Redox-responsive and liver-targeted nanoplatform for paclitaxel delivery toward hepatocellular carcinoma therapy

Conventional paclitaxel (PTX) chemotherapy for hepatocellular carcinoma (HCC) is severely restricted by insufficient tumor-targeting specificity, unsatisfactory therapeutic efficacy, and marked systemic toxicity. To address these drawbacks, a redox-responsive and liver-targeted nanoplatform was designed for efficient PTX delivery in HCC therapy. Herein, we synthesized a disulfide-bridged amphiphilic glycyrrhetinic acid-indomethacin prodrug conjugate (GA-ss-IND), which could spontaneously self-assemble into uniform nanomicelles driven by hydrophobic interaction and van der Waals forces, as verified by molecular dynamics simulations. After PTX encapsulation, the fabricated PTX@GA-ss-IND nanomicelles (NMs) displayed regular spherical morphology and favorable colloidal stability. In vitro drug release experiments showed that the nanomicelles displayed prominent redox-responsive release behavior, achieving rapid and on-demand PTX release in high-glutathione intracellular tumor microenvironments. Benefiting from the glycyrrhetinic acid-mediated receptor targeting, cellular uptake assays and ex vivo organ imaging results demonstrated the prominent liver-targeting accumulation of PTX@GA-ss-IND NMs. In vitro cytotoxicity evaluation revealed that the fabricated nanosystem exhibited better antiproliferative activity against HepG2 cells compared with free PTX. Moreover, this nanoplatform effectively improved the in vivo bioavailability of PTX and reduced systemic adverse effecs. In conclusion, the constructed redox-responsive and liver-targeted nanodelivery system presents a feasible and promising strategy for precise and safe chemotherapy toward hepatocellular carcinoma.