Endovascular ChemoFilter to Reduce Doxorubicin Toxicity during Intra-Arterial Chemotherapy

项目总结 化疗药物的剂量受到全身毒副作用的限制。我们正在开发一种新的形象- 导引式临时可展开的、基于血管内导管的医疗设备，可选择性地将特定药物从 血液流动，以减少全身毒性。建议的ChemoFilter结合了绑定目标的专门材料 药物通过多种机制在体内发挥作用。在动脉内化疗(IAC)期间向靶器官(例如，固体 包含肿瘤的器官)，未被困在靶器官中的过量药物通过排出器官的静脉并 然后被循环到身体的其他部位，在遥远的地方造成中毒。通过将ChemoFilter临时部署在 静脉(S)引流正在进行IAC的器官，我们寻求在过量的药物逃逸导致全身毒性之前与其结合。这个 在IAC手术后不久，ChemoFilter将在介入放射学套件中被移除，从而移除 病人过量的药物。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 它的治疗作用部位在一个部位，剂量限制毒性部位在另一个部位，这是最引人注目的 这项技术的应用正在提高局部癌症化疗的有效性和安全性。 原发性和转移性肝肿瘤是全球癌症死亡的前三大原因之一。图像制导 肝动脉化疗栓塞术(TACE)是IAC的一种形式，它可以经济有效地提高这一人群的存活率。阿霉素 阿昔洛韦(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。我们最初的项目已经产生了ChemoFilters 在动物模型中，这可以将Dox在心脏中的沉积减少46%。我们寻求在成功的基础上，通过设计 建立和测试新的设备，可以更容易地导航到人类患者的肝静脉。 将对原型化学过滤器进行建模、建造、体外有效性验证，并在大型动物模型中进行体内测试 由来自Filtro，Inc.和加州大学旧金山分校的经验丰富的团队在第一阶段进行导航。在第二阶段，从第一阶段开始的优化设备 然后将在大型动物模型中进行有效性和安全性测试，并在患者中进行首例人类安全性和有效性研究 不能切除的肝癌将被计划和启动。这些目标的实现将创造新的微创医学 应显著提高影像引导下局部动脉内化疗疗效的装置 作为TACE的一部分，通常剂量的Dox的全身药物浓度和减少全身毒性。完成这项工作 这项研究将使ChemoFilter技术用于一项关键的临床试验，该试验将评估任何给定的Dox剂量增加 IAC/TACE手术可在较少的IAC/TACE疗程中实现更好的局部肿瘤控制。

PROJECT SUMMARY Dosing of chemotherapeutics is limited by systemic toxic side effects. We are developing a new class of image- guided temporarily deployable, endovascular catheter-based medical devices that selectively remove specific drugs from the blood stream to reduce systemic toxicities. The proposed ChemoFilters incorporate specialized materials that bind target drugs in situ through a variety of mechanisms. During intraarterial chemotherapy (IAC) infusion to a target organ (e.g., a solid organ containing a tumor), excess drug 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 interventional radiology 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. Primary and metastatic liver tumors are among the top three causes of cancer death worldwide. Image-guided transarterial chemoembolization (TACE), a form of IAC, 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. Our initial project has yielded ChemoFilters that can reduce Dox deposition in the heart by 46% in animal models. We seek to build upon that success by designing, building, and testing new devices that can be more easily navigated to the hepatic veins in human patients. Prototype ChemoFilters will be modeled, built, validated in vitro for efficacy, and tested in vivo in a large animal model for navigability in Phase I by experienced teams from Filtro, Inc and UCSF. In phase II, the optimized devices from phase I will then be tested for efficacy and safety in a large animal model and a first-in-man safety and efficacy study in patients with unresectable liver cancer will be planned and initiated. Achievement of these aims will create new minimally invasive medical devices that should markedly increase the efficacy of image-guided locoregional intraarterial chemotherapy by lowering systemic drug concentrations and reducing systemic toxicities for the usual dose of Dox as part of TACE. Completion of this study will poise the ChemoFilter technology for a pivotal clinical trial that would assess Dox dose escalation in any given IAC/TACE procedure to achieve better local tumor control in fewer IAC/TACE sessions.