Nanoparticles as carriers of miltefosine for treatment of cryptococcal meningitis.

• Grant number: 18/12149-2
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2018
• End date: January 31, 2022
• Field of knowledge: Biological Sciences - Microbiology
• Principal Investigator: Kelly Ishida
• Grantee: Cristina de Castro Spadari
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Cryptococcosis is an opportunistic disease and causative of meningitis, occurring ~ 223,100 cases/ year. The therapeutic arsenal for fungal diseases is limited by problems of selectivity, toxicity, pharmacokinetics and resistance profiles of fungi to the available antifungal agents, being even more difficult in cryptococcal meningitis due to the difficulty of crossing the blood-brain barrier (BBB). Previous studies indicate that miltefosine (hexadecylphosphocholine) may be an alternative as an antifungal agent; has broad spectrum of action and fungicide profile; however it presents high toxicity. The use of nanoparticles for improved efficacy, pharmacokinetics/ bioavailability, and decreased drug toxicity has been increasingly employed in the development of novel options for the treatment of diseases. In this context, we propose in this project the use of alginate nanoparticles containing miltefosine (recently standardized by our research group and with promising results for its use) as a new alternative in the treatment of meningitis caused by Cryptococcus yeasts. The biodistribution of these particles in vivo, as well as polysorbate 80 coated nanoparticles, will be evaluated to improve their targeting to the brain. In addition, due to the important role of BBB in the treatment of diseases in the CNS and the interaction of Cryptococcus yeasts in the BBB causing meningitis, the standardization and implementation of a BBB model will be carried out. The activity of nanoparticles containing miltefosine will be evaluated in vitro by model of BBB and in vivo in a model of systemic cryptococcosis in mice.

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SPADARI, CRISTINA DE CASTRO; WIRTH, FERNANDA; LOPES, LUCIANA BIAGINI; ISHIDA, KELLY. New Approaches for Cryptococcosis Treatment. MICROORGANISMS, v. 8, n. 4, APR 2020. (17/19374-9, 18/12149-2, 18/13877-1)

DE JESUS, DANIEL FELIPE FREITAS; DE FREITAS, ALINE LUIZA DUARTE; DE OLIVEIRA, ISADORA MARIA; DE ALMEIDA, LARISSA COSTA; BASTOS, RAFAEL WESLEY; SPADARI, CRISTINA DE CASTRO; MELO, ANALY SALES DE AZEVEDO; SANTOS, DANIEL DE ASSIS; COSTA-LOTUFO, LETICIA VERAS; REIS, FLAVIA C. G.; et al. Organoselenium Has a Potent Fungicidal Effect on Cryptococcus neoformans and Inhibits the Virulence Factors. Antimicrobial Agents and Chemotherapy, v. 67, n. 3, p. 16-pg., 2023-02-23. (16/04289-3, 17/15226-5, 21/01279-5, 18/12149-2, 20/00295-4, 15/17177-6)

SPADARI, CRISTINA DE CASTRO; MENDES DA SILVA DE BASTIANI, FERNANDA WALT; LOPES, LUCIANA BIAGINI; ISHIDA, KELLY. Alginate nanoparticles as non-toxic delivery system for miltefosine in the treatment of candidiasis and cryptococcosis. INTERNATIONAL JOURNAL OF NANOMEDICINE, v. 14, p. 5187-5199, 2019. (13/16617-7, 18/12149-2, 15/07993-0)

YUKUYAMA, MEGUMI NISHITANI; ISHIDA, KELLY; BARROS DE ARAUJO, GABRIEL LIMA; SPADARI, CRISTINA DE CASTRO; DE SOUZA, ALINE; LOBENBERG, RAIMAR; BAZAN HENOSTROZA, MIRLA ANALI; FOLCHINI, BEATRIZ RABELO; PERONI, CAMILLA MIDORI; CAMASMIE PETERS, MARIA CHRISTINA; et al. y Rational design of oral flubendazole-loaded nanoemulsion for brain delivery in cryptococcosis. COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS, v. 630, DEC 5 2021. (18/12149-2, 17/19374-9, 18/22713-2)