Nanocarriers Provide Sustained Antifungal Activity for Amphotericin B and Miltefosine in the Topical Treatment of Murine Vaginal Candidiasis

Abstract

Topical drug administration is frequently used for the treatment of vaginal candidiasis; however, most formulations using this route do not provide prolonged drug release. Our aim was to evaluate the antifungal efficacy of amphotericin B (AMB) and miltefosine (MFS) incorporated in nanocarriers for sustained drug release, in a murine model of vaginal candidiasis. AMB and MFS were incorporated in different topical formulations, namely: conventional vaginal cream (daily dose for 6 days; MFS-CR and AMB-CR groups), microemulsion that transforms into a liquid crystalline gel in situ (single dose, or in three doses, every 48 h; AMB-ME and MFS-ME groups) and alginate nanoparticles (single dose; MFS-AN group). Formulations were administered intravaginally in BALB/c female mice 24 h post-infection by Candida albicans yeasts. On the 7th day postinfection the animals were euthanized for mycological and histological analyses. Formulation persistence in the vaginal canal was assessed for 7 days by in vivo imaging, using nanocarriers labeled with Alexa-Fluor 647. AMB-ME(3×), MFS-ME(3×), and MFS-AN(1×) formulations were able to control fungal infection at comparable levels to those vaginal cream formulations. Notably, a single dose of MFS-AN was sufficient to reduce the fungal burden as effectively as MFS-ME(3×) and MFS-CR(6×). In vivo imaging showed that nanocarriers allowed prolonged antifungal activity by intravaginal administration reducing drug administration frequency. Therefore, AMB and MFS incorporated into a microemulsion and MFS encapsulated in alginate nanoparticles could be effective therapeutic alternatives for vaginal candidiasis, likely due to the sustained antifungal activity provided by these nanocarriers.

Antifungal Activity and Mode of Action of Miltefosine Against Clinical Isolates of Candida krusei

“…According to the data on clinical safety and pharmacokinetics of miltefosine (Castro et al, 2017;Mbui et al, 2019), the MIC value of miltefosine in this study is much lower than the plasma concentration observed during the treatment of leishmaniasis patients. In addition, miltefosine was shown to have significant antifungal activity against C. albicans in vitro and in vivo (Vila et al, 2015;de Bastiani et al, 2019;Spadari et al, 2019). This indicates that miltefosine should be a good candidate for in vivo studies in the future.…”

“…It has been reported that miltefosine has the in vivo efficacy in a murine model of oral candidiasis caused by C. albicans (Vila et al, 2015). In previous studies, miltefosine displayed good therapeutic effects against vaginal candidiasis in mice and against candidiasis and cryptococcosis in the larval models of Galleria mellonella (de Bastiani et al, 2019;Spadari et al, 2019). Many studies have established the activity of miltefosine against Candida species planktonic cells and biofilms (Vila et al, 2013(Vila et al, , 2016, but the antifungal effect of miltefosine against C. krusei has not been reported.…”

Repurposing of Miltefosine as an Adjuvant for Influenza Vaccine

“…A recent study showed that liposomal formulation of miltefosine was successful as a topical treatment of leishmania [ 58 ]. The potential required dosage of adjuvant could be achieved by currently available miltefosine cream [ 14 , 58 , 59 , 60 ]. Therefore, the evaluations and observations of miltefosine adjuvant on mice are likely to be transferrable to human topical adjuvant applications.…”

Delivery strategies of amphotericin B for invasive fungal infections

“…So, surface charge and size of NPs are critical for their transport mechanism, which directly influence the drug bioavailability after oral administration 163 , 164 . For localized therapy and improved antifungal activity, various nanocarriers have been proposed for ocular, vaginal and dermal delivery 107 , 165 , 166 . These delivery systems allowed noninvasive administration of AmB with active targeting and immunomodulation to obtain excellent efficacy in IFIs.…”