Coamorphous system of tamoxifen and curcumin: Tailored release, synergism and enhanced pharmacological outcomes to combat breast cancer

Abstract

The therapeutic potential of Tamoxifen, a frontline drug in the treatment of breast cancer is limited by its poor aqueous solubility and limited bioavailability resulting in sub-optimal therapeutic benefits. Herein, we report a novel coamorphous system of tamoxifen with rational-driven selected coformer curcumin demonstrating dual-function role, wherein stabilizing tamoxifen in its amorphous state with boosted anticancer activity. The coamorphous phase was extensively characterized using PXRD, modulated DSC, and IR spectroscopy and was also found to be stable as revealed by accelerated and long term stability studies. The modified form showed significant improvement in the solubility and dissolution compared to the pristine drug. Ex vivo gut sac permeability revealed greater intestinal permeability while in vivo pharmacokinetic profile in female SD rats demonstrated improved oral bioavailability with prolonged T_max showing extended systemic drug exposure. Remarkably, excellent synergism was noted between the components, wherein the bioavailability of tamoxifen was enhanced by curcumin and vice versa. In vitro pharmacological assays using MCF-7 breast cancer cells showed enhanced ROS generation, mitochondrial membrane disintegration, and flow cytometry analysis revealed early onset of apoptosis and cell cycle arrest at G0/G1 phase. Western blotting analysis further confirmed modulation of key apoptotis related proteins, Bcl-2, Bax, and Caspase-3 revealing the pro-apoptotic activity of CAM system. The modified formulation was found to be superior in suppressing cell migration and proliferation of the cancer cells. In vitro biocompatibility assays in non cancerous cells and haemolytic assays revealed CAM has good tolerability and safety profile. These findings prove the potential of the modified coamorphous form as a promising strategy for developing synergistically effective formulation of tamoxifen, offering superior therapeutic outcomes compared to the pristine drug in the treatment of breast cancer therapy.