In-Situ Gelling Protein Polymer Intravascular Embolic Agent for Hepatic Carcinoma

摘要 这项STTR第二阶段提案解决了改善患者治疗方案的重大需求 肝癌，世界上第五高的癌症发病率。由于缺乏症状，肝细胞 84%的病例为晚期癌，其1年生存率为22%， 以5年为基准，利率为5%。晚期肝癌的唯一治疗选择是手术切除和肝移植， 不幸的是，由于缺乏供肝和进展迅速，大多数患者无法获得供肝。 疾病。由于肝细胞癌对全身化疗一般无反应，经动脉插管 化疗栓塞术(TACE)是应用最广泛的局部治疗方法，可以延缓肿瘤的进展。 疾病。目前的栓塞剂缺乏导管输送的精确度或有效的配伍性 化学治疗药物，特别是高分子量生物治疗药物的输送。该计划的目标是 提出的工作是表征由基因工程组成的新型液体栓塞剂 基于我们以前的工作证明了蛋白质聚合物SELP(丝弹性蛋白)-815K 唯一适合此应用程序的属性。与现有的药物不同，SELP-815K将作为液体注射， 能够穿透肿瘤动脉，并在原位转化为不溶于水的水凝胶，形成基本上 持久的咬合。栓塞液将是完全含水的，并与药物和新的 生物疗法，使其能够局部控制释放。以蛋白质为基础的SELP-815K最终将 生物降解，使随后的TACE治疗成为可能。SELP-815K液体栓塞剂将使受控释放成为可能 化疗药物和新的生物治疗药物具有更高的经导管给药精度 更有选择性的栓塞，减少了非靶点毒性，并减少了对健康肝脏的附带损害。 因此，TACE治疗将被提供给更多的具有更多肿瘤数量的患者 和/或更大的肿瘤体积。 这项研究的目的是：(1)表征通过SELP-815K的单药和多药的输送 凝胶网络；(2)在MCA-RH7777肝细胞癌大鼠模型中进行体内研究，以评价治疗效果 性能；(3)进行SELP-815K制造和分析方法开发；以及(4)进行 制造的SELP-815K栓塞剂的GLP临床前毒理学和性能测试。

SUMMARY This STTR Phase II proposal addresses the significant need for improved treatment options for patients with liver cancer, the fifth highest incidence of cancer in the world. Because of the lack of symptoms, hepatocellular carcinoma (HCC) is detected at advanced stages in 84% of cases, for which the 1-year survival rate is 22% and at 5 years it is 5%. The only curative option for advanced HCC is surgical liver resection and liver transplantation, unfortunately not available to most patients due to the lack of donor livers and the rapid progression of the disease. As HCC is generally unresponsive to systemic chemotherapy, transcatheter arterial chemoemobolization (TACE) is the most widely used, localized treatment that can slow the progression of the disease. Current embolizing agents are deficient in precision of catheter delivery or compatibility for effective delivery of chemotherapeutic agents, especially high-molecular weight biotherapeutics. The objective of the proposed work is to characterize the novel liquid embolizing agent composed of the genetically engineered protein polymer, SELP (silk-elastinlike protein)-815K, which based on our previous work has demonstrated properties uniquely suited for this application. Unlike existing agents, SELP-815K will be injectable as a liquid, able to penetrate into the tumor arteries, and transform to an insoluble hydrogel in-situ forming a substantially durable occlusion. The embolizing liquid will be completely aqueous and compatible with drugs and new biotherapeutics, enabling their localized controlled release. The protein-based SELP-815K will eventually biodegrade, enabling subsequent TACE treatments. SELP-815K liquid embolic will enable the controlled delivery of chemotherapeutic drugs and new biotherapeutic agents with increased precision of transcatheter delivery for more selective embolization, reduced off-target toxicity, and reduced collateral damage to the healthy liver. Consequently, TACE treatment will be offered to a larger patient population having a greater number of tumors and/or greater tumor size. The aims of the research are: (1) to characterize the delivery of single and multiple drugs via the SELP-815K gel network; (2) to conduct in vivo studies in the McA-RH7777 HCC liver tumor rat model to evaluate therapeutic performance; (3) to conduct SELP-815K manufacturing and analytical methods development; and (4) to conduct GLP preclinical toxicology and performance testing of manufactured SELP-815K embolic.