Dectin-2-Targeted Antifungal Liposomes Exhibit Enhanced Efficacy

• Published in: mSphere Vol. 4; no. 5
• Main Authors: Ambati, Suresh, Ellis, Emma C, Lin, Jianfeng, Lin, Xiaorong, Lewis, Zachary A, Meagher, Richard B
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 30.10.2019
• Subjects: Amphotericin B; Amphotericin B - chemistry; Amphotericin B - pharmacology; Animal models; Antifungal agents; Antifungal Agents - pharmacology; Aspergillosis; Aspergillus fumigatus; Aspergillus fumigatus - drug effects; Cancer therapies; Candida albicans; Candida albicans - drug effects; Candidiasis; Cell walls; Coatings; Cryptococcosis; Cryptococcus neoformans; Cryptococcus neoformans - drug effects; Dectin-2; Drugs; exopolysaccharide matrix; Exopolysaccharides; Extracellular matrix; Fungal infections; Fungi; Fungi - drug effects; Fungicides; HEK293 Cells; HIV; HT29 Cells; Human immunodeficiency virus; Humans; Immunosuppressive agents; Inflammatory diseases; invasive fungal disease; Lectins, C-Type - chemistry; Lipids; Liposomes; Liposomes - chemistry; Liposomes - pharmacology; Mannan; Monomers; Mycoses - drug therapy; Patients; Pesticides; Polyethylene glycol; Protein Binding; Proteins; Stem cells; Therapeutics and Prevention; Toxicity; United States > US; Georgia; invasive fungal disease; exopolysaccharide matrix; amphotericin B; mannan; Dectin-2; liposomes
• ISSN: 2379-5042; 2379-5042
• DOI: 10.1128/MSPHERE.00715-19

, , and cause life-threatening candidiasis, cryptococcosis, and aspergillosis, resulting in several hundred thousand deaths annually. The patients at the greatest risk of developing these life-threatening invasive fungal infections have weakened immune systems. The vulnerable population is increasing due to rising numbers of immunocompromised individuals as a result of HIV infection or immunosuppressed individuals receiving anticancer therapies and/or stem cell or organ transplants. While patients are treated with antifungals such as amphotericin B, all antifungals have serious limitations due to lack of sufficient fungicidal effect and/or host toxicity. Even with treatment, 1-year survival rates are low. We explored methods of increasing drug effectiveness by designing fungicide-loaded liposomes specifically targeted to fungal cells. Most pathogenic fungi are encased in cell walls and exopolysaccharide matrices rich in mannans. Dectin-2 is a mammalian innate immune membrane receptor that binds as a dimer to mannans and signals fungal infection. We coated amphotericin-loaded liposomes with monomers of Dectin-2's mannan-binding domain, sDectin-2. sDectin monomers were free to float in the lipid membrane and form dimers that bind mannan substrates. sDectin-2-coated liposomes bound orders of magnitude more efficiently to the extracellular matrices of several developmental stages of , , and than untargeted control liposomes. Dectin-2-coated amphotericin B-loaded liposomes reduced the growth and viability of all three species more than an order of magnitude more efficiently than untargeted control liposomes and dramatically decreased the effective dose. Future efforts focus on examining pan-antifungal targeted liposomal drugs in animal models of fungal diseases. Invasive fungal diseases caused by , , and have mortality rates ranging from 10 to 95%. Individual patient costs may exceed $100,000 in the United States. All antifungals in current use have serious limitations due to host toxicity and/or insufficient fungal cell killing that results in recurrent infections. Few new antifungal drugs have been introduced in the last 2 decades. Hence, there is a critical need for improved antifungal therapeutics. By targeting antifungal-loaded liposomes to α-mannans in the extracellular matrices secreted by these fungi, we dramatically reduced the effective dose of drug. Dectin-2-coated liposomes loaded with amphotericin B bound 50- to 150-fold more strongly to , , and than untargeted liposomes and killed these fungi more than an order of magnitude more efficiently. Targeting drug-loaded liposomes specifically to fungal cells has the potential to greatly enhance the efficacy of most antifungal drugs.