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）：以最小的全身毒性实现高剂量区域化疗 摘要：这项拟议研究的主要目标是开发一种过滤系统，最大限度地从血液中去除（>90%）化疗药物，如阿霉素，同时最大限度地减少过滤对血液化学和血液学参数的不利影响。 Vascular Vision Pharmaceuticals Co. (VVP) 和 Delcath Systems 处于癌症治疗的最前沿。 Delcath 的局部药物输送专有技术“经皮肝灌注”(PHP) 与全身输送相比，可以将显着更高剂量的抗癌药物直接输送到癌症部位，而无需使整个身体暴露于强效药物水平。肝癌患者临床研究的初步结果证实，与全身癌症治疗相比，将较高水平的抗癌药物直接输送到肿瘤部位，同时尽量减少身体其他区域的暴露，可以增强肿瘤缩小并提高生活质量。 PHPTM 目前正在针对多种肝癌进行 II 期临床试验。 拟议的研究计划涉及 PHPTM 在局部癌症治疗和靶向药物输送中的应用。目前的德尔卡特过滤器由涂有聚甲基丙烯酸酯的活性炭组成，以防止血液与过滤材料直接接触。这些过滤器表现出较低的首过提取能力，导致化疗剂的去除效果不佳，碳碎片脱落，导致凝血级联激活和血液损伤。因此，迫切需要具有更好效率和生物相容性的过滤器。第一阶段 STTR 提案的具体目标如下： 具体目标 1：确定有效去除血液中阿霉素所需的过滤材料类型。这将通过以下方式实现：a) 制备具有三种不同涂层的碳珠（含肝素的纤维素、PMMA 和含肝素的 PMMA），以增强碳过滤器在血液灌注过程中的生物相容性，然后 b) 在批量模式过滤器中测试涂层碳从牛血液中去除阿霉素的效率和能力。具体目标 2：通过 a) 测量凝血参数的变化和 b) 测量血小板活化状态的变化来确定不同涂层过滤器的血液生物相容性。具体目标 3：使用优化的过滤器进行灌注研究。这将按如下方式完成： a) 根据目标 1 和 2 的结果制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。 公共健康相关性：这项拟议研究的主要目的是开发一种新型聚甲基丙烯酸甲酯涂层活性炭过滤器，其具有不同的成分（包括纤维素和肝素），以最大程度地去除血液中的化疗药物（如阿霉素和其他药物），同时最大限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初步临床结果证实，与全身癌症治疗相比，向肿瘤部位输送更多的化疗药物，而不是向身体的其他区域输送更少的化疗药物，可以增强肿瘤缩小，提高生活质量。