Recombinant Polymers for Transarterial Chemoembolization of Liver Cancer

用于肝癌经动脉化疗栓塞的重组聚合物

• 批准号: 8595890
• 负责人: Azadeh Poursaid
• 金额: $ 3.24万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-11-16 至 2016-11-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8595890
• 关键词: Address; Adverse effects; Am 80; Amino Acids; Animals; BAY 54-9085; Blood Tests; Blood Vessels; Blood capillaries; Blood flow; Body Temperature; Bypass; Caliber; Cancer Etiology; Catheters; Cessation of life; Characteristics; Charge; Chemistry; Chemoembolization; Devices; Diagnosis; Disease; Dose; Doxorubicin; Drug Delivery Systems; Drug Formulations; Early treatment; Elastin; Embolism; Emulsions; Endothelial Cells; Engineering; Ensure; Environment; Excision; Fracture; Gel; Gelatin; Genetic Engineering; Gold; Growth; Health; Hepatic; Hepatic artery; Hydrogels; Hypoxia; Image; In Situ; In Vitro; Injectable; Injection of therapeutic agent; Interventional radiology; Ischemia; Laws; Liquid substance; Liver; Liver Failure; Malignant neoplasm of liver; Methods; Microfluidic Microchips; Modeling; Modification; Molecular Weight; Mutation; Necrosis; Neoplasm Metastasis; Oils; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Palliative Care; Patients; Penetration; Performance; Pharmaceutical Preparations; Physiological; Polymers; Prevalence; Primary carcinoma of the liver cells; Procedures; Property; Proteins; Pulmonary Circulation; Quality of life; Recombinants; Research; Silk; Simulate; Solid; Solutions; Staging; Survival Rate; System; Techniques; Temperature; Therapeutic; Therapeutic Embolization; Time; Toxic effect; Treatment Efficacy; Trees; Ultrasonography; United States; Vascular blood supply; Viscosity; Work; angiogenesis; aqueous; artery occlusion; base; bevacizumab; capillary; capillary bed; chemotherapeutic agent; chemotherapy; design; efficacy testing; improved; in vitro Model; in vitro testing; in vivo; killings; liver function; liver transplantation; novel; outcome forecast; palliative; particle; prevent; public health relevance; small molecule; standard care; trend; tumor; tumor progression; tumor vascular supply

DESCRIPTION (provided by applicant): Globally, hepatocellular carcinoma (HCC) of the liver is diagnosed in over 500,000 people annually and trends indicate increasing prevalence. Current improvements in diagnosis and treatment, however, have not produced an increase in survival rates. The majority of cases, >80%, are detected at advanced stages where systemic chemotherapies have little efficacy and 85% of patients diagnosed with HCC at any stage die within 5 years either from liver failure or metastatic disease. The primary curative treatment is liver transplant, but if a donor liver is not available, only palliative care such as transarterial chemoembolization (TACE) are possible. TACE targets the tumor blood supply. An embolic containing a chemotherapeutic agent is injected into the tumor's vasculature via an endovascular catheter, subsequently shutting down blood flow while delivering localized chemotherapy. A presently approved product, Lipiodol, is an oily emulsion mixed with a chemotherapeutic used in conjunction with gelatin particles or synthetic polymer beads that act as emboli. Calibrated spherical drug eluting beads are now gaining favor for this procedure, replacing the multistep oil emulsion system. These beads, however, have several shortcomings: aggregation of smaller diameter beads, fracturing of beads while under strain in the catheter, off target embolization particularly in pulmonary circulation, elution of only charged small molecule therapeutics, non-degradability, limited tumor depth penetration, and revascularization induced by a hypoxic state. To address these limitations a genetically engineered silk-elastinlike protein polymer (SELP) will be designed to create a liquid-to-solid embolic agent capable of retaining and releasing a wider range of therapeutics both in chemistry and molecular weight, capable of controlled degradation into non-toxic amino acids, and capable of superior tumor penetration. Aqueous solutions of SELP are unique in that they remain soluble until injected into the body where they transition irreversibly to a solid hydrogel network. This provides the potential for ideal injectability as a low viscosity fluid at room temperature followed by optimal embolization by a highly stable hydrogel at body temperature. The first aim of the proposed research consists of engineering a SELP formulation with suitable viscosity for injection into the tumor vasculature via a microcatheter and a suitable gelation rate and gel strength for stable embolization. In the second aim, the drug release properties of the polymer matrix will be determined for small molecule chemotherapeutics such as doxorubicin and anti-angiogenic sorafenib and large biologics such as bevacizumab. Finally, the third aim intends to evaluate the in vivo performance of the novel system for TACE using the established VX2 HCC rabbit model. As a complete chemoembolizing system, this polymer will block blood flow inducing ischemia and necrosis of the tumor, locally deliver a chemotherapeutic to kill surrounding tumor, and locally deliver an anti-angiogenic to block angiogenesis induced by ischemia preventing revascularization, tumor seeding, and metastasis.

描述（由申请人提供）：在全球范围内，每年有超过500，000人被诊断为肝细胞癌（HCC），并且趋势表明患病率不断增加。然而，目前诊断和治疗的改进并没有提高生存率。大多数病例（> 80%）在晚期被发现，此时全身化疗几乎没有疗效，85%的任何阶段诊断为HCC的患者在5年内死于肝衰竭或转移性疾病。主要的治愈性治疗是肝移植，但如果供体肝脏不可用，只有姑息治疗，如经动脉 化疗栓塞（TACE）是可能的。TACE靶向肿瘤血液供应。通过血管内导管将含有化疗剂的栓塞剂注射到肿瘤的脉管系统中，随后在输送局部化疗的同时关闭血流。目前批准的产品碘油是一种油性乳剂，与化疗药物混合，与明胶颗粒或合成聚合物珠粒一起用作栓塞剂。校准的球形药物洗脱珠现在越来越受到青睐的这一程序，取代多步油乳剂系统。然而，这些珠粒具有几个缺点：较小直径珠粒的聚集、在导管中处于应变下时珠粒的破裂、特别是在肺循环中的脱靶栓塞、仅洗脱带电的小分子治疗剂、不可降解性、有限的肿瘤深度渗透和由缺氧状态诱导的血管再生。为了解决这些局限性，将设计基因工程丝弹性蛋白样蛋白聚合物（SELP）以产生能够在化学和分子量方面保留和释放更宽范围的治疗剂、能够受控降解成无毒氨基酸并且能够上级肿瘤穿透的液体到固体栓塞剂。SELP的水溶液是独特的，因为它们保持可溶，直到注射到体内，在体内它们不可逆地转变为固体水凝胶网络。这提供了在室温下作为低粘度流体的理想可注射性的可能性，随后在体温下通过高度稳定的水凝胶进行最佳栓塞。所提出的研究的第一个目的包括工程化具有合适粘度的SELP制剂，用于通过微导管注射到肿瘤脉管系统中，以及用于稳定栓塞的合适凝胶化速率和凝胶强度。在第二个目标中，将确定聚合物基质的药物释放性质，用于小分子化学治疗剂如阿霉素和抗血管生成索拉非尼以及大生物制剂如贝伐单抗。最后，第三个目的旨在使用建立的VX 2 HCC兔模型评价用于TACE的新型系统的体内性能。作为一个完整的化学栓塞系统，该聚合物将阻断血流诱导肿瘤缺血和坏死，局部递送化学治疗剂以杀死周围肿瘤，并局部递送抗血管生成剂以阻断由缺血诱导的血管生成，防止血管再生、肿瘤种植和转移。