Folic Acid‐Mediated Reduction‐Sensitive Curcumin Prodrug Enhances the Delivery Performance of Curcumin in Liver Cancer Cells

Abstract In order to improve the delivery performance of curcumin (CUR) in liver cancer cells, we prepared a targeted and reduction‐sensitive prodrug, folic acid‐polyethylene glycol‐disulfide bond‐curcumin (FA‐PEG‐SS‐CUR). The synthesis involved the conjugation of CUR with NH 2 ‐PEG‐NH 2 through a disulfide bond, followed by the connection of CUR‐SS‐PEG‐NH 2 to FA‐COOH via acylation. The resultant FA‐PEG‐SS‐CUR prodrug self‐assembled into nano micelles in aqueous solutions, displaying excellent dispersibility with an approximate particle size of 119 nm. In vitro drug release studies demonstrated the sensitivity of FA‐PEG‐SS‐CUR to glutathione (GSH), displaying sustained release performance. After 72 h, FA‐PEG‐SS‐CUR exhibited a drug release rate of 38% at low GSH concentration and 59% at high GSH concentration. Notably, FA‐PEG‐SS‐CUR micelles exhibited favorable biocompatibility. The hemolysis rate resulting from co‐incubation with red blood cells remained below 3%. Furthermore, cytotoxicity experiments unveiled the substantial cytotoxicity of FA‐PEG‐SS‐CUR micelles against HepG2 tumor cells. Cellular uptake studies confirmed the greater internalization of FA‐PEG‐SS‐CUR by HepG2 cells compared to the non‐targeted PEG‐SS‐CUR. The findings highlight the potential of FA‐PEG‐SS‐CUR as an ideal drug delivery system for CUR due to its facile synthesis and strong self‐assembly performance.