Lipid-polymer conjugated nanocarriers of ferulic acid for obesity intervention via oxidative stress regulation.

OBJECTIVE

Ferulic acid (FA) exhibits antioxidant and metabolic regulatory properties; however, its clinical translation in obesity management is limited due to poor aqueous solubility, low permeability, and rapid systemic clearance (BCS class IV).

SIGNIFICANCE: To develop and optimize a chitosan-conjugated hybrid polymer-lipid nanocarrier system to enhance the oral bioavailability of FA and evaluate its anti-obesity efficacy via oxidative stress-mediated metabolic modulation.

METHODS

FA-loaded nanocarriers were prepared using emulsification solvent evaporation followed by probe sonication and optimized through central composite design (17 experimental runs). Physicochemical characterization included particle size, polydispersity index (PDI), zeta potential, %encapsulation efficiency, %drug loading , and in vitro release kinetics. Anti-obesity efficacy was assessed in a high-fructose diet-induced obese Sprague-Dawley rat model (n = 6 per group). Data were expressed as mean ± SD and analyzed using two-way analysis of variance (ANOVA) followed by Tukey's post hoc test (p < 0.05).

RESULTS

The optimized formulation (F8) exhibited a mean particle size of 110.3 ± 0.2 nm, PDI of 0.241 ± 0.02, zeta potential of -37.21 ± 0.21 mV, %encapsulation efficiency of 86.96 ± 4.4%, and % drug loading of 17.39 ± 3.2%. Sustained drug release of 80.24 ± 2.6% was observed over 24 hour, following Korsmeyer-Peppas kinetics (R2 = 0.99; n = 0.4). In vivo administration significantly reduced plasma insulin (5.84 ± 0.42 to 1.21 ± 0.18 ng/mL), total cholesterol (186.4 ± 8.7 to 97.9 ± 6.3 mg/dL), triglycerides (168.2 ± 7.9 to 98.7 ± 5.8 mg/dL), and LDL (121.5 ± 6.4 to 44.9 ± 4.2 mg/dL), while increasing HDL (38.6 ± 3.1 to 49.8 ± 2.9 mg/dL) compared with high-fructose controls (p < 0.05). Anti-obesity evaluation revealed significant reductions in oxidative stress markers and improved lipid profile: 4.8-fold reduction in insulin, 1.9-fold decrease in cholesterol, 1.7-fold reduction in triglycerides, 1.2-fold increase in HDL, and 0.37-fold reduction in LDL (p < 0.05). These effects were accompanied by attenuation of oxidative stress markers, suggesting restoration of redox-sensitive metabolic pathways.

CONCLUSION

These nanocarriers could - significantly enhanced systemic exposure and metabolic efficacy of FA, demonstrating sustained antioxidant-mediated improvement in insulin sensitivity and lipid homeostasis. Thus representing a promising oral therapeutic platform for obesity-associated metabolic dysfunction.