Targeted chemotherapy delivery and capture

摘要 化疗是癌症患者的主要治疗选择。然而，来自 这些药物会显著影响患者的生活质量和总体生存。预防和 有效管理化疗药物的副作用是 今天的肿瘤学。许多处于I期试验的药物已经被放弃，许多患者被 由于相关的不良全身副作用，拒绝了对有希望的治疗方案的希望 效果(4)。此外，FDA批准的药物的毒性，如白细胞介素2，阻止了它们 尽管有疗效，但仍可使用。为了解决化疗的这些局限性，我们建议一种 变革性的技术，其中化疗药物是从一种药物动脉内注入的- 洗脱支架(DES)和捕获沿静脉流出的肿瘤使用血管内 毒品捕获装置(DCD)。我们认为，通过使用DES/DCD对系统，肿瘤部位 将接受高度局部化疗，同时全身存在过量的药物分子 将被最小化或消除(图1)。这一策略可以应用于许多癌症，即内癌 髂静脉/动脉治疗盆腔肿瘤，支气管动脉/肺静脉治疗肺癌，内乳房 静脉/动脉治疗乳腺癌。在这份提案中，我们将重点关注肝癌，因为我们的肝脏 血管造影术经验，肝脏有双重血供，肝脏血管足够大 适应支架的放置，并降低兔的成像、实验和维护成本。 作为原则性的证明，我们将以肝癌为模型来演示这本小说的有效性。 战略，通过提供DNA靶向抗癌药物阿霉素，它的天然荧光强度为480 NM，便于检测和量化。我们的初步数据显示了令人兴奋的结果 展示了我们在制造抗血栓生物材料方面的能力，这种材料可以选择性地释放和 捕获药物分子。此外，我们在导管给药方面拥有丰富的经验。 用于许多体内应用的生物材料，这将确保成功完成 建议的项目。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的概念(目标3)。成功 这种系统的开发将代表着肿瘤学社区的范式转变 提高患者的生活质量，潜在地延长生存期，使失败的I期复苏 药物毒性试验，增加FDA批准的先前有毒药物的使用，以及 开启了新的临床试验，以测试更高的剂量。提出的药物释放和释放的想法 捕捉代表着一种平台技术，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 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.