The fungus Aspergillus fumigatus causes pulmonary invasive aspergillosis resulting in nearly 100,000 deaths each year. Patients are often treated with antifungal drugs such as amphotericin B (AmB) loaded into liposomes (AmB-LLs), but all antifungal drugs, including AmB-LLs, have serious limitations due to human toxicity and insufficient fungal cell killing. Even with the best current therapies, 1-year survival among patients with invasive aspergillosis is only 25 to 60%. Hence, there is a critical need for improved antifungal therapeutics. Dectin-1 is a mammalian protein that binds to beta-glucan polysaccharides found in nearly all fungal cell walls. We coated AmB-LLs with Dectin-1 to make DEC-AmB-LLs. DEC-AmB-LLs bound strongly to fungal cells, while AmB-LLs had little affinity. DEC-AmB-LLs killed or inhibited A. fumigatus 10 times more efficiently than untargeted liposomes, decreasing the effective dose of AmB. Dectin-1-coated drug-loaded liposomes targeting fungal pathogens have the potential to greatly enhance antifungal therapeutics.

No abstract

15 Aspergillus species cause pulmonary invasive aspergillosis resulting in nearly a hundred 16 thousand deaths each year. Patients at the greatest risk of developing life-threatening 17 aspergillosis have weakened immune systems and/or various lung disorders. Patients are 18 treated with antifungals such as amphotericin B (AmB), casofungin acetate, or triazoles 19 (itraconazole, voriconazole etc.), but these antifungal agents have serious limitations due to lack 20 of sufficient fungicidal effect and human toxicity. Liposomes with AmB intercalated into the lipid 21 membrane (AmBisomes, AmB-LLs), have several-fold reduced toxicity compared to detergent 22 Importance 41 The fungus Aspergillus fumigatus causes pulmonary invasive aspergillosis resulting in 42 nearly a hundred thousand deaths each year. Patients are often treated with antifungal drugs 43 such as amphotericin B loaded into liposomes, AmB-LLs, but all antifungal drugs including 44 AmB-LLs have serious limitations due to human toxicity and insufficient fungal cell killing. Even 45with the best current therapies, one-year survival among patients with invasive aspergillosis is 46 only 25 to 60%. Hence, there is a critical need for improved antifungal therapeutics. 47Dectin-1 is a mammalian protein that binds to beta-glucan polysaccharides found in 48 nearly all fungal cell walls. We coated AmB-LLs with Dectin-1 to make DEC-AmB-LLs. DEC-49