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

Abstract

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.

References

[1] Bajetta E, Zilembo N, Dowsett M, et al. Double-blind, randomised, multicentre endocrine trial comparing two letrozole doses, in postmenopausal breast cancer patients. Eur J Cancer. 1999; 35(2): 208-213.

[2] Del Mastro L, Mansutti M, Bisagni G, et al. Extended therapy with letrozole as adjuvant treatment of postmenopausal patients with early-stage breast cancer: a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2021; 22(10): 1458-1467.

[3] Johannessen DC, Engan T, Di Salle E, et al. Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmenopausal breast cancer patients: a phase I study. Clin Cancer Res. 1997; 3(7): 1101-1108.

[4] Serrano D, Gandini S, Thomas P, et al. Efficacy of alternative dose regimens of exemestane in postmenopausal women with stage 0 to II estrogen receptor-positive breast cancer: a randomized clinical trial. JAMA Oncol. 2023; 9(5): 664-672.

[5] Pagani O, Walley BA, Fleming GF, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer: long-term follow-up of the combined TEXT and SOFT trials. J Clin Oncol. 2023; 41(7): 1376-1382.

[6] Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival with Ribociclib plus Letrozole in advanced breast cancer. N Engl J Med. 2022; 386(10): 942-950.

[7] Valle M, di Salle E, Jannuzzo MG, et al. A predictive model for exemestane pharmacokinetics/pharmacodynamics incorporating the effect of food and formulation. Br J Clin Pharmacol. 2005; 59(3): 355-364.

[8] Traina TA, Poggesi I, Robson M, et al. Pharmacokinetics and tolerability of exemestane in combination with raloxifene in postmenopausal women with a history of breast cancer. Breast Cancer Res Treat. 2008; 111(2): 377-388.

[9] Kukobat R, Skrbic R, Vallejos-Burgos F, et al. Enhanced dissolution of anticancer drug letrozole from mesoporous zeolite clinoptilolite. J Colloid Interface Sci. 2024; 653: 170-178.

[10] Liu H, Chen X, Jia Y, et al. Facing inevitable PARPis resistance: mechanisms and therapeutic strategies for breast cancer treatment. Interdiscip Med. 2023; 1(2):e20220013.

[11] Gerken P. Letrozole (Femara). Clin J Oncol Nurs. 2004; 8(3): 314-315.

[12] Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol. 2008; 26(11): 1261-1268.

[13] Chakraborty A, Alexander S, Luo W, et al. Engineering multifunctional adhesive hydrogel patches for biomedical applications. Interdiscip Med. 2023; 1(4):e20230008.

[14] He J, Chen W, Chen X, et al. Tetrahedral framework nucleic acid loaded with glabridin: a transdermal delivery system applicated to anti-hyperpigmentation. Cell Prolifer. 2023; 56(12): e13495.

[15] Phatale V, Vaiphei KK, Jha S, Patil D, Agrawal M, Alexander A. Overcoming skin barriers through advanced transdermal drug delivery approaches. J Control Release. 2022; 351: 361-380.

[16] Gao L, Zhu L, Shen C, et al. The transdermal cream of formestane anti-breast cancer by controlling PI3K-Akt pathway and the tumor immune microenvironment. Front Immunol. 2023; 14: 1041525.

[17] Huang S, Wu Z, Chen Y, et al. Dermal repeated dose toxicity study of the anti-breast cancer drug Formestane cream in Bama minipig. Food Chem Toxicol. 2023; 178: 113927.

[18] Lonning PE. The potency and clinical efficacy of aromatase inhibitors across the breast cancer continuum. Ann Oncol. 2011; 22(3): 503-514.

[19] NMPA. Technical Guidelines for Repeated Drug Administration Toxicity Testing. The National Medical Products Administration; 2014 https://www.nmpa.gov.cn/directory/web/nmpa/xxgk/ggtg/qtggtg/20140513120001448.html

[20] Brodie AM, Garrett WM, Hendrickson JR, Tsai-Morris CH. Effects of aromatase inhibitor 4-hydroxyandrostenedione and other compounds in the 7, 12-dimethylbenz(a)anthracene-induced breast carcinoma model. Cancer Res. 1982; 42(8): 3360-3364.

[21] Yamasaki K, Sawaki M, Ohta R, et al. OECD validation of the Hershberger assay in Japan: phase 2 dose response of methyltestosterone, vinclozolin, and p,p'-DDE. Environ Health Perspect. 2003; 111(16): 1912-1919.

[22] Gao L, Bao Z, Deng H, et al. The beneficial androgenic action of steroidal aromatase inactivators in estrogen-dependent breast cancer after failure of nonsteroidal drugs. Cell Death Dis. 2019; 10(7): 494.

[23] Gu Y, Yang M, Tang X, et al. Lipid nanoparticles loading triptolide for transdermal delivery: mechanisms of penetration enhancement and transport properties. J Nanobiotechnol. 2018; 16(1): 68.

[24] Gomes MJ, Martins S, Ferreira D, Segundo MA, Reis S. Lipid nanoparticles for topical and transdermal application for alopecia treatment: development, physicochemical characterization, and in vitro release and penetration studies. Int J Nanomed. 2014; 9: 1231-1242.

[25] Luo Y, Han Y, Hu X, et al. Live-cell imaging of octaarginine-modified polymer dots via single particle tracking. Cell Prolif. 2019; 52(2):e12556.

[26] Lei H, Pei Z, Jiang C, Cheng L. Recent progress of metal-based nanomaterials with anti-tumor biological effects for enhanced cancer therapy. Exp Dermatol. 2023; 3(5):20220001.

[27] Buzdar AU, Robertson JF, Eiermann W, Nabholtz JM. An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and exemestane. Cancer. 2002; 95(9): 2006-2016.

[28] Ashafa AO, Orekoya LO, Yakubu MT. Toxicity profile of ethanolic extract of Azadirachta indica stem bark in male Wistar rats. Asian Pac J Trop Biomed. 2012; 2(10): 811-817.

[29] Maronpot R, Ramot Y, Nyska A, et al. Chronic toxicity and carcinogenicity study of dietary gardenia blue in Sprague Dawley rats. Food Chem Toxicol. 2023; 176: 113734.

[30] Mohammed RS, Aadim KA, Ahmed KA. Histological, haematological, and thyroid hormones toxicity of female rats orally exposed to CuO/ZnO core/shell nanoparticles synthesized by Ar plasma jets. Arch Toxicol. 2023; 97(4): 1017-1031.

[31] Gharia B, Seegobin K, Maharaj S, Marji N, Deutch A, Zuberi L. Letrozole-induced hepatitis with autoimmune features: a rare adverse drug reaction with review of the relevant literature. Oxf Med Case Rep. 2017; 2017(11):omx074.

[32] Hannan FM, Elajnaf T, Vandenberg LN, Kennedy SH, Thakker RV. Hormonal regulation of mammary gland development and lactation. Nat Rev Endocrinol. 2023; 19(1): 46-61.

[33] Qureshi R, Picon-Ruiz M, Aurrekoetxea-Rodriguez I, et al. The major pre- and postmenopausal estrogens play opposing roles in obesity-driven mammary inflammation and breast cancer development. Cell Metab. 2020; 31(6): 1154-1172.e1-e9.

RIGHTS & PERMISSIONS

2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.