NanoDisk containing super aggregated amphotericin B: a high therapeutic index antifungal formulation with enhanced potency.
OBJECTIVES
NanoDisk-amphotericin B (ND-AMB) is a protein-phospholipid bioparticle containing a "super aggregate" form of antifungal AMB. While lipid-based formulations of AMB, including liposomal AMB (L-AMB), are safer than the deoxycholate (DOC) solubilized form (DOC-AMB), the potency of lipid-based formulations is attenuated. We have developed an AMB-based therapy that is both well tolerated and fully efficacious.


METHODS
Potency was determined using broth culture growth-inhibition assays and candidacidal kinetics by quantitative culture plating. Toxicology studies were performed in healthy mice. Efficacy was assessed using both immune-competent and leukopenic murine models of systemic Candida albicans infection.


RESULTS
ND-AMB C. albicans and Aspergillus fumigatus minimum inhibitory concentrations were fourfold and sixfold lower, respectively, than that observed for L-AMB. ND-AMB exhibited candidacidal activity at 0.125 mg/L, 16-fold lower than L-AMB. In mice, ND-AMB produced no statistically significant kidney or liver toxicity at 15 mg/kg, the highest dose tested. When evaluated in immune-competent mice infected with C. albicans, ND-AMB was at least as effective as DOC-AMB or L-AMB. In a leukopenic model of candidiasis, the 50% effective dose of ND-AMB was around threefold lower than L-AMB.


CONCLUSION
These results indicate that ND-AMB exhibits a more favorable safety profile while maintaining uncompromised antifungal properties compared to both DOC-AMB and L-AMB. ND-AMB is a promising therapy for the treatment of invasive fungal infections.
['Burgess|Braydon L|BL|', 'He|Yumin|Y|', 'Baker|Mandie M|MM|', 'Luo|Bing|B|', 'Carroll|Stephen F|SF|', 'Forte|Trudy M|TM|', 'Oda|Michael N|MN|']
D000666:Amphotericin B D000818:Animals D000935:Antifungal Agents D002176:Candida albicans D002177:Candidiasis D005260:Female D053208:Kaplan-Meier Estimate D051379:Mice D008807:Mice, Inbred BALB C D008826:Microbial Sensitivity Tests D049329:Nanostructures D018675:Toxicity Tests
candidiasis apolipoprotein A-I drug delivery infectious diseases nanoparticles