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（由适用提供）：从癌症化学治疗药到抗菌剂再到溶栓剂的药物剂量受到全身有毒副作用的限制。我们建议开发一类新的图像引导暂时可部署的基于血管内导管的医疗设备，这些设备有选择地去除特定的药物或其他诊断或治疗剂从血液流中，以降低全身毒性。拟议的化学滤光器结合了专门的机制，这些机制通过多种机制结合了靶向药物。在临床标准的介入放射学（IR）方法中，X射线荧光透镜引导的疗法内化疗（IAC）输注对靶器官（例如，含有肿瘤的固体器官），过量的药物不会被困在靶器官中，靶器官在静脉中渗透到器官中，然后流动到器官，并散布到身体的静脉内，并在身体上散发出浓度的毒性，并在身体上静止，在毒性中含有远处的毒性。通过临时在静脉中暂时部署化学滤纸，排出正在经历IAC的器官的静脉，我们试图将超过药物结合到可以逃脱以引起全身毒性之前。然后将在IAC手术后不久将Chemofilter在IR套件中删除，从而从患者那里清除过量药物。尽管理论上可以将配对的物质内输注和静脉过滤用于任何在某个位置进行治疗部位的药物及其在另一个位置的剂量限制毒性部位，但该技术的最引人注目的应用是详细的疗效和安全性癌症化疗的安全性和安全性。肝细胞癌（HCC）是全球癌症死亡的第三主要原因。图像引导的跨型化学团体化（TACE）是IAC的一种形式，在IR中进行，是无法切除的HCC的一种护理标准。 TACE成本效益可提高该人群的生存。阿霉素（DOX）是一种经常在IAC中使用的低成本，高效的化学治疗剂。 DOX的使用受到全身毒性的限制，最重要的是不可逆的心力衰竭。 DOX遵循一种治疗性线性剂量反应模型，其中增加的剂量线性增加了肿瘤细胞的杀伤，从而为高剂量DOX治疗提供了动力。诸如Dox和Cisplatinum（具有已知剂量限制性毒性）之类的已建立剂，在选择性器官期间从其作用部位从其作用部位移除），而新的药物（如纳米颗粒（不确定的毒性））是血管形化学术的临床翻译的最引人注目的首次候选者。具有专门的离子或DNA寡核苷酸涂层膜的原型化学滤器设备将进行建模，建造，在体外进行验证，以提高效率，并在体内进行效率和安全性测试。 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) evaluated optimized filter designs in vivo for safety and capacity to capture drugs or therapeutic particles, and （SA4）在肝化学疗法输注的猪模型中测试优化过滤器在体内的临床前效率。这些目标的实现将创建一个微创的医疗设备系列，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区域内化疗的效率，从而允许在任何给定的IAC程序中剂量升级，从而在较少的IAC IAC IC会议中更好地控制剂量。