Engineering Nanogels for Drug Delivery to Pathogenic Fungi Aspergillus fumigatus by Tuning Polymer Amphiphilicity

Abstract

Invasive aspergillosis is a serious threat to immunodeficient and critically ill patients caused mainly by the fungus Aspergillus fumigatus. Here, poly(glycidol)-based nanogels (NGs) are proposed as delivery vehicles for antifungal agents for sustained drug release. NGs are formed by simple self-assembly of random copolymers, followed by oxidative cross-linking of thiol functionalities. We investigate the impact of copolymer amphiphilicity on NG interaction with mature fungal hyphae in order to select the optimal drug delivery system for model antifungal drug amphotericin B. The results show that drug-loaded NGs decrease minimal inhibitory concentration (MIC) for around four times and slow down the fungal biofilm synthesis at concentrations lower than MIC. Our results suggest that amphiphilicity of nanoparticle's polymer matrix is an important factor in understanding the action of nanocarriers toward fungal cells and should be considered in the development of nanoparticle-based antifungal therapy.

Nanogels as Antifungal‐Drug Delivery System Against Aspergillus Fumigatus

“…For STEM analysis, samples were prepared as described earlier. [ 10 ] Fluorescence spectra, fluorescence intensity, and UV–vis absorbance were estimated by a Spark 20M microplate reader (TECAN, Switzerland). CLSM was carried out on Leica TCS SP8 STED (Leica Microsystems, Germany).…”

“…Synthesis of thiol‐modified poly(glycidol) (pG‐SH) was carried out according to previously described methods. [ 10,11 ] The poly(ethoxyethyl glycidyl ether) with 60 repeat units was synthesized from the monomer ethoxyethyl glycidyl ether. Polymer was deprotected under acidic conditions in tetrahydrofuran (THF), purified by dialysis and lyophilized to yield pG.…”

“…Biofilm biomass was quantified using a modified version of a protocol developed by Mowat et al and O'Toole et al [ 26,27 ] following the procedure described earlier. [ 10 ]…”

“…Vero kidney cells and hepatocytes were incubated at conditions as described earlier. [ 10 ] Cells were seeded in 96 well plates (50 000 cells well −1 ) and after 24 h, the medium was changed with the medium containing ITZ‐loaded NGs, empty NGs (3 mg mL −1 ) or 5% DMSO. Incubation proceeded for 48 h. Metabolically active cells were determined by the CellTiter‐Glo Luminescent Cell Viability Assay (Promega, Germany) according to manufacturer's instructions.…”

“…We have thus very recently explored the use of NGs by tuning the amphiphilicity of the polymeric precursors for pG NG formation through self‐assembly and thereby optimizing uptake into A. fumigatus . [ 10 ] Here, we reported on an alternative, straightforward, robust, and scalable method of preparation of pG‐based NGs by inverse nanoprecipitation without the use of surfactants and without the need for energy input such as sonification. To maximize the chances for drug delivery and internalization, NGs were designed to be both, redox‐sensitive and hydrolytically degradable.…”