Synthesis and optimization of fluoxetine-loaded polymeric nanoparticles for dual therapeutic applications in cancer and depression.

Abstract

Background: Fluoxetine, an antidepressant, has shown potential anticancer effects. However, its therapeutic efficacy is limited by its poor bioavailability and rapid metabolism. Nanotechnology is advancing medicine, particularly in developing suitable drug delivery systems to improve therapeutic effects and reduce drug side effects.

Objectives: This study aims to synthesize chemically conjugated fluoxetine-dextran nanoparticles (FLX-DEX NPs) to improve the pharmacokinetic profile in plasma and brain to improve antidepressant and anticancer activity against glioma and breast cancer. Besides this, it also targets to reduce the side effects of the drug via delivering the payload to pathological cells.

Methods: Fluoxetine was conjugated to aldehyde-functionalized dextran to give pH stimulus release from its nanoparticles. The spectral and morphological characterization was performed using dynamic light scattering (DLS), atomic force microscopy (AFM), UV, FTIR and ¹HNMR. The stability was determined using thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) to evaluate thermal stability and phase transitions of the fluoxetine-dextran nanoparticles. Non-compartmental model was employed to compare the pharmacokinetics of FLX and its nanoparticles in the plasma and various parts of Sprague-Dawley rats. Furthermore, the in vitro safety profile, cytotoxic activity on MCF-7 breast cancer and U87 glioma cell lines and antidepressant effects were measured using various animal models. The levels of dopamine and serotonin in brain were monitored after a fortnight treatment of FLX and its NPs.

Results: The nanoparticles were found to be round to slightly elliptical, having size less than 50 nm and charge -15-20 mV. These nanoparticles were more stable to the drug as depicted by thermoanalysis. The particles showed a controlled and pH stimuli released. The C_max, T_max, t_1/2, volume of distribution and plasma elimination values were 5.23, 2, 15 h, 1.94 and 0.045, respectively, on oral administration of 30 mg/ kg/day. They passed 20% and 18% viability against MCF-7 and glioma cancer at 10 mg/kg/day dose without retarding its anti-depressant effect.

Conclusion: FLX-DEX NPs offer dual therapeutic benefits, enhancing anticancer activity and antidepressant effects. The extended half-life and controlled fluoxetine release improved the pharmacokinetics and therapeutic outcomes, suggesting a promising nanotechnology-based approach for cancer and depression treatment.