Drug-loaded degradable biopolymeric scaffolds for augmenting preoperative liver growth - PROJECT SUMMARY The surgical resection of liver tumors is the only solution for long-term tumor-free survival. The quality and vol- ume of the future liver remnant (FLR) are the criteria for resectability. If the FLR volume is insufficient, there is a high chance that patients will develop small-for-size syndrome, which increases the risk of post- hepatectomy liver failure, resulting in significant morbidity and mortality. Novel interventions, such as portal vein emboliza- tion or ligation, have been used to increase the FLR, with limited success. Obeticholic acid (OCA), a novel semi-synthetic bile acid analogue, shows evidence of enhancing liver growth by promoting hepatocyte prolifer- ation, reducing inflammation and fibrosis, improving bile homeostasis, and regulating lipid metabolism. OCA thereby increases the number of patients who are potential surgical candidates; however, challenges in drug dosing of OCA lead to unwanted hepatoxicity and diminished efficacy. Three urgent needs are addressed by this proposal: devising an effective and efficient delivery system that improves the controlled retention and therapeutic benefits conferred by OCA, developing a clinically translatable animal model to understand the mechanism of action of OCA and the novel delivery system in relation to liver hypertrophy, and developing a non-invasive imaging modality to evaluate FLR growth and tumor progression. Therefore, this proposal aims to (1) develop a rat tumor model with a cirrhosis background, (2) fabricate resorbable polymeric scaffolds with optimal physicochemical properties for the sustained delivery of OCA, and (3) utilize [18F]FSPG, a novel radio- tracer, for in vivo positron emission tomography monitoring of post-intervention FLR growth and tumor progres- sion. We will then correlate imaging findings with histologic and transcriptomic profiles of the liver and the tu- mor to provide mechanistic insights as to how OCA treatment affects liver growth. The proposed work is sig- nificant and innovative because there is currently no available in vivo model of portal vein ligation in the con- text of hepatocellular carcinoma and cirrhosis, and the step-by-step optimization of the physicochemical prop- erties of the polymeric scaffold will improve OCA delivery and efficacy, thus enhancing liver growth and regen- eration. Our long-term goal is developing resorbable delivery materials that help in liver regeneration, thereby increasing the number of patients who are suitable for surgical resection while furthering our understanding of how drug-polymer constructs exert therapeutic efficacy. Given the potential of OCA to modulate pathologic in- flammation, we can expand our research into other disease processes that follow a progression from inflam- mation to fibrosis to permanent end-organ dysfunction (e.g., hepatitis/steatohepatitis/cholestasis to liver fibro- sis/cirrhosis, renal fibrosis to end-stage renal disease). Furthermore, while we propose to develop a construct that can sustain the therapeutic efficacy of OCA at safe levels by enveloping them within an alginate polymer, our findings could lead to the creation of other therapeutic drug/alginate combinations using mechanism-spe- cific compounds (e.g., anti-inflammatory compounds, antioxidant compounds, matrix-degrading agents).
