Enhanced intracellular delivery and antifungal potency of amphotericin B via PEG15HS-lipid nanoparticles.

Authors

Kévin Brunet, Adrien Baillod, Jonathan Clarhaut, Henri Grau, Sandrine Marchand, Frédéric Tewes

Published in

International journal of pharmaceutics: X. Volume 12. Pages 100605. Epub Jul 11, 2026.

Abstract

Cryptococcus neoformans is responsible for life-threatening infections with persistently high mortality despite current amphotericin B (AmB)-based treatments. Although liposomal AmB (AmBisome®) remains the standard of care, its complex composition and high production cost limit accessibility and the development of generic versions. Improving AmB efficacy therefore represents a priority. We previously demonstrated that PEG-15 hydroxystearate (PEG15HS) enhances the antifungal activity of AmB by modulating its aggregation state toward more active, less toxic species. Building on these findings, we aimed to develop a simple and scalable lipid-nanoparticle (LNP) formulation combining AmB and PEG15HS to potentiate AmB activity against C. neoformans.
AmB-loaded LNPs were produced by the phase-inversion temperature method using a Labrafac™ WL1349/tributyrin (1:1, w/w) oil phase selected for optimal AmB solubility and colloidal stability. Two particle sizes (∼40 nm and ∼ 100 nm) were obtained by varying the surfactant-to-oil ratio. Formulations were characterized physicochemically and evaluated in vitro against clinical C. neoformans isolates by MIC determination and time-kill curve analysis. Cellular localization was investigated by confocal and transmission electron microscopy.
Both AmB-LNP formulations markedly enhanced antifungal efficacy, reducing MICs up to 32-fold compared with liposomal AmB and demonstrating faster and more extensive fungicidal activity. Microscopy revealed that AmB-LNPs were internalized by C. neoformans, whereas blank LNPs remained extracellular, indicating that AmB may facilitate nanoparticle passage through the fungal cell wall and plasma membrane.
PEG15HS-stabilized lipid nanoparticles substantially improve the antifungal performance of AmB, likely through controlled aggregation and enhanced interaction with fungal cells. This simplified, non-liposomal system offers a promising and more accessible alternative to AmBisome® for treating C. neoformans infections.

PMID:
42502436
Bibliographic data and abstract were imported from PubMed on 26 Jul 2026.

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