Drug eluting injectable biomaterials for next generation chemoembolization

用于下一代化疗栓塞的药物洗脱可注射生物材料

• 批准号: 10397659
• 负责人: Ali Khademhosseini
• 金额: $ 65.04万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10397659
• 关键词: Animal Model; Apoptosis; Biocompatible Materials; Biomedical Engineering; Blood Vessels; Catheters; Cell Cycle Inhibition; Cell Death; Cessation of life; Chemoembolization; Coupled; Data; Development; Dose; Doxorubicin; Drug Controls; Drug Delivery Systems; Drug Kinetics; Engineering; Europe; Evaluation; Fluoroscopy; Formulation; Gel; Gelatin; Goals; Hepatic; Histology; Hydrogels; Image; Immune checkpoint inhibitor; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; Inflammatory Response; Injectable; Ischemia; Liver; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Modeling; Modulus; Molecular; Oncolytic viruses; Oryctolagus cuniculus; Patients; Penetration; Performance; Persons; Pharmaceutical Preparations; Primary carcinoma of the liver cells; Procedures; Property; Public Health; Risk; Roentgen Rays; Safety; Solid; Solid Neoplasm; Survival Rate; Technology; Testing; Therapeutic; Therapeutic Embolization; Thinness; Time; Tissues; Toxic effect; Travel; United States; Virus Diseases; Viscosity; World Health Organization; anti-CTLA4; anti-cancer; anti-tumor immune response; base; cancer cell; cancer therapy; chemotherapy; chimeric antigen receptor T cells; drug distribution; improved; in vivo; in vivo evaluation; liquid chromatography mass spectrometry; liver cancer model; liver cancer patient; liver transplantation; neoplastic cell; next generation; novel; novel therapeutics; prevent; programmed cell death ligand 1; programmed cell death protein 1; side effect; success; tumor; tumor ablation; tumor progression; ultrasound

Abstract Hepatocellular carcinoma (HCC), the most common type of liver cancer, is a major worldwide public health concern because it is often detected at advanced stages where treatment options are limited. According to the World Health Organization, each year there are ~750,000 new HCC cases resulting in 700,000 deaths worldwide. While historically systemic chemotherapy has been the cornerstone to cancer treatment, inability to achieve uniform drug delivery to tumors, collateral toxicity to the non-cancerous liver and systemic side-effects have limited progress in the development of novel therapies for liver cancer. Recently, novel immunotherapeutic agents (immune checkpoint inhibitors (ICI), CAR-T cells, oncolytic virus) have been developed, but there are still limitations to their use due to systemic side effects and difficulty to deliver to solid tumors. Although transcatheter arterial chemoembolization (TACE), a procedure performed using an X-ray guided catheter to deliver chemotherapy coupled to embolization beads into the blood vessels that perfuse the liver tumor has shown success in liver cancer management, the embolization efficiency is relatively low as the beads cannot be readily delivered into downstream microvasculature to achieve uniform ischemia and chemotherapy delivery. Here we propose a transformative technology that uses a catheter-based locoregional approach to deliver X-ray visible bioengineered biomaterial, i.e. next-generation TACE, to induce a more efficient ischemic cell death within the tumor microvasculature coupled with efficient chemo- and immunotherapy delivery. We aim to combine TACE with both chemo- and immuno-therapeutics (e.g. ICIs) in order to enhance the anti-tumor immune response. Maintaining and even enhancing the inflammatory response induced after chemotherapy may potentially yield improved tumor regression assisted by localized ICI delivery. To achieve this goal we will mix doxorubicin (DOX) and / ICI (α-PD1, α-PDL1, α-CTLA-4) within an injectable shear-thinning hydrogel (STH) to enhance tumor ablation. We hypothesize that STH, a semi-solid gel like embolic material, which is composed of gelatin and nanosilicate, will achieve more efficient endovascular embolization reaching vessels as small as 50 microns than the current TACE beads. Simultaneously, DOX/ICI delivery will be used to locally ablate the liver cancer cells. Our preliminary data demonstrates exciting results showing our ability to synthesize and deliver STHs using catheters, to release drugs controllably from STHs, as well as in vitro and rabbit liver cancer models. In Aim 1, we will optimize STH compositions for effective endovascular chemoembolization. In Aim 2, we will develop the novel drug-eluting STH (DESTH) for endovascular Immuno-chemoembolization. In Aim 3 we will evaluate the in vivo performance of the DESTH.

抽象的 肝细胞癌（HCC）是最常见的肝癌类型，是全球主要的公共卫生 关心，因为通常在治疗方案有限的高级阶段被检测到。根据 世界卫生组织，每年有〜750,000个新的HCC病例，导致700,000例死亡 全世界。虽然历史上系统性化疗一直是癌症治疗的基石，但无法 实现统一的药物递送到肿瘤，对非癌性肝脏的附带毒性和全身副作用 肝癌的新疗法发展的进展有限。最近，小说 免疫治疗剂（免疫检查点抑制剂（ICI），CAR-T细胞，溶瘤病毒）已是 开发的，但由于系统性副作用，其使用仍然存在局限性，并且难以传递到固体 尽管经导管动脉化学栓塞（TACE），但使用X射线执行的程序 引导导管将化学疗法连接到栓塞珠到血管中，以使 肝肿瘤在肝癌管理中表现出成功，栓塞效率相对较低 不能轻易将珠子传递到下游微脉管系统中，以达到均匀的缺血和 化学疗法递送。在这里，我们提出了一种使用基于导管的局部区域的变革性技术 提供X射线可见生物材料的方法，即下一代TACE，以诱导更多 肿瘤微脉管系统内有效的缺血细胞死亡以及有效的化学和 免疫疗法提供。我们旨在将TACE与化学和免疫疗法（例如ICIS）结合起来 为了增强抗肿瘤免疫反应。维持甚至增强炎症 化学疗法后诱导的反应可能有可能产生改善局部辅助的肿瘤消退 ICI交付。为了实现这一目标，我们将在一个内混合阿霉素（dox）和 / ici（α-pd1，α-pdl1，α-ctla-4） 可注射剪切的水凝胶（STH）以增强肿瘤消融。我们假设STH，一个半固体 由明胶和纳米硅酸盐组成的凝胶像栓塞材料一样，将实现更有效的效率 血管内栓塞到达比当前TACE珠小至50微米的血管。 同时，DOX/ICI的递送将用于局部消除肝癌细胞。我们的初步数据 展示令人兴奋的结果，表明我们使用导管合成和交付STH的能力，以释放 由STH以及体外和兔肝癌模型控制的药物。在AIM 1中，我们将优化STH 有效血管内化学栓塞的组成。在AIM 2中，我们将开发新颖的药物洗脱 STH（DESTH）用于血管内免疫栓塞。在AIM 3中，我们将评估体内性能 desth。