Developing Mixed Micelle Delivery Systems for Aromatase Inhibitors.

Aromatase, an enzyme that facilitates the last stage in estrogen synthesis (estrogen is identified for a significant impact in the development of breast cancer), has been recognized as a potential target for therapeutic advancements for cancer. Although clinically approved aromatase inhibitors are the cornerstones of estrogen receptor-positive (ER+) breast cancer, their use is often accompanied by adverse side effects and pharmacokinetic limitations, which lead to patient compliance issues and limit therapeutic outcomes. In previous studies, compound 1-(a) was identified for its superior inhibition of aromatase with an IC50 value of 54.0 nM and appreciable tumor growth inhibitory activities. Here, we demonstrated the pharmaceutical capability of 1-(a) while evaluating its various features, including acute toxicity, bioavailability by developing a nanodrug delivery system, and therapeutic efficacy. In vivo acute toxicity studies confirmed the safety of compound 1-(a), with no significant alterations observed. To improve the aqueous solubility and pharmacokinetic profile, a mixed micelle-based delivery system by using Pluronics P123 and F127 was developed, and a 2:1 formulation was optimized for demonstrating excellent drug loading (8.8%) and entrapment efficiency (80%). The micellar formulation significantly enhanced the solubility, stability, % growth inhibition, and cellular uptake of 1-(a) against MCF-7 and MDA-MB-231 cell lines and intestine permeability. An in vitro drug release study performed at pH 1.2, 6.8, and 7.4 indicated the sustained release behavior of 1-(a). Overall, the results of these experiments supported the potential of Pluronics as a drug delivery system for the potent aromatase inhibitor.