Targeted chemotherapy delivery and capture

摘要 化疗是癌症患者的主要治疗选择。但是， 这些药物可显著影响患者的生活质量和总体存活率。预防和 化疗药物的副作用的有效管理代表了 肿瘤学今天I期试验中的许多药物被放弃，许多患者被 由于相关的不良全身性副作用， 影响（4）。此外，FDA批准的药物（如白细胞介素-2）的毒性也阻止了他们的治疗。 使用，尽管有功效。为了解决化疗的这些局限性，我们提出了一个 变革性技术，其中化疗药物是从药物动脉内输注， 洗脱支架（DES），并使用血管内支架沿肿瘤的静脉流出道捕获沿着 药物捕获装置（DCD）。我们相信通过使用DES/DCD对系统， 将接受高度局部化的化疗，同时全身存在过量的药物分子， 将被最小化或消除（图1）。这种策略可以应用于许多癌症，即，内部 髂静脉/动脉用于盆腔肿瘤，支气管动脉/肺静脉用于肺癌，内乳 静脉/动脉用于乳腺癌。在这个提案中，我们将重点放在肝癌，因为我们的肝脏 根据血管造影经验，肝脏有双重血液供应，肝脏血管足够大， 适应支架放置，降低成像、实验和维持兔子的成本。 作为原理的证明，我们将使用肝癌作为模型来证明这种新的疗效。 战略，通过提供DNA靶向抗癌药物阿霉素，自然荧光在480 nm，易于检测和定量。我们的初步数据显示了令人兴奋的结果 显示了我们在制造抗血栓生物材料方面的能力， 捕获药物分子。此外，我们在导管输送方面也有丰富的经验， 用于多种体内应用的生物材料，这将确保成功完成 拟议项目。首先，我们将开发DES（目标1），然后开发DCD（目标2），最后 在大鼠和兔动物模型中测试药物释放和捕获概念（目的3）。成功 这种系统的开发将代表肿瘤学领域的范式转变， 改善患者的生活质量，可能延长生存期，使I期失败的患者复活 药物毒性试验，增加FDA批准的先前有毒药物的使用， 开展新的临床试验来测试更高的剂量。提出的药物释放的想法， 捕获是一种平台技术，可能对其他疾病产生无与伦比的影响。为 例如，该系统可以被设计成隔离暴露于溶栓治疗，或者 免疫抑制剂

Abstract Chemotherapy is the major treatment option for cancer patients. However, systemic toxicity from these drugs can significantly impact patient's quality of life and overall survival. Prevention and effective management of side effects of chemotherapy drugs represents a significant bottleneck in oncology today. Many drugs in Phase I trials have been abandoned and many patients have been denied hope from promising treatment regimens because of the associated adverse systemic side effects (4). Furthermore, toxicity from FDA-approved drugs, like interleukin-2, have prevented their use despite having efficacy. To address these limitations of chemotherapy, we propose a transformative technology where the chemotherapy drug is intra-arterially infused from a drug- eluting stent (DES) and captured along the venous outflow of the tumor using an intravascular drug-capturing device (DCD). We believe that by using the DES/DCD pair system, the tumor site will receive highly localized chemotherapy while systemic presence of the excessive drug molecules will be minimized or eliminated (Fig. 1). This strategy can be applied to many cancers, i.e., internal iliac vein/artery for pelvic tumors, bronchial artery/pulmonary vein for lung cancers, internal mammary vein/artery for breast cancer. In this proposal, we will focus on liver cancer because of our liver angiography experience, the liver has a dual blood supply, liver vasculature is large enough to accommodate stent placements and lower cost of imaging, experimentation and maintaining rabbits. As proof of principle, we will use liver cancer as a model to demonstrate the efficacy of this novel strategy, by delivering DNA-targeting anti-cancer drug doxorubicin, which naturally fluoresces at 480 nm allowing easy detection and quantification. Our preliminary data demonstrates exciting results showing our capability in fabrication of anti-thrombotic biomaterials that can selectively release and capture drug molecules. In addition, we have rich experience in catheter-based delivery of biomaterials for a number of in vivo applications, which will ensure successful completion of the proposed project. First we will develop the DES (Aim 1), then develop the DCD (Aim 2) and finally test the drug release and capture concept in rat and rabbit animal models (Aim 3). Successful development of such a system will represent a paradigm shift in the oncology community by improving patient's quality of life, potentially prolonging survival, resurrecting failed Phase I trials from drug toxicity, increasing the use of FDA-approved previously toxic drugs, and opening up new clinical trials to test much higher doses. The proposed idea of drug release and capture represents a platform technology and may have unparalleled impact in other diseases. For example, the system can be designed to isolate exposure to thrombolytic therapy or immunosuppressants.