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.
Hepatocellular carcinoma is diagnosed annually in over half a million people worldwide, with 200,000 new cases in the United States, and is the third leading cause of cancer related death. Prognosis remains poor unless it is discovered very early, and treatment is often only palliative. Transarterial chemoembolization is a treatment option, which we aim to improve by engineering a liquid-to-solid embolic agent, capable of penetrating into tumor vasculature, blocking off blood supply and simultaneously delivering multiple chemotherapeutics to halt tumor progression, improve patient survival, minimize systemic side effects, and therefore enhance and prolong quality of life.
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