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.
Highlights
Our goal with DectiSomes is to dramatically improve the effectiveness of antifungal drugs by targeting them to fungal cells and away from host cells (Fig 1)
DectiSomes are drugloaded liposomes coated with a protein(s) that targets them to fungal cell walls and their exopolysaccharide matrices (Fig 1A) [9,10]
DEC1-amphotericin B (AmB)-LLs and DEC2-AmBLLs bind to the cell walls and more efficiently to the exopolysaccharide matrices of in vitro grown Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans 50- to 200-fold more strongly than untargeted AmB-LLs [9,10]
Summary
Our goal with DectiSomes is to dramatically improve the effectiveness of antifungal drugs by targeting them to fungal cells and away from host cells (Fig 1). DectiSomes are drugloaded liposomes coated with a protein(s) that targets them to fungal cell walls and their exopolysaccharide matrices (Fig 1A) [9,10]. DectiSomes bring antifungal drugs in close proximity to fungal cells to increase their local concentrations and to lower their concentration in host cells, thereby lowering the mg/kg effective dose of drug needed to control the pathogen [9,10,11], reducing host toxicity, and allowing temporally extended treatment regimens.
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