Antifungal Liposomes Targeted to Fungal Cells Have Dramatically Increased Efficacy

Author:

RB Meagher1, ZA Lewis2, X Lin2, M Momany3, S Ambati1

Author address:

1Genetics, University of Georgia, Athens, USA
2Microbiology, University of Georgia, Athens, USA
3Plant Biology, University of Georgia, Athens, USA

Full conference title:

9th Advances Against Aspergillosis

Date: 26 February 2020

Abstract:

Purpose: Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus cause life-threatening candidiasis, cryptococcosis and aspergillosis, resulting in several hundred thousand deaths annually and several billions of dollars in medical costs annually. 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. While patients are treated with antifungals such as Amphotericin B (AmB), all antifungals have serious limitations due to lack of sufficient fungicidal effect and host toxicity. Even with treatment, one-year survival rates for patients with these diseases are low. Very few new antifungal drugs have gained acceptance in the last two decades. The purpose or our research team’s effort was to develop a pan-antifungal drug delivery system that would target drugs specifically to the surface of pathogenic fungal cells and increase the efficacy of any existing or new antifungal agent.

Methods: First, we designed new simplified protein chemical methods that allowed us to easily and inexpensively manipulate the relatively insoluble carbohydrate recognition domains of Dectins. Dectins are a subclass of C-type lectin receptors expressed on dendritic cells that signal fungal infection. Second, we developed methods to rapidly construct small batches of drug loaded liposomes and coating them with different Dectins proteins that enabled reiterative testing of novel liposomal constructs. Third, we constructed AmB-loaded 100-nanometer diameter liposomes coated with 1,500 Dectin monomers and 3,000 rhodamine molecules. The Dectin monomers were engineered to float in the liposome membrane such that they were conformationally free to form the dimers necessary for tight binding to their target polysaccharides. The rhodamine tag allowed us to monitor binding to the fungal cell wall and exopolysaccharide matrix microscopically and to quantify the relative levels of binding.

Results: Dectin-coated AmB-loaded liposomes, DEC-AmB-LLs, bound to the surface of C. albicans, C. neoformans, and A. fumigatus cells and their exopolysaccharide matrices more than 100-fold more efficiently than an untargeted AmBisome® equivalent, AmB-LLs. Binding was specific for two different classes of target polysaccharides. Binding was rapid and essentially irreversible, perhaps due to the high avidity provided by multiple Dectins on the surface of each liposome binding cooperatively to fungal cells. DEC-AmB-LLs liposomes inhibited or killed C. albicans, C. neoformans, and A. fumigatus 10-fold to 100-fold more efficiently than AmBisome®-likeAmB-LLs delivering the same concentration of Amphotericin B, and when delivering AmB concentrations near the minimum inhibitory concentrations for AmBisome® reported for these three species. In short, we have reduced the effective dose for inhibition and killing of all three species more than 10-fold.

Conclusion: By decreasing the effective dose of an antifungal drug, we should reduce the fungal burden in various host organs at drug concentrations that have reduced host toxicity. This targeting technology has the potential to increase the efficacy of all antifungal drugs against nearly all fungal pathogens and produce a paradigm shift in antifungal therapies. The technology should also work against protozoan parasites. Our immediate future efforts focus on examining pan-antifungal targeted liposomal drugs in mouse models of candidiasis, cryptococcosis, and aspergillosis.

Abstract Number: 5

Link to conference website:

Link Conference abstract: 

AAAM 2020

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