Endovascular Chemofiltration: Optimizing Removal of Chemotherapeutics and Nanoparticles from the Blood to Reduce Toxicity

血管内化学过滤：优化从血液中去除化疗药物和纳米颗粒以降低毒性

• 批准号: 9269167
• 负责人: Steven William Hetts
• 金额: $ 51.39万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269167
• 关键词: Achievement; Adverse effects; Angiography; Animals; Area; Binding; Blood; Blood Vessels; Blood flow; Cancer Etiology; Cardiac; Cardiac Output; Cardiotoxicity; Catheters; Cessation of life; Chemistry; Chemoembolization; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical; DNA; DNA Binding; Devices; Diagnostic; Disease; Distant; Dose; Dose-Limiting; Doxorubicin; Drug Targeting; Drug toxicity; Excision; Family; Family suidae; Filtration; Fluoroscopy; Geometry; Goals; Heart failure; Hepatic; Histologic; In Situ; In Vitro; Infusion procedures; Interventional radiology; Link; Liquid substance; Location; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of liver; Measurement; Measures; Mediating; Medical Device; Membrane; Modeling; Motivation; New Agents; Oligonucleotides; Optics; Organ; Patients; Pharmaceutical Preparations; Physiological; Plasma; Population; Positron-Emission Tomography; Preclinical Testing; Primary carcinoma of the liver cells; Procedures; Rest; Roentgen Rays; Safety; Serum; Site; Solid; Stream; Surface; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Thrombosis; Time; Tissue Sample; Tissues; Toxic effect; Unresectable; Veins; Venous; antimicrobial; base; cancer therapy; cancer type; cell killing; chemical property; chemotherapeutic agent; chemotherapy; clinical candidate; clinical translation; cost; cost efficient; design; efficacy testing; electric impedance; experience; experimental study; fighting; hemodynamics; image guided; improved; in vivo; interest; iron oxide; minimally invasive; nanoparticle; neoplastic; neoplastic cell; novel; particle; physical property; preclinical efficacy; pressure; prototype; public health relevance; response; small molecule; standard of care; systemic toxicity; targeted agent; targeted treatment; tumor

 DESCRIPTION (provided by applicant): Dosing of drugs ranging from cancer chemotherapeutics to anti-microbials to thrombolytics is limited by systemic toxic side effects. We propose to develop a new class of image-guided temporarily deployable, endovascular catheter- based medical devices that selectively remove specific drugs or other diagnostic or therapeutic agents from the blood stream in order to reduce systemic toxicities. The proposed ChemoFilters incorporate specialized membranes that bind target drugs in situ through a variety of mechanisms. During the clinically standard interventional radiology (IR) approach of x-ray fluoroscopically guided intraarterial chemotherapy (IAC) infusion to a target organ (e.g., a solid organ containing a tumor), excess drug that is not trapped in the target organ passes through to the veins draining the organ and then is circulated to the rest of the body, causing toxicities in distant locations. By temporarily deploying a ChemoFilter in the vein(s) draining the organ undergoing IAC, we seek to bind excess drug before it can escape to cause systemic toxicity. The ChemoFilter would then be removed in the IR suite shortly after the IAC procedure, thus removing excess drug from the patient. Although paired intraaterial infusion and venous filtration can theoretically be used for any drug that has its site of therapeutic action in one location and its site of dose-limiting toxicity in another location, the most compelling application for this technology is increasing efficacy and safety of locoregional cancer chemotherapy. Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Image-guided transarterial chemoembolization (TACE), a form of IAC, is performed in IR and is a standard of care for unresectable HCC. TACE cost- effectively increases survival in this population. Doxorubicin (Dox) is a low-cost, highly effective, chemotherapeutic agent frequently used in IAC. Dox use is limited by systemic toxicities, most importantly irreversible cardiac failure. Dox follows a therapeutic linear dose-response model, in which increasing dose linearly increases tumor cell kill, providing motivation for higher-dose Dox therapy. Established agents like Dox and cisplatinum (with known dose-limiting toxicities that are spatially removed from their site of action during selective organ IAC) and new agents like nanoparticles (with uncertain toxicities) are the most compelling first candidates for clinical translation of endovascular chemofiltration. Prototype ChemoFilter devices with specialized ionic or DNA oligonucleotide coated membranes will be modeled, built, validated in vitro for efficacy, and tested in vivo for efficacy and safety. Experienced teams from UCSF, UC Berkeley, Caltech, and ChemoFilter will undertake the following specific aims: (SA1) determine optimal geometry and chemistry for endovascular filtration devices, (SA2) validate optimized filter designs in vitro for capacity to capture drugs or therapeutic particles, (SA3) evaluate optimized filter designs in vivo for safety and capacity to capture drugs or therapeutic particles, and (SA4) test preclinical efficacy of optimized filter in vivo in a pig model of hepatic chemotherapy infusion. Achievement of these aims will create a family of minimally invasive medical devices that could markedly increase the efficacy of locoregional intraarterial chemotherapy by lowering systemic drug concentrations and reducing systemic toxicities, thus permitting dose escalation in any given IAC procedure and consequently better local tumor control in fewer IAC sessions.

 描述（由申请人提供）：从癌症化疗药物到抗微生物药物再到溶栓药物等药物的剂量均受到全身毒副作用的限制。我们建议开发一类新型图像引导的临时可部署、基于血管内导管的医疗设备，该设备可选择性地使用。所提出的化学过滤器结合了特殊的膜，可在临床过程中通过多种机制在原位结合目标药物。标准介入放射学 (IR) 方法，通过 X 射线荧光镜引导动脉内化疗 (IAC) 输注至目标器官（例如，含有肿瘤的实体器官），未滞留在目标器官中的过量药物通过静脉排出通过在接受 IAC 的器官引流的静脉中临时部署化学过滤器，我们试图在其排出之前结合多余的药物。化学过滤器会在 IAC 手术后不久在 IR 套件中被移除，从而从患者体内去除多余的药物，尽管理论上配对的动脉内输注和静脉过滤可用于任何有其作用部位的药物。该技术最引人注目的应用是提高局部癌症化疗的疗效和安全性，而肝细胞癌 (HCC) 是导致肝癌的第三大原因。图像引导经动脉化疗栓塞 (TACE) 是 IAC 的一种形式，是在 IR 中进行的一种治疗方法，可有效提高该人群的生存率。 IAC 中常用的廉价、高效化疗药物受到全身毒性的限制，最重要的是，Dox 遵循治疗线性剂量反应。模型中，增加剂量线性增加肿瘤细胞杀伤力，为高剂量 Dox 治疗提供动力，如 Dox 和顺铂（具有已知的剂量限制毒性，在选择性器官 IAC 期间从空间上消除其作用部位）和新药物。纳米粒子（具有毒性不确定性）等药物是血管内化学过滤临床转化最引人注目的候选药物，将模拟具有特殊离子或 DNA 寡核苷酸涂层膜的原型 ChemoFilter 装置。来自加州大学旧金山分校、加州大学伯克利分校、加州理工学院和 ChemoFilter 的经验丰富的团队将实现以下具体目标：（SA1）确定血管内过滤装置的最佳几何形状和化学成分，（ SA2）在体外验证优化的过滤器设计捕获药物或治疗颗粒的能力，（SA3）在体内评估优化的过滤器设计的安全性和捕获药物或治疗颗粒的能力，以及（SA4）在体内测试优化的过滤器的临床前功效肝脏化疗输注的猪模型的实现将创建一系列微创医疗设备，这些设备可以通过降低全身药物浓度和减少全身毒性来显着提高局部动脉内化疗的功效，从而允许在任何特定的 IAC 手术中增加剂量。从而在更少的 IAC 疗程中更好地控制局部肿瘤。