Lyophilized mixed micelles of exemestane: A novel paradigm to improve its absorption and anticancer activity

Abstract

The objective of the present investigation was to prepare and optimize lyophilized mixed micelles (Lyp‐EXE‐MMs) of exemestane (EXE) with improved solubility, bioavailability, in vivo anticancer activity, and physical stability, by using various cryoprotectants. The prepared lyophilized mixed micelles were characterized by various techniques, including dynamic light scattering, zeta potential, powdered X‐ray diffraction, differential scanning calorimetry (DSC), nuclear magnetic resonance (1H NMR), transmission electron microscopy (TEM), and so on. Thereafter, the lyophilized micelles were evaluated for ex vivo permeation, in vitro drug release and gene/protein expression (RT‐PCR and Western blot analysis) in MCF‐7 breast cancer cells. The developed formulation was also investigated for its in vivo anticancer study in BALB/c mice with induced breast cancer. The use of trehalose (10% w/w) was proven to be a suitable cryoprotectant for these micelles. Lyp‐EXE‐MMs were spherical, with a particle size of 42.9 ± 3.8 nm and a polydispersity index of 0.307 ± 0.122. Furthermore, % drug loading and % entrapment efficiency were found to be 5.8 ± 1.4 and 89.1 ± 1.1, respectively. Lyp‐EXE‐MMs showed sustained release behavior as compared to EXE‐suspensions in SGF/SIF (pH 1.2 and 6.8) and phosphate buffer saline (pH 7.4). The micelles induced apoptosis through the regulation of BAX, BCL2, Caspase‐3, p53, and CYP19A1 in MCF‐7 cells, which was correlated to enhanced ex vivo drug permeation. Animals receiving EXE micelle formulations showed reduced tumor volume and improved survivability and pharmacokinetic parameters as compared to pure EXE. Lyp‐EXE‐MMs were found to withstand simulated harsh conditions of SGF/SIF during stability studies. The fabricated EXE micellar preparations hold a promising approach for breast cancer treatment.