Bioinspired zein-chitosan nanocomplexes for co-delivery of 5-fluorouracil and silibinin: Optimization, characterization and anticancer activity in colorectal cancer.

Colorectal cancer (CRC) is one of the most significant global health concerns, necessitating innovative therapeutic strategies for its effective management. Despite advances in treatment therapies, chemotherapy remains the mainstay of CRC treatment, with 5-Fluorouracil (5-FU) as a standard first-line agent. However, its clinical effectiveness is hindered by drug resistance, rapid clearance and systemic toxicity, underscoring the need for innovative drug delivery strategies. In this context, the current work involves engineering of a bioinspired nanocomplex (NX) comprising zein and a biological macromolecule, such as chitosan, using a Quality by Design (QbD) approach. The resulting NX was characterized for particle size (186.13 ± 8.61 nm), polydispersity index (0.194 ± 0.03), and %entrapment of 5-FU (54.39 ± 3.1%) and silibinin (97.44 ± 1.16%), respectively. SEM and TEM analysis revealed the smooth and spherical nature of NX. Thermal analysis was performed using TGA and DSC and XRD was employed for structural characterization. Subsequently, spectroscopic investigations were carried out using FTIR, Raman and fluorescence spectroscopy to examine the potential interactions between the drugs and polymers used in the formulation of the NX system. In vitro studies confirmed controlled drug release with Weibull release kinetic model. The dual-drug-loaded-NX exhibited a significant increase in cytotoxicity compared to individual 5-FU and silibinin, and achieving nearly a 5-fold increase in cytotoxicity compared to silibinin. The NX demonstrated apoptosis induction, S/G2 cell cycle arrest, and improved cellular uptake compared to control group. The current investigation suggests that QbD-engineered zein-chitosan-based-NX could be a promising therapeutic strategy for managing CRC.