Varying coat properties of chitosan-surface modified polya (lactic-co-glycolic acid) nanoparticles for controlled delivery of 5-fluorouracil

5-fluorouracil (5-FU) is a chemotherapeutic agent typically used in the treatment of colon or rectum carcinomas. However, its effectiveness is hindered by its low oral bioavailability, short half-life and serious side effects due to non-specificity. To overcome these limitations, nanoparticles (NPs) of poly (lactic-co-glycolic acid) (PLGA) surface modified with chitosan (CS), both biocompatibility and biodegradability polymers, are suggested as a nanoformulation for the delivery of 5-FU. However, a deeper understanding of how manipulating the properties of the chitosan coat can influence the therapeutic performance of such nanocarrier could unlock a multitude of opportunities. In this study, PLGA NPs were fabricated using a double emulsion technique and subsequently coated with CS dissolved in an acidic solution at concentrations of 1%, 5%, and 10% w/v. With increasing CS concentration, the average particle size and zeta potential of the NPs increased from approximately 220 nm–330 nm and from around −23 mV–44 mV, respectively. Furthermore, the entrapment efficiency was 72.7%, 58.7%, 62.4% and 67.5% for PLGA, PLGA-CS 1%, PLGA-CS 5% and PLGA-CS 10% NPs, correspondingly. CS-coated NPs, especially at higher CS concentrations, demonstrated significant abilities to extend drug release, increase cytotoxicity against colorectal cancer cells, and enhance cellular uptake compared to unmodified NPs. These effects were inversely correlated with the concentration of CS used during NP preparation. Additionally, CS-PLGA NPs displayed strong association with mucin, as evidenced by the change in NPs' zeta potential to negative values. The penetration percentage of 5-FU from NPs across an artificial mucus model was 81.6%, 57.1%, 43.6%, and 29.1% for PLGA, PLGA-CS 1%, PLGA-CS 5%, and PLGA-CS 10%, respectively. Overall, varying CS concentrations used in NP fabrication, and subsequent changes in zeta potential and particle size, resulted in remarkable differences in the NPs' capacity for drug delivery in vitro. These findings highlight the potential of CS-coated PLGA NPs as promising carriers for improving 5-FU delivery in cancer treatment.