Development and optimization of a nitric oxide releasing microparticle-basedtopical treatment for onychomycosis

甲真菌病是一种非常常见和难以治疗的真菌指甲感染，导致指甲毁容， 疼痛、相关感染和对生活质量产生负面影响的社会心理影响。所致 主要由皮肤真菌如红色毛癣菌（Trichophyton rubrum（T.红色），但也可能涉及酵母， 白色念珠菌或非皮肤真菌霉菌。典型的风险因素包括创伤、衰老和糖尿病史。 但其他合并症如糖尿病、肥胖和免疫抑制也是显著的风险 这些因素正在日益普遍。甲真菌病是典型的治疗抗真菌药物管理 局部或全身，但每种方法都有显著的缺点，导致完全治愈率低， 分别低于30%和60% 5，6.局部抗真菌药物的局限性在于药物的输送困难 通过指甲盖，这是一个高度角质化，难以渗透的保护屏障3，4。系统性 抗真菌药通常成本高，可能受到到达感染部位的有限血管通路的限制， 与潜在的严重不良反应相关，包括肝毒性。此外， 甲真菌病可通过生物膜生长的发展或通过外排泵的诱导而显现 和突变。因此，甲真菌病的改进治疗的发展将填补一个空白。 这将有助于消除严重的未满足需求，并改善受疾病影响者的生活质量。 本提案的目标将通过两个相互关联的具体目标来实现。在特定目标1中，zMPNO 在评价体外抗真菌活性之前， 抗犬弓红色和其他与甲真菌病相关的真菌菌株以及初步的细胞毒性。在 具体目标2，递送足够的NO所需的代表性乳膏媒介物中的zMPNO浓度 通过指甲盖来达到杀菌活性，将其建立起来。然后，该公式将用于 评估zMPNO治疗T. rubrum和C. RoMar™离体感染指甲模型中的白色念珠菌 （MedPharm）。 在该I期研究结束时，将建立优化的制剂，其中定义了 适用于进一步制剂开发、扩大规模、安全性研究和体外试验的zMPNO浓度 II期体内疗效研究。

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.