Aiming for a bull's-eye: Targeting antifungals to fungi with dectin-decorated liposomes

Abstract

Globally, there are several million individuals with life-threatening invasive fungal diseases such as candidiasis, aspergillosis, cryptococcosis, Pneumocystis pneumonia (PCP), and mucormycosis. The mortality rate for these diseases generally exceeds 40%. Annual medical costs to treat these invasive fungal diseases in the United States exceed several billion dollars. In addition to AIDS patients, the risks of invasive mycoses are increasingly found in immune-impaired individuals or in immunosuppressed patients following stem cell or organ transplant or implantation of medical devices. Current antifungal drug therapies are not meeting the challenge, because (1) at safe doses, they do not provide sufficient fungal clearance to prevent reemergence of infection; (2) most become toxic with extended use; (3) drug-resistant fungal isolates are emerging; and (4) only one new class of antifungal drugs has been approved for clinical use in the last 2 decades. DectiSomes represent a novel design of drug delivery to drastically increase drug efficacy. Antifungals packaged in liposomes are targeted specifically to where the pathogen is, through binding to the fungal cell walls or exopolysaccharide matrices using the carbohydrate recognition domains of pathogen receptors. Relative to untargeted liposomal drug, DectiSomes show order of magnitude increases in the binding to and killing of Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus in vitro and similarly improved efficacy in mouse models of pulmonary aspergillosis. DectiSomes have the potential to usher in a new antifungal drug treatment paradigm.

Fig 1. DectiSomes are designed to target antifungal drugs specifically to fungal cells.

(A) Coating antifungal drug-loaded liposomes with glycan-binding proteins concentrates drugs on fungal cells. Current antifungal drugs are untargeted (left side). Having no selective affinity for fungal cells over host cells demands higher doses of antifungal drugs to inhibit or kill fungal cells. DectiSomes (right side) are drug-loaded liposomes coated with the glycan recognition domains of glycan-binding host receptors such as dectins. They bind specifically to fungal cell walls and their extracellular matrices within biofilms, which reduce the effective dose needed to clear fungal infections and host toxicity. Infection sites composed of fungal cells with Y or F morphologies are shown. (B) Structure of a DectiSome. One iteration of a DectiSome is an antifungal drug-loaded liposome coated with the glycan recognition domain of a Dectin. We coupled its glycan-binding domain (purple globular structure) to a lipid carrier to make DEC-PEG-DSPE, which is intercalated into the liposomal membrane via the DSPE moiety. Dectin monomers floating in the liposome membrane form dimers as they bind to fungal oligoglycans (yellow sugar moieties). Rhodamine-B-DHPE is intercalated via its DHPE moiety to allow fluorescent monitoring of liposome binding to fungal cells. Amphiphobic antifungal drugs (blue ovoid structure) are positioned within the lipid bilayer of liposomes. Each approximately 100-nm diameter liposome contains approximately 1,500 Dectin monomers, thousands of antifungal drug molecules, and 3,000 rhodamine molecules. DEC, dectin; DHPE, dihexadecanoyl-glycero-phospho-ethanolamine; DSPE, distearoyl-glycero-phospho-ethanolamine; F, filamentous; PEG, poly(ethylene glycol); Y, yeast.