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

描述(由申请者提供)：这项第一阶段的提案解决了改善肝癌患者治疗方案的重大需求，肝癌的发病率在世界上排名第五。由于缺乏症状，84%的病例被发现为晚期肝细胞癌，其中1年生存率为22%，5年生存率为5%。晚期肝细胞癌的唯一治疗选择是手术切除和肝移植，不幸的是，由于缺乏供体肝脏和疾病的快速发展，大多数患者无法获得这些选择。由于肝细胞癌对全身化疗一般无反应，经导管动脉化疗栓塞术(TACE)是应用最广泛的局部治疗方法，可以减缓疾病的进展。目前的栓塞剂在导管输送的精确度和有效输送化疗药物，特别是高分子量生物治疗药物的配伍性方面存在不足。这项拟议工作的目标是开发一种新型液体栓塞剂，由基因工程蛋白聚合物SELP(丝弹性蛋白)组成，它基于我们之前的工作已经证明了独特的适合于这一应用的性质。与现有的药物不同，SELP栓塞剂可以作为液体注射，能够穿透肿瘤动脉，并在原位转化为不溶的水凝胶，形成基本上持久的闭塞。栓塞液将是完全含水的，并与药物和新的生物疗法相容，使其能够局部控制释放。以蛋白质为基础的SELP最终会被生物降解，从而实现随后的TACE治疗。如果成功，SELP液体栓塞剂将能够控制化疗药物和新的生物治疗药物的输送，提高经导管输送的精确度，以实现更有选择性的栓塞，减少靶外毒性，并减少对健康肝脏的附带损害。因此，TACE治疗可以提供给更多的肿瘤数量和/或更大的肿瘤大小的患者。本研究的目的是：(1)研制SELP液体栓塞剂；(2)测定SELP液体的凝胶化速率和凝胶强度。 在其最大可注射粘度下；(3)评估其对模拟动脉通道的阻塞 使用微流体设备进行体外实验；以及(4)评估SELP液在体内肝动脉栓塞术中的性能。 与公共卫生相关：这份第一阶段提案详细说明了开发一种新型液体栓塞剂的原理和研究计划，该液体栓塞剂由基因工程蛋白聚合物SELP(丝弹性蛋白)组成，用于通过经导管动脉化疗栓塞术(TACE)治疗不能切除的肝细胞癌。SELP栓塞剂将提高栓塞术的精确度、与新药的配伍性和肿瘤特异性治疗的选择性。因此，TACE治疗可以提供给更多的肿瘤数量和/或更大的肿瘤大小的患者，而这些患者几乎没有治疗选择。

DESCRIPTION (provided by applicant): This Phase I proposal addresses the significant need for improved treatment options for patients with liver cancer, the fifth highest incidence of cance 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 develop a novel liquid embolizing agent composed of the genetically engineered protein polymer, SELP (silk- elastinlike protein), which based on our previous work has demonstrated properties uniquely suited for this application. Unlike existing agents, the SELP embolizing agent would 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 would be completely aqueous and compatible with drugs and new biotherapeutics, enabling their localized controlled release. The protein-based SELP would eventually biodegrade, enabling subsequent TACE treatments. If successful, SELP liquid embolic would 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 could be offered to a larger patient population with greater number of tumors and/or greater tumor size. The aims of the research are: (1) to develop SELP liquid embolic injection solution formulations; (2) to determine the gelation rate and gel strength of SELP fluids at their maximum injectable viscosity; (3) to assess their occlusion of simulated arterial channels in-vitro using a microfluidic device; and (4) evaluate the performance of SELP fluids in transcatheter arterial embolization in-vivo in the liver. PUBLIC HEALTH RELEVANCE: This Phase I proposal details the rationale and the research plan for the development of a novel liquid embolizing agent composed of the genetically engineered protein polymer, SELP (silk- elastinlike protein), for treatment of unresectable hepatocellular carcinoma by transcatheter arterial chemoembolization (TACE). The SELP embolic would improve the precision of embolization, the compatibility with newly developed drugs, and the selectivity of tumor-specific therapy. Consequently, TACE treatment could be offered to a larger patient population with greater number of tumors and/or greater tumor size, for which few treatment options exist.