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

原位胶凝蛋白聚合物血管内栓塞剂治疗肝癌

• 批准号: 8314876
• 负责人: Hamid Ghandehari
• 金额: $ 10万
• 依托单位: THERATARGET
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-21 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8314876
• 关键词: Address; Amino Acid Sequence; Antineoplastic Agents; Arterial Embolization; Arteries; Biocompatible Materials; Biological; Biological Products; Biological Response Modifier Therapy; Blood Circulation; Blood capillaries; Blood flow; Caliber; Carcinoma; Catheters; Chemicals; Chemoembolization; DNA biosynthesis; Development Plans; Dimethyl Sulfoxide; Disease Progression; Drug Formulations; Effectiveness; Embolism; Engineering; Excision; Gel; Gene Delivery; Genes; Head and Neck Squamous Cell Carcinoma; Hepatic; Hydrogels; Image; Implant; In Situ; In Vitro; Incidence; Injectable; Injection of therapeutic agent; Learning; Length; Liquid substance; Liver; Malignant neoplasm of liver; Mediating; Microfluidic Microchips; Microfluidics; Modeling; Molecular Weight; Nature; Necrosis; Oils; Operative Surgical Procedures; Oryctolagus cuniculus; Palliative Care; Particulate; Patients; Performance; Pharmaceutical Preparations; Phase; Polymers; Primary carcinoma of the liver cells; Property; Protein Engineering; Proteins; Radiation therapy; Recombinant DNA; Relative (related person); Research; Silk; Simulate; Solid; Solid Neoplasm; Solutions; Specific qualifier value; Staging; Survival Rate; Suspension substance; Suspensions; Symptoms; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Embolization; Time; Tissues; Toxic effect; Unresectable; Venous; Viscosity; Work; aqueous; artery occlusion; base; cancer therapy; capillary; chemotherapeutic agent; chemotherapy; controlled release; improved; in vivo; liver transplantation; novel; particle; patient population; prevent; response; tumor

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.

描述（由申请人提供）：该第一阶段提案解决了肝癌患者改善治疗方案的重大需求，肝癌是世界上第五大癌症发病率。由于缺乏症状，84% 的肝细胞癌 (HCC) 病例在晚期才被发现，其 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，由于缺乏供体肝脏且疾病进展迅速，大多数患者无法实现。由于 HCC 通常对全身化疗没有反应，因此经导管动脉化疗栓塞 (TACE) 是使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递送的精确度或有效递送化疗药物（尤其是高分子量生物治疗药物）的相容性方面存在缺陷。这项工作的目的是开发一种由基因工程蛋白质聚合物 SELP（丝弹性蛋白样蛋白）组成的新型液体栓塞剂，基于我们之前的工作，它已证明其独特的特性适合该应用。与现有药物不同，SELP栓塞剂可以液体形式注射，能够渗透到肿瘤动脉中，并在原位转化为不溶性水凝胶，形成基本上持久的闭塞。栓塞液体将完全是水性的，并且与药物和新的生物治疗药物相容，从而实现它们的局部控释。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型生物治疗药物的输送，提高经导管输送的精确度，从而实现更具选择性的栓塞，减少脱靶毒性，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肿瘤数量更多和/或肿瘤尺寸更大的患者群体。 研究目的是：（1）开发SELP液体栓塞注射液制剂； (2)测定SELP流体的凝胶速率和凝胶强度 在其最大可注射粘度； (3) 评估其模拟动脉通道的闭塞情况 使用微流体装置进行体外实验； (4)评估SELP液体在肝脏体内经导管动脉栓塞术中的性能。 公共健康相关性：本第一阶段提案详细介绍了开发一种新型液体栓塞剂的基本原理和研究计划，该液体栓塞剂由基因工程蛋白质聚合物 SELP（丝弹性蛋白样蛋白）组成，用于通过经导管动脉化疗栓塞治疗不可切除的肝细胞癌（TACE）。 SELP栓塞将提高栓塞的精度、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 治疗可以提供给更多肿瘤数量较多和/或肿瘤尺寸较大的患者群体，而针对这些患者的治疗选择很少。