Development of pH-tunable PLGA nanoparticles for targeted liver delivery of obeticholic acid

Abstract

Obeticholic acid (OCA), a potent farnesoid X receptor agonist, is approved for the treatment of primary biliary cholangitis and is being investigated for broader applications in hepatic inflammation. However, systemic exposure following oral administration often leads to off-target effects. In this study, we developed poly(lacticco-glycolic acid) (PLGA) nanoparticles (NPs) to improve the therapeutic profile of OCA through targeted liver delivery. The NPs were prepared using a rapid, scalable, and pH-responsive nanoprecipitation method that enabled precise control of particle size and encapsulation efficiency. Two PLGA compositions (50:50 and 75:25 lactic-to-glycolic acid ratios) were used, yielding NPs ranging from 35 to 193 nm with encapsulation efficiency decreasing from 89% at pH 2.5 to 15% at pH 10.0. In vitro release studies demonstrated a pH-responsive release profile, with significantly slower OCA release under acidic conditions. OCA-loaded NPs showed excellent biocompatibility in primary murine macrophages and significantly reduced the cytotoxicity associated with free OCA. Moreover, they retained OCA's anti-inflammatory activity in LPS-stimulated THP-1 macrophages, reducing IL-6 expression and inducing SHP upregulation. Biodistribution confirmed preferential liver accumulation of DiR-labeled OCA-loaded NPs following intravenous administration. Collectively, these results demonstrate that pH-tunable PLGA NPs represent a promising platform for targeted hepatic delivery and controlled release of OCA.