Targeted Delivery of Celastrol via Chondroitin Sulfate Derived Hybrid Micelles for Alleviating Symptoms in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is caused by an accumulation of excess fat in the liver leading to oxidative stress and liver cell injury, as well as overproduction of inflammatory cytokines. CD44 has been identified as a potential therapeutic target in the development of NAFLD to nonalcoholic steatohepatitis. Here, chondroitin sulfate (CS) is selected to construct a CD44-targeted delivery system for the treatment of NAFLD. Specifically, two CS-derived amphiphilic materials including CS conjugated with either 4-aminophenylboronic acid pinacol ester (CS-PBE) or phenformin (CS-PFM) were synthesized, respectively. The presence of PBE moieties on CS-PBE rendered the vehicle with enhanced loading capacity and scavenging potential against reactive oxygen species, while the presence of guanidine moieties on CS-PFM enhanced the internalization of vehicles in the differentiated hepatocytes. Next, celastrol (CLT) was encapsulated in the hybrid micelle to afford CS-Hybrid/CLT, which demonstrates sufficient stability, enhanced cellular uptake efficiencies in differentiated HepG2 cells, and therapeutic potential to alleviate lipid accumulation in differentiated HepG2 cells. In a high-fat-diet-induced NAFLD rat model, CS-Hybrid/CLT micelles demonstrated the capacity to dramatically decrease hepatic lipid accumulation and free fatty acid levels with greatly improved pathologic liver histology and downregulated hepatic inflammation levels. These results suggest that CS-based amphiphilic micelles may offer a promising strategy to effectively deliver therapeutic cargos to the liver for the treatment of NAFLD.