality of life; Regional Cancer; Regional Chemotherapy; Research; Site; Small Business Technology Transfer Research; System; Systemic disease; Technology; Testing; Toxic effect; Vision; abstracting; base; biomaterial compatibility; blood perfusion; cancer site; cancer therapy; chemotherapeutic agent; chemotherapy; improved; novel; polymethacrylate; programs; public health relevance; tumor

DESCRIPTION (provided by applicant): Enabling high dose regional chemotherapy with minimal systemic toxicity Abstract: The primary objective of this proposed study is to develop a filtration system that maximizes the removal (>90%) of chemotherapeutic agents, such as doxorubicin, from blood while minimizing adverse effects of filtration on blood chemistry and hematological parameters. Vascular Vision Pharmaceuticals Co. (VVP) and Delcath Systems are at the forefront of cancer treatment. Delcath's proprietary technology for localized drug delivery, Percutaneous Hepatic Perfusion" (PHP"), allows the delivery of significantly higher doses of anti-cancer drug directly to the cancer site as compared to systemic delivery without exposure of the entire body to potent levels of drug. Initial results from clinical studies in liver cancer patients have confirmed that delivery of higher levels of anti-cancer drug directly to the tumor site with minimal exposure of other regions of the body enhances tumor shrinkage and improves quality of life as compared to systemic cancer therapies. PHPTM is currently under testing in Phase II clinical trials for a variety of cancers of the liver. The proposed research program relates to the application of PHPTM to localized cancer therapy and targeted drug delivery. Current Delcath filters consist of activated carbon coated with polymethacrylate to insulate the blood from direct contact with the filter material. These filters exhibit low first-pass extraction capability, resulting in suboptimal removal of chemotherapeutic agent, and shedding of carbon debris, resulting in activation of the clotting cascade and damage to the blood. Thus, there is an urgent need for filters with better efficiency and biocompatibility. The specific aims of this Phase I STTR proposal are as follows: Specific Aim 1: Determine the type of filter material required for the efficient removal of doxorubicin from blood. This will be accomplished by a) preparing carbon beads with three different coatings (cellulose with heparin, PMMA and PMMA with heparin) to enhance the biocompatibility of the carbon filters during blood perfusion, and then b) testing the efficiency and capacity of coated carbon in a batch mode filter to remove doxorubicin from bovine blood. Specific Aim 2: Determine the blood biocompatibility of the different coated filters by a) measuring changes in blood coagulation parameters and b) measuring changes in platelet activation state. Specific Aim 3: Carry out a perfusion study using optimized filters. This will be accomplished as follows: a) prepare large-scale optimized coated carbon filters based on the results of Aims 1 and 2; and b) test the efficiency of the optimized filter to remove doxorubicin from bovine blood. PUBLIC HEALTH RELEVANCE: The primary objective of this proposed study is to develop a novel Polymethyl methacrylate coated activated carbon filter with different compositions including cellulose and heparin for the maximum removal chemotherapy such as doxorubicin and others from blood while minimizing filter impact on blood chemistry. Initial clinical results from studies treating hepatic cancer patients confirm that delivering more chemotherapy drug to the tumor site, and less to the other regions of the body, enhances tumor shrinkage with improved quality of life over systemic cancer therapies.

描述（由申请人提供）：具有最小全身毒性的高剂量区域化疗摘要：这项拟议研究的主要目的是开发一种过滤系统，该系统最大化（> 90％）的化学治疗剂（例如阿霉素）（例如阿霉素），同时使血液对血液的不良影响对血液化学的不良影响对血液化学化学的不良影响和血液学参数最小化。 血管视觉药品公司（VVP）和Delcath系统处于癌症治疗的最前沿。 Delcath的专有技术用于局部药物输送，经皮肝灌注“（PHP”），与全身性递送相比，将明显更高剂量的抗癌药物直接递送到癌症部位，而无需将整个身体暴露于有效水平的药物水平。肝癌患者临床研究的最初结果证实，与全身性癌症治疗相比，对肿瘤其他区域的最小暴露直接将较高水平的抗癌药物直接递送到肿瘤部位，从而增强了肿瘤收缩并改善了生活质量。 PHPTM目前正在对II期临床试验中的各种肝脏癌症进行测试。 拟议的研究计划与PHPTM在局部癌症治疗和靶向药物递送中的应用有关。当前的Delcath过滤器由涂有多甲基丙烯酸酯的活性碳组成，以使血液与过滤材料直接接触。这些过滤器表现出较低的第一频繁提取能力，导致化学治疗剂的次优去除和碳碎片的脱落，从而激活了凝血的级联反应和对血液的损害。因此，迫切需要具有更好效率和生物相容性的过滤器。该阶段ISTTR建议的具体目的如下：特定目的1：确定有效去除阿霉素从血液中有效去除所需的过滤材料的类型。这将通过a）a）用三种不同的涂层（用肝素，PMMA和肝素的PMMA纤维素）制备碳珠来增强碳过滤器在血液灌注过程中的生物相容性，然后b）测试在批处理模式过滤器中涂有碳的效率和容量，以去除牛油蛋白从牛油血液中去除牛sorubibicin。具体目标2：通过a）测量血液凝血参数的变化并b）测量血小板激活状态的变化来确定不同涂层过滤器的血液生物相容性。特定目标3：使用优化的过滤器进行灌注研究。这将如下完成：a）根据目标1和2的结果准备大规模优化的涂层碳过滤器； b）测试优化过滤器从牛血中去除阿霉素的效率。 公共卫生相关性：这项拟议的研究的主要目标是开发一种新型的甲基甲基丙烯酸甲基丙烯酸甲酯涂层活性炭过滤器，其中包括不同组合物（包括纤维素和肝素），以最大程度地去除化学疗法，例如阿霉素和其他血液中的其他成分，同时最大程度地减少过滤器对血液化学的影响。治疗肝癌患者的研究的最初临床结果证实，将更多的化学疗法药物递送到肿瘤部位，并较少向人体的其他区域递送，从而增强了肿瘤收缩，随着全身性癌症治疗的生活质量改善。