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

描述（由申请人提供）：该I期提案解决了肝癌患者改善治疗选择的重大需求，肝癌是世界上第五高的癌症发病率。由于缺乏症状，84%的病例在晚期发现肝细胞癌（HCC），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，大多数患者无法获得。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，可以减缓疾病的进展。目前的栓塞剂在导管递送的精确性或有效递送化疗剂（特别是高分子量生物治疗剂）的相容性方面存在缺陷。所提出的工作的目的是开发一种新的液体栓塞剂，其由基因工程蛋白质聚合物SELP（丝弹性蛋白样蛋白）组成，基于我们先前的工作，其已经证明了独特地适合于该应用的性质。与现有试剂不同，SELP栓塞剂将作为液体可注射，能够渗透到肿瘤动脉中，并原位转化为不溶性水凝胶，形成基本上持久的闭塞。栓塞液体将是完全水性的，并且与药物和新的生物治疗剂相容，使得它们能够局部控制释放。基于蛋白质的SELP最终会生物降解，从而能够进行后续的TACE治疗。如果成功，SELP液体栓塞剂将能够控制化疗药物和新生物制剂的递送，提高经导管递送的精度，以实现更有选择性的栓塞，降低脱靶毒性，并减少对健康肝脏的附带损伤。因此，TACE治疗可以提供给具有更多肿瘤数量和/或更大肿瘤尺寸的更大患者群体。 本研究的目的是：（1）研制SELP液体栓塞注射液配方;（2）测定SELP液的凝胶速率和凝胶强度 在它们的最大可注射粘度下;（3）评估它们对模拟动脉通道的阻塞 体外使用微流体装置;和（4）评价SELP流体在肝脏中的体内经导管动脉栓塞中的性能。 公共卫生相关性：该I期提案详细说明了开发由基因工程蛋白聚合物SELP（丝弹性蛋白样蛋白）组成的新型液体栓塞剂的原理和研究计划，用于通过经导管动脉化疗栓塞（TACE）治疗不可切除的肝细胞癌。SELP栓塞剂将提高栓塞的精确性、与新开发药物的相容性以及肿瘤特异性治疗的选择性。因此，TACE治疗可以提供给具有更多肿瘤数量和/或更大肿瘤尺寸的更大患者群体，对于这些患者群体，存在很少的治疗选择。

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.