Ionic liquid-mediated delivery of a BCL-2 inhibitor for topical treatment of skin melanoma

• Published in: Journal of controlled release 2022-09, Vol.349, p.783-795
• Main Authors: Huda, Md Nurul, Deaguero, Isaac G., Borrego, Edgar A., Kumar, Raj, Islam, Tamanna, Afrin, Humayra, Varela-Ramirez, Armando, Aguilera, Renato J., Tanner, Eden E.L., Nurunnabi, Md
• Format: Article
• Language: English
• Subjects: Administration, Cutaneous; Animals; Antineoplastic Agents; Apoptosis; Caprylates - pharmacology; Caprylates - therapeutic use; Chemotherapeutic; Choline; Humans; Ionic liquid; Ionic Liquids; Melanoma; Melanoma - drug therapy; Melanoma - pathology; Melanoma, Cutaneous Malignant; Mice; Proto-Oncogene Proteins c-bcl-2; Skin; Skin Neoplasms - drug therapy; Skin Neoplasms - pathology; Topical delivery
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2022.07.035

Skin melanoma is one of the most common cancer types in the United States and worldwide, and its incidence continues to grow. Primary skin melanoma can be removed surgically when feasible and if detected at an early stage. Anti-cancer drugs can be applied topically to treat skin cancer lesions and used as an adjunct to surgery to prevent the recurrence of tumor growth. We developed a topical formulation composed of Navitoclax (NAVI), a BCL-2 inhibitor that results in apoptosis, and an ionic liquid of choline octanoate (COA) to treat early-stage melanoma. NAVI is a small hydrophobic molecule that solubilizes at 20% (w/v) when dissolved in 50% COA. Although NAVI is a highly effective chemotherapeutic, it is equally thrombocytopenic. We found that COA-mediated topical delivery of NAVI enhanced its penetration into the skin and held the drug in the deeper skin layers for an extended period. Topical delivery of NAVI produced a higher cancer-cell killing efficacy than orally administrated NAVI. In vivo experiments in a mouse model of human melanoma-induced skin cancer confirmed the formulation's effectiveness via an apoptotic mechanism without any significant skin irritation or systemic absorption of NAVI. Overall, this topical approach may provide a safe and effective option for better managing skin cancer in the clinic. [Display omitted] •Ionic liquid solubilized the hydrophobic molecule Navitoclax (NAVI) without any solubilizer.•Combination of ionic liquid and NAVI form nano-structured micelles.•Facilitate transportation of the drug through the skin, tested in pig skin.•Minimize systemic circulation and maximize retention in dermis layer of skin.•The formulation induced apoptosis and provided a safe and potent topical delivery for the treatment of melanoma.