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Dermal dermatophytoses, also known as ring worm infection, is a fungal infection of the skin that is characterized by a red, itchy, scaly and circular rash that could be found in multiple locations of the skin. Systemic therapies are usually preferred to treat this infection due to an inadequate penetration of the drugs administered topically, however, systemic treatments to antifungals are associated with limited penetration of the drug into the target tissue, as well as side effects and resistance.
To address these problems, Researchers at the Albert Einstein College of Medicine, in collaboration with the George Washington School of Medicine and Health Sciences, have recently discovered that topical nitric oxide releasing nanoparticles (NO-np) could be effective in treating dermal dermatophytosis.
Millions of people are affected by dematophytoses, and treatment failure may occur depending upon the depth and location of fungal invasion. Patients who are immuno-suppressed as a result of the use of certain drugs such as corticosteroids, or diseases such as HIV, are particularly vulnerable to this infection. An effective topical treatment which could penetrate deeper layers of skin, while also retaining its potency and evading microbial resistance, would work well in effectively treating this fungal infection.
Nanoparticles which measure 1- 100 nm can penetrate into deeper layers of the skin, while also having an increased likelihood of interacting with fungal cells due to their large surface area. Nitric oxide (NO), a gaseous immunomodulator that is ubiquitously present in the body, seems to be an attractive agent to treat dermatophytosis based on its previously found effectiveness against superficial infections and bacterial abscesses when delivered as nanoparticles.
Because NO is highly reactive and very short lived under physiological conditions, NO-np that could release NO for a sustained period could be very beneficial.
Adam Friedman’s team from the Albert Einstein College of Medicine conducted a series of in vitro studies to determine the minimum inhibitory concentration (MICs) and minimum fungicidal concentration (MFCs) of the NO-np for two reference strains of Trichophyton rubrum (ATCC MYA-4438 and ATCC 28189), along with one clinical isolated strain.
The MICs of the reference strains and the clinical isolate were found to be 10 mg/mL and 5 mg/mL, respectively, while the empty nanoparticles did not demonstrate any fungicidal activity, even at a concentration of 20 mg/mL.
Transmission electron microscopy (TEM) images revealed that the Trichophyton rubrum treated with 10 mg/mL NO-np showed an accumulation of materials suggestive of intracellular vesicles and black granules within vacuole observed in the fungal cells.
To test if the NO-np will be effective in vivo, BALB/c mice were stimulated with ATCC MYA-4438 on the dorsal surface to induce dermal dermatophytoses. After 7 days post-infection, mice were divided into groups that received treatment with 100 µL of either saline, coconut oil, 10 mg/mL empty nanoparticles, 10 mg/mL NO-np, or 1 % terbinafine, respectively.
Tissue samples were collected after 3 and 7 days, homogenized, filtered and cultured on potato dextrose agar to examine the colony forming units (CFUs). As evidenced by the CFUs from the animal study, the NO-np group decreased the fungal burden after only 3 days.
In fact, there were lesser CFUs found in the NO-np treated group as compared to the positive control, 1% terbinafine. After 7 days, there was no fungal burden in the NO-np treated group, while all other groups showed the presence of fungal CFUs, thereby suggesting that the NO-np could completely clear the fungal infection.
Flow cytometry analysis of the supernatant from the homogenized tissues collected 3 days after the treatment revealed that the NO-np group showed decreased levels of cytokines interleukin (IL)-2, IL-6, IL-10 and tumor necrosis factor (TNF) alpha, indicating the early attenuation of the host immune response and decreased tissue morbidity. Taken together, the results of this study suggest that NO-np shows promise as a potential topical treatment for dermal dermatophytoses, and because the nanoparticles act locally, there will be minimal side effects.
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References:
- “Topical nitric oxide releasing nanoparticles are effective in a murine model of dermal Trichophyton rubrum dermatophytosis” B. Mordorski, C. Costa-Orlando, et al. Nanomedicine: Nanotechnology, Biology and Medicine. (2017). DOI: 10.1016/j.nano.2017.06.018.
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