Low intensity ultrasound-mediated drug-loaded nanoparticles intravaginal drug delivery: an effective synergistic therapy scheme for treatment of vulvovaginal candidiasis

Abstract

Purpose Vulvovaginal candidiasis (VVC) is a mucosal infection of the female lower genital tract for which treatment using conventional antifungal drugs shows limited effectiveness. Herein, amphotericin B-loaded poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) nanoparticles (AmB-NPs) were fabricated and combined with low intensity ultrasound (US) to mediate AmB-NPs intravaginal drug delivery to achieve productive synergistic antifungal activity in a rabbit model of VVC. Methods Polymeric AmB-NPs were fabricated by a double emulsion method and the physical characteristics and biosafety of nanoparticles were analyzed. The distribution and tissue permeability of nanoparticles after intravaginal ultrasound irradiation (1.0 MHz, 1.0 W/cm2, 5 min, 50% duty ratio) were observed in the vagina. The synergistic therapeutic activity of US-mediated AmB-NPs treatment was evaluated using an experimental rabbit model of VVC. Vaginal C. albicans colony counts, the pathological structure of the vagina epithelium, and Th1/Th2/Th17-type cytokine and oxidative stress levels were analyzed to investigate the therapeutic effect in vivo. Results The prepared AmB-NPs showed an obvious shell and core structure with uniform size and good dispersion and displayed high biosafety and US-sensitive slow drug release. Ultrasound significantly enhanced nanoparticle transport through the mucus and promoted permeability in the vaginal tissue. US-mediated AmB-NPs treatment effectively increased drug sensitivity, even in the presence of the vaginal mucus barrier in vitro. On the seventh day after treatment in vivo, the combination treatment of AmB-NPs and US significantly reduced the fungal load in the vagina, achieving over 95% clearance rates, and also improved the pathological epithelium structural damage and glycogen secretion function. The expression of Th1 (IFN-γ, IL-2) and Th17 (IL-17) cytokines were significantly increased and Th2 (IL-6, IL-10) cytokines significantly decreased in the US + AmB-NP group. Furthermore, US-mediated AmB-NPs treatment effectively increased C. albicans intracellular reactive oxygen species (ROS) levels and promoted vaginal oxidation and antioxidants to normal levels. Conclusion US-mediated drug-loaded nanoparticles with intravaginal drug delivery exhibited a productive synergistic antifungal effect, which may provide a new non-invasive, safe, and effective therapy for acute or recurrent fungal vaginitis. Graphical Abstract

Mucus-Permeable Sonodynamic Therapy Mediated Amphotericin B-Loaded PEGylated PLGA Nanoparticles Enable Eradication of Candida albicans Biofilm

“…Further analysis at the phylum level revealed that US treatment markedly increased the relative abundance of Firmicutes , reshaping the healthy vaginal microbiome ( Figure 12H ). On the basis of effective antifungal results obtained in the previous study of US-mediated AmB-NPs therapy for VVC infection, 20 these part results further confirmed that US-mediated AmB-NPs treatment exhibits excellent therapeutic efficacy against C. albicans vaginal biofilms in vivo, promotes the recovery of damaged mucosal epithelial ultrastructure, and contributes to the reshaping of a healthier vaginal microbiome.

Figure 12 Antifungal effects of US-mediated AmB-NPs on vaginal C. albicans biofilms in vivo.

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“… 19 In previous studies, we have demonstrated that ultrasound-mediated AmB-loaded nanoparticles can improve the efficiency of intravaginal drug delivery and play a highly effective antifungal role in in vitro plankton Candida and in vivo VVC infection. 20 However, how ultrasound-mediated nanoparticles penetrate the double barrier of mucus and biofilm, as well as the clearance effect of sonodynamic effects on the Candida biofilm associated with the epithelium under the mucus barrier and the local antifungal immunomodulation effect on cells remain unclear.…”

The Formulation and Evaluation of Melaleuca alternifolia Cheel and Cymbopogon flexuosus Linn Essential Oils Emulgel for the Treatment of Vulvovaginal Candidiasis

“…Some of these approaches have leveraged on the growing applications of nanotechnologies to enhance drug delivery. One such effort was the development of low-intensity ultrasound-mediated drug-loaded nanoparticles to facilitate the intravaginal delivery of amphotericin B against VVC [17]. Although this approach led to some improvement in the antifungal activity of the drug candidate (amphotericin B), the formulation technique (and required materials) can be characterized as quite sophisticated and may not be feasible for bulking-up and commercial development, especially in developing and underdeveloped regions of the world.…”