Enabling high dose regional chemotherapy while minimizing systemic toxicity

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，该系统能最大限度地去除血液中的化疗药物，如阿霉素，同时将过滤对血液化学和血液学参数的不利影响降至最低。血管视觉制药公司(VVP)和Delcath系统公司处于癌症治疗的前沿。Delcath用于局部给药的专利技术“经皮肝脏灌流”(PHP)，与全身给药相比，可以将更大剂量的抗癌药物直接输送到癌症部位，而不会使全身暴露于强效药物水平。对肝癌患者的临床研究的初步结果证实，与全身癌症治疗相比，将更高水平的抗癌药物直接输送到肿瘤部位，并最大限度地减少身体其他部位的暴露，可以增强肿瘤缩小并改善生活质量。PHPTM目前正处于多种肝癌的第二阶段临床试验中。拟议的研究计划涉及PHPTM在局部癌症治疗和靶向药物输送方面的应用。目前的Delcath过滤器由涂有聚甲基丙烯酸酯的活性碳组成，以隔离血液与过滤材料的直接接触。这些过滤器表现出较低的一次通过提取能力，导致化疗药物的次优去除，以及碳碎片的脱落，导致凝血级联激活和对血液的损害。因此，迫切需要具有更好的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的类型。这将通过a)制备具有三种不同涂层(含肝素的纤维素、PMMA和含肝素的PMMA)的碳珠，以增强碳过滤器在血液灌流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去除牛血中多柔比星的效率和能力。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。具体目标3：使用优化的过滤器进行灌流研究。这将完成如下工作：a)根据AIMS 1和2的结果制备大规模优化涂层碳过滤器；以及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：这项拟议研究的主要目标是开发一种新型的聚甲基丙烯酸甲酯涂层活性碳过滤器，该过滤器具有不同的组成，包括纤维素和肝素，用于最大限度地去除血液中的阿霉素等化学物质，同时将过滤器对血液化学的影响降至最低。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，向肿瘤部位提供更多的化疗药物，而向身体其他区域提供更少的化疗药物，可以促进肿瘤缩小，改善生活质量。

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.