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.
This STTR Phase II 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)-815K, for treatment of hepatocellular carcinoma by transcatheter arterial chemoembolization (TACE). SELP-815K embolic will improve the precision of embolization, the compatibility with newly developed drugs, and the selectivity of tumor-specific therapy. Consequently, TACE treatment will be offered to a larger patient population having a greater number of tumors and/or greater tumor size, for which few treatment options exist.
| Isaacson, Kyle J; Jensen, Mark Martin; Watanabe, Alexandre H et al. (2018) Self-Assembly of Thermoresponsive Recombinant Silk-Elastinlike Nanogels. Macromol Biosci 18: |
| Isaacson, Kyle J; Martin Jensen, M; Subrahmanyam, Nithya B et al. (2017) Matrix-metalloproteinases as targets for controlled delivery in cancer: An analysis of upregulation and expression. J Control Release 259:62-75 |
| Poursaid, Azadeh; Jensen, Mark Martin; Huo, Eugene et al. (2016) Polymeric materials for embolic and chemoembolic applications. J Control Release 240:414-433 |
| Poursaid, Azadeh; Price, Robert; Tiede, Andrea et al. (2015) In situ gelling silk-elastinlike protein polymer for transarterial chemoembolization. Biomaterials 57:142-52 |
