Application of Box-Behnken Design in the Preparation, Optimization, and In Vitro Evaluation of Self-Assembly-Based Tamoxifen- and Doxorubicin-Loaded and Dual Drug-Loaded Niosomes for Combinatorial Breast Cancer Treatment

Abstract

This study was developed with the objective to prepare self-assembled niosomes to support sufficient entrapment and sustained drug release of the drugs having different solubility and mechanisms. In the current work, Tamoxifen- and Doxorubicin-loaded niosomes were prepared for combinatorial breast cancer treatment with statistical optimization by Box-Behnken experimental design. Atomic force microscopy revealed a spherical shape morphology of the niosomes. The entrapment efficiencies for the drugs were found to be 74.3% and 72.7% for Tamoxifen and Doxorubicin, respectively. The drug release experiments at different pH values displayed a sustained release up to 3 days. Fourier transform infrared spectroscopy and differential scanning calorimetry showed a robust drug-excipient compatibility. The niosomes were stable over a period of 6 months with no significant changes. In vitro cytotoxicity studies on MCF-7 cell line showed a 15-fold improvement (0.01 μg per mL) and a better synergistic effect of the niosomes in comparison to the free drug combination (0.15 μg per mL). Moreover, the nanocarrier uptake studies by fluorescence microscopy and flow cytometry showed a good distribution and greater uptake of the niosomes throughout the cells. These results suggest a profound therapeutic application of the niosomes for a combinatorial breast cancer treatment.

Keywords: Synergism; box-behnken; breast cancer; combinatorial drug delivery; niosomes.