Recombinant Polymers for Transarterial Chemoembolization of Liver Cancer

描述(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，并且有增加的趋势。然而，目前诊断和治疗的改进并没有带来存活率的提高。大多数病例(80%)是在全身化疗效果不佳的晚期发现的，在任何阶段被诊断为肝癌的患者中，85%的人在5年内死于肝功能衰竭或转移疾病。主要的根治疗法是肝移植，但如果没有供体肝脏，只有姑息治疗，如经动脉移植。 化疗栓塞术(TACE)是可能的。TACE的目标是肿瘤的血液供应。通过血管内导管将含有化疗药物的栓塞剂注入肿瘤的血管系统，随后在进行局部化疗的同时切断血流。目前批准的一种产品，碘化油，是一种油性乳剂，与化疗药物混合使用，与用作栓子的明胶颗粒或合成聚合物珠子一起使用。校准的球形药物洗脱微珠现在正在取代多步油乳剂系统，在这一过程中受到青睐。然而，这些微球有几个缺点：较小直径的微珠聚集，微珠在导管中处于紧张状态时破裂，偏离靶点的栓塞术，特别是在肺循环中，仅洗脱带电的小分子药物，不可降解，肿瘤深度穿透有限，以及低氧状态导致的血管重建。为了解决这些限制，将设计一种基因工程丝状弹性蛋白聚合物(SELP)，以创建一种液-固栓塞剂，能够在化学和分子质量上保留和释放更广泛的治疗药物，能够受控地降解为无毒氨基酸，并能够出色地渗透肿瘤。SELP的水溶液是独一无二的，因为它们在注入体内之前保持可溶状态，在体内不可逆转地转变为固体水凝胶网络。这为在室温下作为低粘度流体提供了理想的注射性，随后在体温下用高度稳定的水凝胶进行了最佳的栓塞。拟议研究的第一个目标是设计一种具有适当粘度的SELP配方，以通过微导管注射到肿瘤血管中，并为稳定的栓塞提供合适的凝胶率和凝胶强度。在第二个目标中，将确定小分子化疗药物(如阿霉素和抗血管生成的索拉非尼)和大生物制剂(如贝伐单抗)的聚合物骨架的药物释放性能。最后，第三个目的是使用已建立的VX2肝癌兔模型来评估TACE新系统的体内性能。作为一个完整的化疗栓塞系统，该聚合物将阻断导致肿瘤缺血和坏死的血流，局部传递化疗药物以杀死周围的肿瘤，并局部传递抗血管生成物质以阻断缺血诱导的血管生成，防止血管重建、肿瘤种植和转移。

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.