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

Abstract

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 .

Repositionable Compounds with Antifungal Activity against Multidrug Resistant Candida auris Identified in the Medicines for Malaria Venture’s Pathogen Box

“…Miltefosine has also been used successfully in a limited number of cases of the extremely rare highly lethal brain infection by the amoeba Naegleria fowleri and, in the United States, has orphan drug status for the treatment of other amebic infections [62]. Our group and others have previously described the antifungal activity of miltefosine [63][64][65][66][67][68]. Iodoquinol (also referred to as diiodohydroxyquinoline) is an halogenated quinoline derivative (see Supplementary Figure S1) that is used as an intestinal antiparasitic drug, mainly in the treatment of Entamoeba histolytica infections [69], apparently acting by chelation of ferrous ions essential for metabolism.…”

Galleria mellonella for the Evaluation of Antifungal Efficacy against Medically Important Fungi, a Narrative Review

“…, Cryptococcus spp. [32,33,[45][46][47][48][49][50][51], Aspergillus spp. [13,29,35,[52][53][54][55][56][57][58][59][60][61], Mucorales [62][63][64], Madurella mycetomatis [65][66][67], and other fungal agents [68][69][70].…”

“…The genus Candida has been extensively studied in the G. mellonella model especially for the evaluation of virulence and antifungal efficacy [10,71,72]. G. mellonella was used to test the efficacy of different antifungal compounds against Candida yeasts including conventional antifungal drugs [13][14][15][16][17][18][19][20][21][22][23], new drugs [25][26][27][30][31][32]34] or non-antifungal compounds in a repurposing perspective [24,28,29,33]. Antifungal combinations against Candida spp.…”

“…Several studies which have focused on the development of new drugs have benefited from the use of G. mellonella as a model for evaluating in vivo efficacy. Several drugs, such as atorvastatin, a cholesterol-lowering agent [24], miltefosine, an anti-leishmanial drug [33], miramistin, an antiseptic [29], and pilocarpine, a muscarinic agonist [28] were evaluated in a repurposing perspective. In other instances, new synthetic compounds or natural products were tested in vivo in the model [25][26][27][30][31][32]34].…”

New Approaches for Cryptococcosis Treatment

“…Studies showed that MFS has a broad-spectrum in vitro antifungal activity, including against C. gattii and C. neoformans isolates in the both planktonic (0.25-4 µg/mL) and biofilm (8 -≥16 µg/mL) lifestyles [79][80][81]. Moreover, MFS was effective to control the fungal infection in the larval model of Galleria mellonella by C. gattii at 10, 20, and 40 mg/kg [82]. MFS at 3.6 and 7.2 mg/kg/day has shown effectiveness in the murine model of disseminated cryptococcosis [80] although this result has been conflicting with other work [83].…”