Miltefosine in alginate nanoparticles in the treatment of sporotrichosis

• Grant number: 23/12443-6
• Support Opportunities: Scholarships in Brazil - Master
• Start date: February 01, 2024
• End date: January 31, 2026
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Kelly Ishida
• Grantee: Andriéli Bacega
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Sporotrichosis is a disease caused by fungi of the genus Sporothrix, endemic in Latin America, able to affect the skin and subcutaneous tissue of humans and animals. The most pathogenic species include Sporothrix schenckii, Sporothrix globosa, Sporothrix luriei, and Sporothrix brasiliensis, the latter being associated with zoonosis in cats and humans. The fungus can easily adapt to body temperature, making warm-blooded organisms, such as humans and susceptible cats, hosts for infection. Sporotrichosis is endemic in several countries in Latin America, Europe, Asia, and Africa. The transmission occurs mainly through direct contact with contaminated material, and cats are the primary agents of transmission to humans. The treatment of sporotrichosis depends on the patient's clinical and immunological status, the type of lesion, and the Sporothrix species involved. The most common medications include potassium iodide, itraconazole, terbinafine, and amphotericin B. Miltefosine is a promising new alternative that has demonstrated efficacy against Sporothrix spp. in vitro and in vivo studies, reducing miltefosine toxicity using controlled release systems such as alginate nanocarriers. Innovations in sporotrichosis treatment are important to improve treatment efficacy and reduce side effects, especially in more severe cases of the disease. This project aims to evaluate the antifungal efficacy of miltefosine in alginate nanoparticle carriers on experimental sporotrichosis, determine the minimum inhibitory concentration (MIC) of free miltefosine and miltefosine incorporated into nanoparticles, and assess its efficacy in larval and murine models of sporotrichosis. The strains used in the experiments will be from Sporothrix brasiliensis. Miltefosine (MFS), amphotericin B deoxycholate (AMB), and itraconazole (ITC) will be used as standard antifungals. The production of miltefosine nanoparticles in alginate functionalized with polysorbate 80 (P80-AN) will follow the external emulsification/gelation method and will be subjected to quality control parameters. The MICs of free miltefosine and miltefosine incorporated into alginate nanoparticles (P80-MFS-AN) will be determined using the broth microdilution method. For the evaluation of anti-Sporothrix activity in Galleria mellonella, larvae will be infected with S. brasiliensis strains and treated with miltefosine or P80-MFS-AN. Treatment efficacy will be assessed by survival, health index, fungal burden, and histopathological analysis. The evaluation of antifungal efficacy in a murine model will be performed with mice infected with S. brasiliensis and treated with different miltefosine and P80-MFS-AN regimens. The progression of the infection will be monitored, and fungal burden and organ histopathology will be evaluated. Analyses will be performed using statistical software, and values of p < 0.05 will be considered significant. Some parameters may be adjusted during the project's development.