Nanoemulsion-based transdermal delivery of third-generation steroidal and non-steroidal aromatase inhibitors in preclinical models

Aromatase inhibitors are effective in treating hormone receptor-positive breast cancer, particularly in postmenopausal women. However, the challenges of inconsistent dissolution, variable absorption and side effects with oral administration persist. To address these issues, transdermal delivery has emerged as a viable alternative. In our study, we have developed nanoemulsion-based transdermal creams containing third-generation aromatase inhibitors Exemestane (EXE) or Letrozole (LE) and evaluated their toxicity, anti-tumour effects and androgenic potency using preclinical models including Bama minipigs, DMBA-induced breast cancer rats and orchidectomized male rats. The results of our study are significant, suggesting that both creams effectively penetrated the skin, demonstrating an impressive anti-breast cancer effect. Importantly, EXE cream had no organ toxicity at the tested dose, providing a reassuring safety profile for its use. In contrast, LE cream displayed reversible toxicity from drug molecule itself in animals at the given dose, dissipating after 3 weeks of withdrawal and recovery. This study establishes a solid foundation for the safe clinical use of third-generation aromatase inhibitors. It highlights transdermal creams as a promising drug delivery carrier for administering them. The formulations of both steroidal and non-steroidal aromatase inhibitors in transdermal creams have demonstrated the ability to permeate the skin and effectively impede breast cancer progression. In particular, steroidal aromatase inhibitor cream exhibited negligible animal toxicity and moderate androgenic activity. In contrast, non-steroidal aromatase inhibitor cream displayed some reversible toxicity.image