Objective(s): Colorectal cancer (CRC) is a prevalent cancer worldwide. The present study aimed to synthesize and investigate the potential of wheat germ agglutinin (WGA) conjugated with polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) incorporating 5-fluorouracil (5-FU). Materials and Methods: The NPs were investigated in terms of various characteristics, such as the particle size, surface charge, surface morphology, entrapment efficiency rate, and in-vitro drug release profile in

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... d gastric and intestinal fluids. The optimized NPs were conjugated with WGA and characterized for the WGA conjugation efficiency, mucoadhesion, and cytotoxicity studies. Results: The zeta potential of the WGA-conjugated NPs decreased (-17.9±1.4 mV) possibly due to the conjugation of the NPs with WGA, which reduced the zeta potential. The WGA-conjugated NPs exhibited sustained drug release effects (p<0.05) compared to the marketed formulation containing 5-FU after 24 hours. In addition, the optimized NPs followed the Higuchi kinetics, showing diffusion-controlled drug release mechanisms. Finally, the WGA-conjugated PLGA NPs could significantly inhibit the growth of colon cancer cells (HT-29 and COLO-205) compared to the non-conjugated NPs and pure drug solution (P<0.05). Conclusion: According to the results, the WGA-conjugated NPs could be potential carrier systems compared to the non-conjugated NPs for the effective management of CRC.