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: 10620134
• 负责人: Ali Khademhosseini
• 金额: $ 63.79万
• 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/10620134
• 关键词: Animal Model; Apoptosis; Biocompatible Materials; Biomedical Engineering; Blood Vessels; Cancer Model; Catheters; Cell Cycle Inhibition; Cell Death; Cessation of life; Chemoembolization; Coupled; Data; Development; Dose; Doxorubicin; Drug Delivery Systems; Drug Kinetics; Elasticity; 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; Perfusion; Persons; Pharmaceutical Preparations; Primary carcinoma of the liver cells; Procedures; Property; Public Health; Recurrent tumor; Risk; Roentgen Rays; Safety; Silicates; 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; cancer cell; cancer therapy; chemotherapy; chimeric antigen receptor T cells; drug distribution; improved; in vivo; in vivo evaluation; liquid chromatography mass spectrometry; liver ablation; liver cancer model; liver cancer patient; liver transplantation; nano; neoplastic cell; next generation; novel; novel therapeutics; prevent; programmed cell death ligand 1; programmed cell death protein 1; side effect; success; technology platform; transcatheter arterial chemoembolization; 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问题 之所以令人担忧，是因为它通常是在治疗选择有限的晚期阶段才被发现的。根据 世界卫生组织，每年约有 75 万新发肝癌病例，导致 70 万人死亡 全世界。虽然历史上全身化疗一直是癌症治疗的基石，但无法 实现对肿瘤的均匀药物输送、对非癌性肝脏的附带毒性和全身副作用 肝癌新疗法的开发进展有限。最近，小说 免疫治疗药物（免疫检查点抑制剂（ICI）、CAR-T细胞、溶瘤病毒） 已开发出来，但由于系统性副作用和难以递送至固体，其使用仍然受到限制 肿瘤。虽然经导管动脉化疗栓塞 (TACE) 是一种使用 X 射线进行的手术 引导导管将化疗药物与栓塞珠一起输送到灌注血管的血管中 肝肿瘤在肝癌治疗方面已取得了成功，但栓塞效率相对较低，因为 珠子不能轻易地输送到下游微血管中以实现均匀的缺血和 化疗递送。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 射线可见生物工程生物材料（即下一代 TACE）的方法，以诱导更多 肿瘤微血管内有效的缺血性细胞死亡加上有效的化疗和 免疫治疗递送。我们的目标是将 TACE 与化疗和免疫治疗（例如 ICI）结合起来 以增强抗肿瘤免疫反应。维持甚至增强炎症 化疗后诱导的反应可能会在局部辅助下改善肿瘤消退 ICI 交付。为了实现这一目标，我们将阿霉素 (DOX) 和/ICI（α-PD1、α-PDL1、α-CTLA-4）混合在一个 可注射剪切稀化水凝胶（STH）以增强肿瘤消融。我们假设 STH，一种半固体 由明胶和纳米硅酸盐组成的凝胶状栓塞材料将实现更有效的 血管内栓塞比目前的 TACE 珠小至 50 微米的血管。 同时，DOX/ICI 递送将用于局部消融肝癌细胞。我们的初步数据 展示了令人兴奋的结果，表明我们有能力使用导管合成和输送 STH，以释放 可控地从 STH 以及体外和兔肝癌模型中获得药物。在目标 1 中，我们将优化 STH 用于有效血管内化疗栓塞的组合物。在目标2中，我们将开发新型药物洗脱 STH (DESTH) 用于血管内免疫化学栓塞术。在目标 3 中，我们将评估体内性能 目标的。