Amphotericin B-Loaded Plant-Inspired Polyphenol Nanoparticles Enhance Its Antifungal Activity and Biocompatibility.

Amphotericin B (AmB) is one of the first-line treatments for systemic fungal infections, yet it suffers from dose-limiting systemic toxicity and high cost of less toxic lipid-based formulations. Here, we report on a facile approach to synthesize an AmB-loaded nanomedicine by leveraging plant-inspired oxidative self-polymerization of the ubiquitous polyphenol quercetin (QCT). Polymerized QCT nanoparticles (pQCT NPs) were formed, loaded with AmB, and functionalized with poly(ethylene glycol) (PEG) to impart steric stability in a simple procedure that relied on mixing followed by dialysis. The AmB-loaded NPs (AmB@pQCT-PEG NPs) were characterized by a drug loading efficiency of more than 90%, a particle size of around 160 nm, a polydispersity index of 0.07, and a partially negative surface charge. AmB release from the NPs was sustained over several days and followed the Korsmeyer-Peppas model with a release exponent (n) value >0.85, denoting drug release by polymer relaxation and swelling. A hemolysis assay revealed the NPs to be highly biocompatible, with negligible hemolytic activity and 30-60% hemolysis after 1 and 24 h of incubation with erythrocytes, respectively, across a wide concentration range (6.25-100.00 μg/mL). Conversely, equivalent concentrations of free AmB caused 90-100% hemolysis within the same timeframe. Importantly, AmB@pQCT-PEG NPs outperformed free AmB in microbial susceptibility assays on Candida albicans, achieving a minimum inhibitory concentration of 62.5 ng/mL after 48 h of incubation, which was 2-fold lower than the free drug. Our results demonstrate that pQCT NPs may serve as a viable AmB delivery platform for the treatment of fungal infections and potentially other AmB-susceptible pathogens.