ChemoFilter: A Novel Catheter Device to Enable High-Dose Chemotherapy Treatment

! 项目摘要： 静脉给药的药物应用范围从癌症化疗到抗微生物剂， 溶解（血凝块溶解）剂受到全身毒性的限制。目前，唯一的方法，以消除药物从 血液是通过自然代谢或昂贵的不切实际的措施，如透析。尽管激烈 这些治疗方法都是昂贵且罕见的，特别是考虑到传统的 较老的药物成本低，但临床有效，可以有针对性地使用，疗效更高，如果 它们可以在作用后被过滤出体外，以防止毒性。动脉内化疗 (IAC)在介入放射学（IR）中进行，通过以下方式将化疗直接输送到肿瘤 引导微导管进入供应这些肿瘤的动脉。IAC与阿霉素（Dox）已被证明是一种 在随机对照试验中成功证明了治疗非糖尿病的死亡率获益（1，2） 手术性原发性肝癌是全球癌症死亡的第三大原因，由于其能够 最大限度地增加肿瘤的药物剂量，同时限制全身剂量和毒性。尽管如此，高达50%的化疗 在IAC中，药物逃逸肿瘤并引起毒性，如心力衰竭，从而限制了高剂量Dox治疗。 透析式滤过已被证明可以增加肿瘤反应和长期缓解，毒性有限 (3-7)但这种方法不安全、成本高且耗时。我们建议使用ChemoFilter导管 过滤装置，其将在X射线引导下类似于中心线被永久放置在 静脉引流接受IAC的器官，以捕获血流中逃逸的化疗药物 通过化学结合机制。该装置将在60分钟内从患者体内取出（不 在IAC手术结束时植入）。 在本I期STTR提案中，我们寻求在体内确认ChemoFilter。我们已经在体外证明了 通过我们的台式流动模型进行概念验证，获得临时美国专利和功能性导管 原型，准备在模拟肝脏的猪动物模型（IACUC批准，n = 24）中进行测试 IAC。我们将证明体内ChemoFilter导管将：（a）有效快速、高容量 从血流中结合Dox（特定目标1），（B）安全展开和生物相容（特定目标2）， 和（c）能够减少短期毒性（具体目标3）。实现这些具体目标将导致 FDA 510（k）批准ChemoFilter作为一种有效、低成本、微创、一次性导管器械 这可以使化疗毒性降低和高剂量治疗的人类，这将得到验证 在一项II期STTR研究中ChemoFilter作为一个平台，最终将成为药物治疗的新范式。 用于潜在的任何药物-疾病组合（肿瘤和非肿瘤）的技术， 动脉甚至静脉途径。 ! !

! Project Summary: Intravenous dosing of drugs for applications ranging from cancer chemotherapy to anti-microbials to lytic (blood clot dissolving) agents is limited by systemic toxicity. Currently, the only ways to remove drugs from the blood are through natural metabolism or costly impractical measures such as dialysis. Despite intense focus on targeted drug delivery agents, these therapies are costly and rare, especially considering traditional older drugs are low-cost yet clinically effective, and can be used in a targeted manner with higher efficacy if they could be filtered out of the body after their effect in order to prevent toxicities. Intra-arterial chemotherapy (IAC) is performed in interventional radiology (IR), enabling direct delivery of chemotherapy to tumors by guiding micro-catheters into the arteries feeding these tumors. IAC with Doxorubicin (Dox) has proven to be a successful method demonstrating mortality benefit in randomized controlled trials (1, 2) for treating non- operative primary liver cancer, the third leading cause of cancer deaths worldwide, due to its ability to maximize drug dosage to tumor while limiting systemic dose and toxicity. Nonetheless, up to 50% of the chemo in IAC escapes the tumor and causes toxicity, such as heart failure, thereby limiting high-dose Dox therapy. Dialysis-style filtration has been shown to increase tumor response and long term remission with limited toxicity (3-7), but this method is unsafe, costly, and time consuming. We propose the use of ChemoFilter, a catheter filtration device that would be percutaneously placed similar to a central line under x-ray guidance within the vein draining the organ undergoing IAC in order to capture this escaping chemotherapy from the bloodstream via chemical binding mechanisms. The device would be removed from the patient within 60 minutes (no implant) at the end of the IAC procedure. In this Phase I STTR proposal, we seek to validate ChemoFilter in-vivo. We have demonstrated in-vitro proof-of-concept with our benchtop flow model resulting in Provisional U.S. Patents, and functional catheter prototypes, which are ready to be tested in a swine animal model (IACUC approved, n=24) simulating hepatic IAC. We will demonstrate that in-vivo the ChemoFilter catheter will be: (a) efficacious in rapid, high-capacity binding of Dox from the bloodstream (Specific Aim 1), (b) safely deployed and biocompatible (Specific Aim 2), and (c) able to reduce short-term toxicities (Specific Aim 3). Achievement of these specific aims will lead to FDA 510(k) approval for ChemoFilter as an effective, low-cost, minimally invasive, disposable catheter device that could enable chemotherapy toxicity reduction and high-dose treatments in humans, which will be validated in a Phase II STTR study. ChemoFilter ultimately will lead to a new paradigm in drug therapy as a platform technology for potentially any drug-disease combination (both oncologic and non-oncologic) treated by intra- arterial or even intravenous routes. ! !