Invasomes nanocarriers for targeted delivery of letrozole derivative: A novel strategy to mitigate breast cancer.

As a non-steroidal aromatase inhibitor, letrozole is primarily used for treating estrogen-dependent breast cancer (BC). However, the long-term use of letrozole is limited due to severe adverse effects, including increased risks of cardiovascular disease and osteoporosis. A new bis-triazole compound derived from letrozole, designated as 19l (BTD-19l), demonstrated significant inhibition of the aromatase enzyme and has shown remarkable anticancer activity. However, preliminary studies have shown that BTD-19l has poor solubility, which may negatively impact its bioavailability and therapeutic efficacy when administered orally. This study aimed to develop a transdermal hydrogel that incorporates BTD-19l invasomes (BTD-19lLI). The objective was to enhance the transdermal permeation, bioavailability, and prolonged systemic exposure of BTD-19l to maximize its therapeutic potential and minimize side effects. Multiple formulas were developed and optimized using the Design Expert software. The optimized BTD-19lLI hydrogel was prepared by incorporating it into a hydrogel matrix consisting of 2% carbopol 934. To assess the efficacy and bioavailability of the optimized BTD-19lLI hydrogel, a rat model of DMBA-induced BC was employed. This approach facilitated a comparison with oral letrozole, which served as a reference drug. The optimal BTD-19lLI formulation included 2% lecithin, 2.5% ethanol, and 1% cineole. The optimized BTD-19lLI hydrogel demonstrated a significant reduction in drug release by 71.60%. At the same time, it increased permeation by a factor of 5.77 and enhanced bioavailability by 5.61-fold when compared to the free BTD-19l suspension. Additionally, the optimized BTD-19lLI hydrogel exhibited superior anticancer activity compared to the oral letrozole. Thus, the transdermal BTD-19lLI hydrogel could be a viable therapy for BC.