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: 9350251
• 负责人: Darwin Leroy Cheney
• 金额: $ 69.45万
• 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 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9350251
• 关键词: Acute; Address; Animals; Arteries; BAY 54-9085; Biological Products; Biological Response Modifier Therapy; Blood; Blood Tests; Blood flow; Caliber; Carcinoma; Catheterization; Catheters; Characteristics; Chemoembolization; Chronic; Clinical; Clinical Treatment; Clinical Trials; Collection; Development Plans; Disease; Disease Progression; Doxorubicin; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Eligibility Determination; Endotoxins; Ensure; Evaluation; Excision; Excretory function; Family suidae; Fermentation; Formulation; Gel; Genetic Engineering; Gold; Grant; Guidelines; Health; Hemolysis; Hepatic; Hepatic artery; Human; Hydrogels; Implant; In Situ; In Vitro; Incidence; Injectable; Injection of therapeutic agent; Interventional radiology; Intramuscular; Laboratories; Laboratory Personnel; Laboratory Procedures; Liquid substance; Liver; Liver neoplasms; Lung; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of liver; Metabolism; Methods; Microfluidic Microchips; Modeling; Molecular Weight; Operative Surgical Procedures; Oryctolagus cuniculus; Patients; Performance; Pharmaceutical Preparations; Phase; Polymers; Preparation; Primary carcinoma of the liver cells; Procedures; Production; Property; Protein Engineering; Proteins; Rattus; Reaction; Research; Safety; Silk; Small Business Technology Transfer Research; Solid; Source; Sterilization; Structure; Survival Rate; Symptoms; Syringes; System; Techniques; Testing; Therapeutic; Therapeutic Embolization; Time; Tissues; Toxic effect; Toxicity Tests; Toxicology; Treatment Efficacy; Urine; Venous system; Viscosity; Work; analytical method; aqueous; base; biomaterial compatibility; bioresorption; cancer cell; cancer imaging; chemotherapeutic agent; chemotherapy; comparative efficacy; controlled release; design; drug distribution; immunoreactivity; implantable device; implantation; improved; in vivo; killings; liver function; liver transplantation; method development; nanoparticulate; novel; patient population; performance tests; pre-clinical; scale up; standard care; standard of care; systemic toxicity; tumor; tumor vascular supply

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.

概括 STTR II 期提案解决了对改善患有以下疾病的患者的治疗方案的重大需求： 肝癌，世界上发病率第五高的癌症。由于缺乏症状，肝细胞 84% 的病例在晚期发现癌症 (HCC)，其 1 年生存率为 22% 5年后是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病情进展迅速，大多数患者无法获得 疾病。由于 HCC 通常对全身化疗无反应，因此经导管动脉化疗 化疗栓塞 (TACE) 是最广泛使用的局部治疗方法，可以减缓病情的进展 疾病。目前的栓塞剂在导管输送精度或有效相容性方面存在缺陷。 化疗药物的递送，尤其是高分子量生物治疗药物。该计划的目标 拟议的工作是表征由基因工程组成的新型液体栓塞剂 蛋白质聚合物，SELP（丝弹性蛋白）-815K，基于我们之前的工作已经证明 独特地适合该应用的特性。与现有制剂不同，SELP-815K 可以液体形式注射， 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 持久闭塞。栓塞液将完全是水性的，并且与药物和新药物相容。 生物治疗药物，使其能够局部受控释放。基于蛋白质的 SELP-815K 最终将 生物降解，使后续 TACE 治疗成为可能。 SELP-815K 液体栓塞将实现控制输送 化疗药物和新型生物治疗药物的经导管输送精度更高 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 治疗将提供给更多肿瘤数量较多的患者群体 和/或更大的肿瘤尺寸。 该研究的目的是：(1) 表征通过 SELP-815K 输送单一和多种药物的特性 凝胶网络； (2) 在McA-RH7777 HCC肝肿瘤大鼠模型中进行体内研究以评估治疗效果 表现; (3) 进行SELP-815K制造和分析方法开发； (4) 进行 对制造的 SELP-815K 栓塞进行 GLP 临床前毒理学和性能测试。