Targeted chemotherapy delivery and capture

靶向化疗递送和捕获

• 批准号: 9913518
• 负责人: Ali Khademhosseini
• 金额: $ 53.84万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-06 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913518
• 关键词: Address; Angiography; Animal Model; Anthracycline; Antineoplastic Agents; Area; Arteries; Binding; Biocompatible Materials; Biomedical Engineering; Blood Circulation; Bypass; Cancer Model; Cancer Patient; Catheters; Chemistry; Clinical Trials; Community Clinical Oncology Program; DNA; DNA delivery; Dangerousness; Data; Detection; Development; Devices; Dialysis procedure; Disease; Dose; Doxorubicin; Drug Utilization; Drug toxicity; Drug usage; Ensure; Evaluation; Excision; Exposure to; FDA approved; Hematologic Agents; Hemofiltration; Hepatic artery; Iliac Vein; Image; Immunosuppressive Agents; In Vitro; Inferior vena cava structure; Infusion procedures; Interleukin-2; Intravenous; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Mammary gland; Microspheres; Modeling; Monitor; Oncology; Oryctolagus cuniculus; Patient-Focused Outcomes; Patients; Pelvis; Performance; Perfusion; Pharmaceutical Preparations; Platinum; Prevention; Procedures; Property; Pulmonary veins; Quality of life; Rattus; Risk; Site; Stents; Stream; Surface; Surface Properties; System; Technology; Testing; Therapeutic; Therapeutic Embolization; Thrombolytic Therapy; Time; Topoisomerase Inhibitors; Toxic effect; Treatment Efficacy; Treatment Protocols; Validation; Vascular blood supply; Veins; Venous; antineoplastic antibiotics; base; bronchial artery; chemotherapy; cost; design; drug testing; experience; femoral artery; improved; in vivo; innovation; malignant breast neoplasm; minimally invasive; novel strategies; phase I trial; prevent; prototype; side effect; systemic toxicity; tumor

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.

抽象的 化疗是癌症患者的主要治疗选择。然而，全身毒性 这些药物可以显着影响患者的生活质量和总体生存率。预防和 化疗药物副作用的有效管理是化疗药物治疗的一个重大瓶颈。 今天的肿瘤学。许多一期试验的药物已被放弃，许多患者已被治愈 由于相关的不良全身副作用，使有希望的治疗方案失去了希望 效果（4）。此外，FDA 批准的药物（如白细胞介素 2）的毒性也阻碍了它们的应用。 尽管有功效但仍使用。为了解决化疗的这些局限性，我们提出了 革命性技术，其中化疗药物是从药物中注入动脉内的 洗脱支架 (DES) 并使用血管内支架沿着肿瘤的静脉流出道捕获 药物捕获装置（DCD）。我们相信，通过使用 DES/DCD 对系统，肿瘤部位 将接受高度局部化疗，同时全身存在过量药物分子 将被最小化或消除（图1）。该策略可应用于许多癌症，即内科癌症 髂静脉/动脉用于盆腔肿瘤、支气管动脉/肺静脉用于肺癌、内乳腺 乳腺癌的静脉/动脉。在这个提案中，我们将重点关注肝癌，因为我们的肝脏 血管造影经验，肝脏有双重血供，肝脏血管足够大 适应支架放置并降低成像、实验和饲养兔子的成本。 作为原理证明，我们将使用肝癌作为模型来证明这部小说的功效 策略，通过提供 DNA 靶向抗癌药物阿霉素，该药物天然发出 480 荧光 nm 可以轻松检测和定量。我们的初步数据显示了令人兴奋的结果 展示了我们制造可选择性释放和释放抗血栓生物材料的能力 捕获药物分子。此外，我们在导管输送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 拟议的项目。首先我们将开发 DES（目标 1），然后开发 DCD（目标 2），最后 在大鼠和兔子动物模型中测试药物释放和捕获概念（目标 3）。成功的 这种系统的开发将代表肿瘤学界的范式转变 改善患者的生活质量，有可能延长生存期，复活失败的第一阶段 药物毒性试验，增加 FDA 批准的先前有毒药物的使用，以及 开展新的临床试验来测试更高的剂量。所提出的药物释放和 capture代表了一种平台技术，可能对其他疾病产生无与伦比的影响。为了 例如，该系统可以设计为隔离溶栓治疗或 免疫抑制剂。

项目成果

Engineering hairy cellulose nanocrystals for chemotherapy drug capture.

工程毛状纤维素纳米晶体用于化疗药物捕获。

• DOI: 10.1016/j.mtchem.2021.100711
• 发表时间: 2022
• 期刊: Materials today. Chemistry
• 作者: Young,SarahAE;Muthami,Joy;Pitcher,Mica;Antovski,Petar;Wamea,Patricia;Murphy,RobertDenis;Haghniaz,Reihaneh;Schmidt,Andrew;Clark,Samuel;Khademhosseini,Ali;Sheikhi,Amir
• 通讯作者: Sheikhi,Amir