Nitric Oxide Releasing Nanoparticles as a Strategy to Improve Current Onychomycosis Treatments

July 2018 | Volume 17 | Issue 7 | Original Article | 717 | Copyright © 2018

Caroline B. Costa-Orlandi PhD,a,b,* Breanne Mordorski BA,c,* Ludmila M. Baltazar PhD,b Maria José S. Mendes-Giannini PhD,a Joel M. Friedman MD PhD,d Joshua D. Nosanchuk MD,b Adam J. Friedman MDc,d,e

aDepartment of Clinical Analysis, Universidade Estadual Paulista, Faculdade de Ciências Farmacêuticas, Araraquara, São Paulo, Brazil bDepartment of Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, Bronx, NY cDepartment of Medicine, Division of Dermatology, Albert Einstein College of Medicine, Bronx, NY dDepartment of Physiology & Biophysics, Albert Einstein College of Medicine, Bronx, NY eDepartment of Dermatology, George Washington School of Medicine and Health Sciences, Washington, DC *These authors contributed equally to this work

Abstract

Topical antimicrobials are the ideal mode of onychomycosis treatment for efficient drug delivery and avoidance of sytemic effects associated with oral medications. However, high treatment costs, tissue penetration limitations, and low cure rates have continued to pose major challenges. To capitalize on the progress made by topical efinaconazole solution, efinaconazole was combined with inexpensive, previously-characterized nitric oxide releasing nanoparticles (NO-np), which have been shown to offer sustained nitric oxide release over time and enhanced barrier penetration, while exerting broad spectrum antimicrobial and immunomodulating properties. NO-np were combined with efinaconazole in varying concentrations and applied against reference strains of Trichophyton rubrum using a checkerboard method. Results demonstrated synergism of NO-np+efinaconazole against T. rubrum, which is noteworthy given the barriers present in the topical treatment of onychomycosis, and the multiple potential benefits offered by NO-np. Overall, this study illustrates the untapped potential of nanotechnology in the treatment of disorders of the skin, hair, and nails where drug delivery remains a challenge. J Drugs Dermatol. 2018;17(7):717-720.

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INTRODUCTION

Onychomycosis afflicts millions world-wide, causing nail disfigurement, pain, and increased risk of soft tissue infections. Although a variety of systemic and topical antifungals are available, treatment failure remains high due to lengthy treatment regimens, lack of intrinsic immune function of the nail plate, and poor drug delivery as a result of suboptimal vascularization at the site of infection (systemic antifungals) and difficulty penetrating and retaining activity across the nail plate (topical antifungals).1,2 Furthermore, systemic antifungals are associated with hepatotoxicity, gastrointestinal upset, and drug-drug interactions. Unfortunately, risk of adverse reaction is highest among patients with greater frequency of infection where polypharmacy is also common, including those who are elderly, diabetic, and/or immunocompromised.1,3 Given these challenges, a potent topical antifungal that penetrates the nail plate, retains activity, and clears infection over a shortened treatment course is highly desired.Recently FDA-approved in 2014, efinaconazole is a broad-spectrum triazole designed for improved nail penetration and subungual pharmacokinetics. It has the highest clinical cure rates compared to other topicals, and its mycologic (53-55%) and complete cure rates (15-18%) rival those of oral itraconazole.1-4 However, a four-milliliter bottle of efinaconazole at a major chain drugstore costs $691, and multiple bottles per nail are required to complete a 48-week treatment course. To capitalize on the progress made by topical efinaconazole while potentially increasing cure rates, shortening treatment time, and lowering treatment costs, efinaconazole was investigated in combination with previously-characterized, inexpensive hydrogel-based nanoparticles (NO-np) that release nitric oxide (NO), a broad-spectrum antimicrobial and immune modulator.5 NO-np release physiologic concentrations of NO in a sustained manner over time, thereby overcoming limitations that would otherwise be posed by NO’s short half-life and high reactivity. Sized on the nanoscale (1-100 nm), NO-np also offer enhanced tissue penetration and permeation, and their enormous surface area increases NO interaction with fungi.5 To evaluate the utility of NO-np in combination with efinaconazole, NO-np were assessed with either efinaconazole or terbinafine against Trichophyton rubrum, the commonest etiologic agent of onychomycosis.NO-np (6 x 10-4 to 10 mg/L) were synthesized via previously described methods and combined with either efinaconazole 10%

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