| Description |
Thermal ablation is widely used, first line local-regional therapy for unresectable hepatocellular carcinoma (HCC). Although high temperature delivered by thermal energy results in efficient coagulation necrosis in tumor cells, various factors including tumor size, shape, location, and cirrhosis can lead to un-uniform heat distribution and inefficient cell damage. As a result, the incomplete ablation causes high rates of tumor recurrence and poor survival for HCC patients. Cells that are not completely ablated can induce heat shock proteins (HSPs), which are cellular gatekeepers to protect tumor cells from thermal damage and prepare them for future neoplastic growth. Synchronous adjuvant chemotherapy targeting those cells can achieve more complete tumor abrogation and prevent future tumor recurrence. This dissertation describes a strategy to combat postablation recurrence by synchronous inhibition of heat shock protein 90 (HSP90) by thermo-responsive, elastin-like polypeptide (ELP)-based biopolymer conjugates. ELP copolymer carries high concentrations of a potent HSP90 inhibitor, geldanamycin (GA), which inhibit the induction of HSP90 and further destabilize numerous HSP90 client proteins critical for cell survival. It is hypothesized that combination of thermal ablation with concomitant inhibition of HSP90 via ELP-GA conjugates can achieve synergistic anticancer effect. Specifically, the ablation-created hyperthermia will sensitize tumor cells to be more vulnerable to the drug, which will be conjugated with high concentrations through thermally targeted, ELP-based biopolymer systems. The ELP conjugates, in turn, will reach and kill the remaining viable cells to prevent future recurrence. ELP-GA conjugates that ferry multiple GAs and rapidly respond to hyperthermia were synthesized, characterized, and evaluated for activity in HCC models. The cytotoxicity of ELP-GA conjugates was enhanced with hyperthermia treatment, and effective HSP90 inhibition was achieved in HCC cell lines. In a tumor-bearing mouse model, electrocautery-based thermal ablation offered effective destruction of tumor core and created a hyperthermia zone for targeted delivery and accumulation of ELP-GA conjugates. Results demonstrate that the combination of thermal ablation and targeted HSP90 inhibition can enhance the anticancer effect and cellular delivery of macromolecular chemotherapeutics to achieve safe, synergistic, and long-term anticancer effect with no tumor recurrence observed. The combination approach paves the way for developing molecular-targeted intervention to increase the efficacy of first-line local-regional therapies for HCC. |
