INNOVATIVE LIPIDIC NANOCARRIERS OF FLUTAMIDE ENHANCING ITS IN VITRO CYTOTOXICITY AND IN VIVO ORAL BIOAVAILABILITY: DESIGN, OPTIMIZATION, CHARACTERIZATION, AND PHARMACOKINETIC ASPECTS

Abstract

Objective: the reduced oral bioavailability of Flutamide has hindered its effectiveness as a chemotherapeutic agent for prostate cancer treatment. Our study aimed to enhance FLUTAMIDE in vitro cytotoxicity and oral bioavailability via its incorporation into lipid nanocarriers that contained solid lipid (Precirol®) alone or in combination with anti-androgenic oils such as Saw Palmetto Oil (SPO) and Pumpkin Seed Oil (PSO). Methods: we employed the Box Behnken Design (BBD) to optimize Flutamide-loaded nanocarriers, focusing on mean vesicular size, zeta potential, and entrapment efficiency. Results: the optimized nanovesicles exhibited dimensions of 330.2 nm, a zeta potential of -43.1 mV, and an entrapment efficiency of 66.1%. Morphological analysis using Transition Electron Microscope (TEM) and Scanning Electron Microscope (SEM) confirmed the spherical shape of the nanovesicles. Differntial Scanning Calorimetry (DSC) thermograms and X-ray diffractograms indicated decreased crystallinity of encapsulated Flutamide compared to free Flutamide. In vitro cytotoxicity studies demonstrated enhanced effects against prostate cancer cells (PC-3) for optimized Flutamide-loaded nanocarriers containing the 2 anti-androgenic oils over both nanocarriers containing no oils and free Flutamide suspension. In vivo pharmacokinetic analysis in male rats showed increased oral bioavailability for flutamide-loaded nanocarriers with Cmax values of 559.35±41.79 ng/ml and 670.9±24.61 ng/ml for different formulations compared to the free flutamide suspension with a Cmax value of 281.4±94.33 ng/ml. Conclusion: These findings support FLUTAMIDE oral bioavailability improvement through nanocarriers encapsulation, advocating its utilization in prostate cancer therapy and approving the additive anti-androgenic effect after its combination with SPO and PSO.