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 化学疗法是癌症患者的主要治疗选择。但是，来自 这些药物可以显着影响患者的生活质量和整体生存。预防和 有效地管理化学疗法药物的副作用，代表着重要的瓶颈 今天的肿瘤学。第一阶段试验中的许多药物已被放弃，许多患者已经被放弃 由于具有不利的全身性方面，有希望的治疗方案拒绝了希望 效果（4）。此外，来自FDA批准的药物（例如白介素2）的毒性已经阻止了它们 尽管有功效，但使用。为了解决化学疗法的这些局限性，我们提出了 化学疗法药物被药物内注入的转化技术，其中 洗脱支架（DES），并使用血管内捕获肿瘤的静脉流出 药物捕获装置（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，而全身性药物分子的存在 将最小化或消除（图1）。该策略可以应用于许多癌症，即内部 骨盆肿瘤，支气管动脉/肺静脉，肺部癌，内部乳腺内部乳房/乳房静脉/动脉 乳腺癌的静脉/动脉。在此提案中，由于我们的肝脏，我们将重点关注肝癌 血管造影经验，肝脏具有双血供应，肝脉管系统足够大，以至于 适应支架放置，并降低成像，实验和维持兔子的成本。 作为原则的证明，我们将使用肝癌作为模型来证明这一小说的功效 策略，通过输送靶向DNA抗癌药物阿霉素，该药物自然荧光在480处 NM允许容易检测和定量。我们的初步数据显示了令人兴奋的结果 显示我们在可以选择性释放和 捕获药物分子。此外，我们在基于导管的交付方面具有丰富的经验 许多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（AIM 1），然后开发DCD（AIM 2），最后 测试大鼠和兔动物模型中的药物释放和捕获概念（AIM 3）。成功的 这种系统的开发将代表肿瘤学社区的范式转变 改善患者的生活质量，可能延长生存率，复活I期失败 来自药物毒性的试验，增加了FDA批准的先前有毒药物的使用，以及 打开新的临床试验以测试更高剂量。拟议的药物释放思想和 捕获代表一种平台技术，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疗法或 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