Folate-Functionalized Polymeric Nanoparticles for 5-Fluorouracil Delivery to Prostate Cancer: Physicochemical and In Vitro/In Vivo Characterization

Prostate cancer is the second most common cancer in men worldwide, highlighting the urgent need for effective and targeted chemotherapeutic approaches. This study reports the development and optimization of 5-fluorouracil (5-FU)-loaded poly-(lactic-<i>co</i>-glycolic acid)-polyethylene glycol-folic acid (PLGA-PEG-FOL) nanoparticles designed for folate receptor-mediated targeted therapy. The PLGA-PEG-FOL conjugate was synthesized via a stepwise carbodiimide coupling reaction and confirmed by FT-IR analysis. Nanoparticles were formulated via a modified emulsification-solvent evaporation method and optimized through a Box-Behnken design. The optimized formulation demonstrated a particle size of 178.47 ± 3.26 nm, a narrow polydispersity index (0.119 ± 0.008), a zeta potential of -23.4 ± 0.35 mV, a high entrapment efficiency (78.93 ± 1.05%), and sustained release of 5-FU for up to 72 h. In vitro cytotoxicity assays in PC-3 prostate cancer cells revealed a 1.6-fold reduction in the IC₅₀ value compared with that of free 5-FU, indicating enhanced therapeutic potency. In vivo efficacy was evaluated in testosterone-induced prostate cancer in male Wistar rats. Compared with the control, treatment with 5-FU-loaded PLGA-PEG-FOL nanoparticles significantly reduced the prostate index and produced a 2.2-fold decrease in serum PSA levels and a 1.9-fold decrease in serum testosterone levels. Histopathological examination confirmed the attenuation of hyperplastic and dysplastic lesions in the nanoparticle-treated group. These findings suggest that PLGA-PEG-FOL nanoparticles are a promising targeted delivery platform for enhancing the therapeutic efficacy of 5-FU in prostate cancer treatment.