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

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 NH₂-PEG-NH₂ through a disulfide bond, followed by the connection of CUR-SS-PEG-NH₂ 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.