Novel pH-Responsive Folic Acid-Conjugated Zein-Carboxymethyl Cellulose Nanoparticles for Enhanced and Controlled Curcumin Release

Abstract Purpose The aim of this study is to develop a novel pH-sensitive drug delivery system by encapsulating curcumin (CR) in carboxymethyl cellulose (CMC)-coated zein (ZN) nanoparticles (NPs). In addition, this study aims to improve a tumour-specific drug delivery system by targeting NPs with folic acid. Methods ZN-NPs were prepared by an antisolvent precipitation technique. Zetasizer, TGA, FT-IR, XRD, SEM and DSC analyses were used in the characterisation studies of the NPs. The dialysis method was used to study the release of CR from CR-ZN-NPs and CR-ZN-CMC-NPs. Results The smallest average ZN-NPs size, 117.2 nm, was obtained with a ultrapure water/ethanol ratio of 10/90 and 0.2 g of ZN. The ZN-NPs size loaded with 1.5 mg of CR was found to be 184 nm. The optimum average ZN-CMC-NPs size was obtained as 277.5 nm with an ideal polydispersity index (0.230) and zeta potential value (-48.1 mV) at a ZN to CMC mass ratio of 1:3. The maximum CR encapsulation efficiency and loading capacity of CR-ZN-NPs containing 2.5 mg of CR were 51% and 0.64%, respectively. For CR-ZN-CMC-NPs, the maximum CR encapsulation efficiency and loading capacity were 70% and 0.58%, respectively. The cumulative release percentages of CR from CR-ZN-NPs and CR-ZN-CMC-NPs loaded with 1.5 mg of CR were 63.6% and 82.5%, respectively, after 72 h in pH 5.6 PBS buffer. Under pH 7.4 conditions, the cumulative CR release percentages from CR-ZN-NPs and CR-ZN-CMC-NPs were 90.6% and 92.1%, respectively, after 72 h. A more controlled, sustained, slower but slightly lower release of CR was obtained at pH 5.6 than at pH 7.4. CR release was slightly retarded by folic acid (FA) conjugation to CR-ZN-CMC-NPs. The release kinetics of CR from both CR-ZN-CMC-NPs and CR-ZN-NPs were best represented by the Higuchi and Korsmeyer-Peppas models, which suggests an "anomalous transport" mechanism. Conclusion The study demonstrates that CMC-coated ZN-NPs were used as an effective CR delivery system by providing optimal CR encapsulation efficiency and controlled release. The study suggests that this pH-responsive, biocompatible drug delivery system could be optimized for dual-drug combinations or synergistic effects in cancer therapy, providing a promising foundation for further research. Graphical Abstract