Abstract
Fungal infections are an important cause of morbidity and mortality in immunocompromised patients. Amphotericin B (AMB), with broad-spectrum antifungal activity, has long been recognized as a powerful fungicidal drug, but its clinical toxicities mainly nephrotoxicity and poor solubility limit its wide application in clinical practice. The fungal metabolism along with the host immune response usually generates acidity at sites of infection, resulting in loss of AMB activity in a pH-dependent manner. Herein, we developed pH-responsive AMB-loaded and surface charge-switching poly(d,l-lactic-co-glycolic acid)-b-poly(l-histidine)-b-poly(ethylene glycol) (PLGA-PLH-PEG) nanoparticles for resolving the localized acidity problem and enhance the antifungal efficacy of AMB. Moreover, we modified AMB-encapsulated PLGA-PLH-PEG nanoparticles with anti-Candida albicans antibody (CDA) (CDA-AMB-NPs) to increase the targetability. Then, CDA-AMB-NPs were characterized in terms of physical characteristics, in vitro drug release, stability, drug encapsulation efficiency, and toxicity. Finally, the targetability and antifungal activity of CDA-AMB-NPs were investigated in vitro/in vivo. The result demonstrated that CDA-AMB-NPs significantly improve the targetability and bioavailability of AMB and thus improve its antifungal activity and reduce its toxicity. These NPs may become a good drug carrier for antifungal treatment.
Highlights
Amphotericin B (AMB), which has been considered to associate with ergosterol in fungal cell membranes to mediate ion-permeable pores, is still one of the most effective agents for the treatment against systemic fungal infections [1,2,3]
Advances in gaining drug potency or in vivo properties of nanoparticles (NPs) for drug delivery applications by increasing targetability and environmental sensing leading to NP property switching and sustained drug release have been improving the bioavailability of AMB with few side effects for the treatment against systemic fungal infections
To evaluate the zeta potential (ZP; mV) property which was key to tailoring NP-fungal interactions, Candida albicans antibody (CDA)-AMBNPs were resuspended in Phosphate-buffered solution (PBS) with appropriate pH (6.8, 7.0, and 7.35)
Summary
Amphotericin B (AMB), which has been considered to associate with ergosterol in fungal cell membranes to mediate ion-permeable pores, is still one of the most effective agents for the treatment against systemic fungal infections [1,2,3]. New lipid formulations of AMB have been developed to reduce the nephrotoxicity and improve the therapeutic index [4, 5], In recent years, advances in gaining drug potency or in vivo properties of nanoparticles (NPs) for drug delivery applications by increasing targetability and environmental sensing leading to NP property switching and sustained drug release have been improving the bioavailability of AMB with few side effects for the treatment against systemic fungal infections. Fungi can adjust to local conditions such as ambient pH, temperature, and nutrient supply through shared metabolic systems including the Pal/PacC pathway in Aspergillus sp. and the RIM101 pathway in Candida sp. to infect tissue [8,9,10].
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