Dendritic hybrid materials comprising polyhedral oligomeric silsesquioxane (POSS) and hyperbranched polyglycerol for effective antifungal drug delivery and therapy in systemic candidiasis.

Abstract

Systemic Candida infections are routinely treated with amphotericin B (AMB), a highly effective antimycotic drug. However, due to severe toxicities linked to the parenteral administration of conventional micellar formulations (Fungizone®), its clinical utility is limited. Hyperbranched polyglycerols (HPGs) are multi-branched three-dimensional hydrophilic macromolecules that can be used to lessen the toxicity of AMB while also increasing its aqueous solubility. In the current research, to improve the safety and therapeutic efficacy of AMB, we developed new polyhedral oligomeric silsesquioxane - hyperbranched polyglycerol dendrimers with cholesterol termini (POSS-HPG@Chol) using azide-alkyne click reaction. Compared with Fungizone®, the as-synthesized POSS-HPG@Chol/AMB had lower minimum inhibitory and fungicidal concentrations against almost all studied Candida spp., as well as much less hemolysis and cytotoxicity. POSS-HPG@Chol/AMB revealed total protection of Balb/C mice from severe Candida infections in an experimental model of systemic candidiasis and can effectively reduce or eliminate AMB liver and kidney tissue injuries. Thanks to their safety, biocompatibility, and unique therapeutic properties, the developed POSS-polyglycerol dendrimers could be viable nanostructures for the delivery of poorly soluble drugs like AMB.