Development and optimization of a nitric oxide releasing microparticle-basedtopical treatment for onychomycosis - onychomycosis is an extremely common and difficult-to-treat fungal nail infection that…

Development and optimization of a nitric oxide releasing microparticle-basedtopical treatment for onychomycosis - onychomycosis is an extremely common and difficult-to-treat fungal nail infection that causes nail disfigurement, pain, associated infections, and psychosocial effects that negatively impact quality of life. IT is caused predominantly by dermatophytes such as trichophyton rubrum (t. Rubrum) but may also involve yeasts such as candida albicans or non-dermatophyte molds. Typical risk factors include trauma, aging, and history of tinea pedis, but additional comorbidities such as diabetes, obesity, and immune suppression are also significant risk factors, which are increasing in prevalence. Onychomycosis is typically treated by antifungal drugs administered topically or systemically, but each approach has significant shortcomings leading to low complete cure rates of less than 30% and 60%, RESPECTIVELY5,6. Topical antifungals are limited by difficulties in delivering the drug through the nail plate, which is a highly keratinized, difficult-to-penetrate protective BARRIER3,4. Systemic antifungals are generally high cost, may be restricted by limited vascular access to the site of infection, and are associated with potentially severe adverse effects, including hepatotoxicity. In addition, drug resistance in onychomycosis may manifest through the development of biofilm growth or through induction of efflux pumps and mutations. Therefore, the development of an improved treatment for onychomycosis would fill a significant unmet need and improve the quality of life for those affected by the disease. The goal of this proposal will be achieved through two interconnected specific aims. In specific aim 1, zmpno for clinical translation will be synthesized and characterized prior to being evaluated for in vitro antifungal activity against t. Rubrum and other fungal strains relevant to onychomycosis as well as for preliminary cytotoxicity. In specific aim 2, the concentrations of zmpno in a representative cream vehicle required to deliver sufficient no through the nail plate to achieve fungicidal activity will be established. This formulation will then be used to assess zmpno efficacy in treating t. Rubrum and c. Albicans in a romar™ EX vivo infected nail model (medpharm). At the conclusion of this phase i study, an optimized formulation will be established with defined concentration of zmpno suitable for further formulation development, scale-up, safety studies, and EX vivo efficacy studies in phase II.