Nitric\nOxide-Releasing Topical Treatments for Cutaneous\nMelanoma

Melanoma is an aggressive skin cancer notorious for high\nlevels\nof drug resistance. Additionally, current treatments such as immunotherapies\nare often associated with numerous adverse side effects. The use of\nnitric oxide (NO) may represent an attractive treatment for melanoma\ndue to NO’s various anticancer properties, unlikeliness to\nfoster resistance, and limited toxicity toward healthy tissues. The\nanticancer effects of chemical NO donors have been explored previously\nbut with limited understanding of the needed characteristics for exerting\noptimal antimelanoma activity. Herein, the in vitro therapeutic efficacy\nof three macromolecular NO donor systems (i.e., cyclodextrin, mesoporous\nsilica nanoparticles, and hyaluronic acid) with tunable NO-release\nkinetics was explored by evaluating skin permeation along with toxicity\nagainst melanoma and healthy skin cells. Cytotoxicity against melanoma\ncells was dependent on NO payload and not donor identity or NO-release\nkinetics. In contrast, cytotoxicity against healthy cells was primarily\ninfluenced by the macromolecular NO donor, with cyclodextrin- and\nhyaluronic acid-based NO donors having the highest therapeutic indices.\nIn vitro skin permeation was influenced by both the size and charge\nof the NO donor, with smaller, more neutral donors resulting in greater\npermeation. A Pluronic F127 organogel was optimized for the delivery\nof a cyclodextrin-based NO donor. Delivery of the NO donor in this\nmanner resulted in increased in vitro skin permeation and reduced\ntumor growth in an in vivo model.