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Alginate nanoparticles as non-toxic delivery system for miltefosine in the treatment of candidiasis and cryptococcosis

Authors Spadari CC, de Bastiani FWMS, Lopes LB, Ishida K

Received 14 February 2019

Accepted for publication 14 May 2019

Published 12 July 2019 Volume 2019:14 Pages 5187—5199

DOI https://doi.org/10.2147/IJN.S205350

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Anderson Oliveira Lobo


Cristina de Castro Spadari,*,1 Fernanda Walt Mendes da Silva de Bastiani,*,1 Luciana Biagini Lopes,2 Kelly Ishida1

1Laboratory of Antifungal Chemotherapy, Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; 2Laboratory of Nanomedicine and Drug Delivery Systems, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

*These authors contributed equally to this work

Introduction and objective: Previous studies indicate that miltefosine (MFS) may be an alternative as an antifungal agent; however, it presents several adverse effects. Thus, the aim of this study was to produce miltefosine-loaded alginate nanoparticles (MFS.Alg) for toxicity reduction to be used as an alternative for the treatment of cryptococcosis and candidiasis.
Methods: Alginate nanoparticles were produced using the external emulsification/gelation method, and their physicochemical and morphological characteristics were analyzed. MFS encapsulation efficiency, release assay and toxicity on red blood cells and on Galleria mellonella larvae were assessed. The antifungal activity was evaluated using in vitro and in vivo larval models of G. mellonella infected with Candida albicans (SC5314 and IAL-40), Cryptococcus neoformans H99 and Cryptococcus gattii ATCC 56990. The treatment efficacy was evaluated by survival curve, colony forming unit (CFU) counting and histopathological analysis.
Results: MFS.Alg nanoparticles presented a mean size of 279.1±56.7 nm, a polydispersity index of 0.42±0.15 and a zeta potential of −39.7±5.2 mV. The encapsulation efficiency of MFS was 81.70±6.64%, and its release from the nanoparticles occurred in a sustained manner. MFS in alginate nanoparticles presented no hemolytic effect and no toxicity in G. mellonella larvae. Treatment with MFS.Alg extended the survival time of larvae infected with C. albicans and C. gattii. In addition, the fungal burden reduction was confirmed by CFU and histopathological data for all groups treated with 200 mg/Kg of MFS.Alg.
Conclusion: These results support the use of alginate-based drug delivery systems as carriers for MFS for drug toxicity reduction and control of the fungal infection in the in vivo model of G. mellonella.

Keywords: nanocarriers, antifungal, drug delivery, Galleria mellonella, invasive fungal infection


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