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给药受到全身毒性副作用的限制。我们建议开发一类新的图像引导的可临时展开的、基于血管内导管的医疗器械，其选择性地从血流中去除特定药物或其他诊断或治疗剂，以减少全身毒性。所提出的ChemoFilters包含通过各种机制原位结合靶药物的专用膜。在X射线荧光镜引导的动脉内化疗（IAC）输注到靶器官（例如，含有肿瘤的实体器官），没有被捕获在靶器官中的过量药物通过排出该器官的静脉，然后循环到身体的其余部分，在远处的位置引起毒性。通过在接受IAC的器官引流的静脉中临时部署ChemoFilter，我们寻求在过量药物逸出并导致全身毒性之前结合过量药物。IAC手术后不久，将在IR套件中取出ChemoFilter，从而清除患者体内多余的药物。虽然配对的动脉内输注和静脉过滤理论上可以用于在一个位置具有治疗作用部位而在另一个位置具有剂量限制毒性部位的任何药物，但该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（HCC）是世界范围内第三大癌症死亡原因。图像引导经动脉化疗栓塞（TACE）是IAC的一种形式，在IR中进行，是不可切除HCC的标准治疗。TACE成本效益高，可提高该人群的生存率。多柔比星（Dox）是一种低成本、高效、常用于IAC的化疗药物。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遵循治疗线性剂量反应模型，其中增加剂量线性增加肿瘤细胞杀伤，为更高剂量的Dox治疗提供动力。已建立的药物如Dox和顺铂（具有已知的剂量限制性毒性，在选择性器官IAC期间从其作用部位空间移除）和新药物如纳米颗粒（具有不确定的毒性）是血管内化学滤过临床转化的最引人注目的首选候选药物。将对具有专用离子或DNA寡核苷酸涂层膜的原型ChemoFilter装置进行建模、构建、体外有效性验证，并进行体内有效性和安全性检测。来自UCSF，UC Berkeley，Caltech和ChemoFilter的经验丰富的团队将承担以下具体目标：（SA 1）确定血管内过滤装置的最佳几何形状和化学性质，（SA 2）在体外验证优化的过滤器设计捕获药物或治疗性颗粒的能力，（SA 3）在体内评价优化的过滤器设计捕获药物或治疗性颗粒的安全性和能力，以及（SA 4）在肝脏化疗灌注的猪模型中体内测试优化的过滤器的临床前功效。这些目标的实现将创造一个微创医疗器械家族，通过降低全身药物浓度和减少全身毒性，可以显著提高局部动脉内化疗的疗效，从而允许在任何给定的IAC程序中增加剂量，从而在更少的IAC疗程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.