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

描述（由申请人提供）：该I期提案旨在解决肝癌患者对改进治疗方案的重大需求，肝癌是世界上发病率第五大的癌症。由于缺乏症状，84%的病例在晚期发现肝细胞癌（HCC），其中1年生存率为22%，5年生存率为5%。晚期HCC的唯一治疗选择是手术肝切除和肝移植，不幸的是，由于缺乏供体肝脏和疾病的快速进展，大多数患者无法接受。由于HCC通常对全身化疗无反应，经导管动脉化疗栓塞（TACE）是最广泛使用的局部治疗方法，可以减缓疾病的进展。目前的栓塞剂在导管输送的精确性和对化疗药物的有效输送的兼容性方面存在不足，尤其是高分子量生物治疗药物。这项工作的目标是开发一种新型的液体栓塞剂，该液体栓塞剂由基因工程蛋白聚合物SELP（丝绸弹性蛋白样蛋白）组成，基于我们之前的工作，SELP已经证明了其独特的特性，适合于这种应用。与现有的栓剂不同，SELP栓剂可以作为液体注射，能够渗透到肿瘤动脉中，并在原位转化为不溶性水凝胶，形成持久的闭塞。栓塞液将完全是水性的，与药物和新的生物疗法相容，使其能够局部控制释放。基于蛋白质的SELP最终会生物降解，从而实现后续的TACE治疗。如果成功，SELP液体栓塞将能够控制化疗药物和新的生物治疗药物的输送，并提高经导管输送的精确度，从而实现更有选择性的栓塞，减少脱靶毒性，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群体。本研究的目的是：(1)开发SELP液体栓塞注射溶液配方；(2)测定SELP液的凝胶速率和凝胶强度

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.