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

 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剂的药物剂量受到全身毒副作用的限制。我们建议开发一种新型的图像引导、临时可展开的、基于血管内导管的医疗设备，它可以选择性地从血液中去除特定的药物或其他诊断或治疗药物，以减少全身毒性。建议的化学过滤器结合了特殊的膜，通过各种机制在原位结合靶向药物。在临床标准介入放射学(IR)方法中，在X射线透视引导下动脉化疗(IAC)介入靶器官(例如，含有肿瘤的实体器官)的过程中，未被困在靶器官内的多余药物会通过引流器官的静脉，然后循环到身体的其他部位，在遥远的位置造成毒性。通过在静脉内临时部署化学过滤器(S)，引流正在进行IAC的器官，我们寻求在过量药物逃逸导致全身毒性之前结合它。在IAC程序结束后不久，ChemoFilter将在IR套件中被移除，从而从患者体内移除多余的药物。尽管配对的静脉输液和静脉过滤理论上可以用于任何药物，其治疗作用部位在一个位置，其剂量限制毒性部位在另一个位置，但这项技术最引人注目的应用是提高局部癌症化疗的有效性和安全性。肝细胞癌是全球第三大癌症死亡原因。影像引导下肝动脉化疗栓塞术(TACE)是IAC的一种，用于IR期，是不能切除的肝细胞癌的标准治疗手段。TACE可成本效益地提高这一人群的存活率。阿霉素(Dox)是一种低成本、高效的化疗药物，常用于IAC。DOX的使用受到全身毒性的限制，最重要的是不可逆转的心力衰竭。DOX遵循治疗线性剂量-反应模型，在该模型中，增加剂量线性增加肿瘤细胞杀伤率，为更高剂量的Dox治疗提供动力。已有的药物如Dox和顺铂(已知的剂量限制毒性，在选择性器官IAC期间可在空间上从作用部位移除)和纳米粒(毒性未知)等新药物是血管内化学滤过临床翻译的最有吸引力的首选候选药物。具有特殊离子或DNA寡核苷酸涂层膜的ChemoFilter原型设备将被建模、建造、在体外验证有效性，并在体内测试有效性和安全性。来自加州大学伯克利分校、加州大学伯克利分校和ChemoFilter的经验丰富的团队将承担以下具体目标：(SA1)确定血管内过滤设备的最佳几何和化学成分，(SA2)体外验证优化过滤器设计的捕获药物或治疗颗粒的能力，(SA3)在体内评估优化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)在活体肝脏化疗输液的猪模型中测试优化过滤器的临床前有效性。这些目标的实现将创造一系列微创医疗设备，通过降低全身药物浓度和减少全身毒性，显著提高局部区域动脉内化疗的疗效，从而允许在任何给定的IAC过程中增加剂量，从而在较少的IAC会议中更好地控制局部肿瘤。

 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.