Enterohepatic circulation-inspired nano-platform for less-hepatotoxicity hepatocellular carcinoma therapy

Hepatocellular carcinoma (HCC) has a poor prognosis because it is often diagnosed after clinical deterioration and lacks effective therapies. The advent of tumor-targeting therapeutics provided a promise in the landscape of advanced HCC but it is still ongoing due to the indistinguishable receptor expression and receptor abundance between hepatocytes and HCC cells. Herein, a GSH-responsive prodrug, CA-PEG-ss-PTX, was synthesized with cholic acid (CA), paclitaxel (PTX) and polyethylene glycol (PEG) and further applied to physically encapsulate PTX, forming PTX/CA-PEG-ss-PTX (PTX/CPSP). PTX/CPSP gained enhanced liver accumulation via CA-mediated active targeting. After internalization in HCC cells, PTX/CPSP could rapidly disassociate and release PTX in response to the high-level GSH for tumor killing. However, it could remain intact in hepatocytes. Furthermore, CA-modification significantly increased the biliary excretion of PTX/CPSP and performed a "fast in ∼ fast out" drug delivery pattern in hepatocytes, thereby reducing the toxicity caused by excessive drug accumulation. Finally, PTX/CPSP displayed superior anti-HCC efficacy with tolerable toxicity. It is worth noting that PTX/CPSP achieved satisfied PTX loading efficiency (more than 30 %) by both chemical synthesis and physical encapsulation. In summary, with all parts being clinically available or endogenous, PTX/CPSP is considered a clinical potential HCC treatment strategy.