Aspergillus fumigatus is an opportunistic pathogenic fungus that predominantly infects immunocompromised patients. It is the most common cause of infectious pneumonic mortality in HIV patients, organ transplant recipients, and cancer patients. Treatment is complicated by the fact that patients are often too fragile for invasive or toxic therapies. The current first-line treatment for aspergillosis is amphotericin B (ampB) but it is both highly nephrotoxic and insoluble. Thus, ampB presents an array of challenges to its therapeutic application and as a result successful outcomes are disturbingly low: 30 to 50%. In response to this problem, we have developed NanoDisks(tm), a novel preparation of lipid and protein for the solubilization and delivery of hydrophobic drugs. NanoDisks are 8 -15 nm diameter disc-shaped structures composed of a lipid bilayer circumscribed by a stabilizing apolipoprotein or peptide mimetic. When ampB is incorporated into NanoDisks (ND-AMB), we observe a dramatic increase in solubility and reduction in toxicity. In comparison to a leading commercial liposomal formulation of ampB (AmBisome), the minimal inhibitory concentration (MIC) of NDAMB against Aspergillus is 25-fold lower and in an animal model of disseminated Candidiasis, ND-AMB is effective at 3 to 5-fold lower doses. Because the normal route of Aspergillus infection is through inhalation of conidia, aspergillosis may be most responsive to therapies that are directed to the lung. Since ND-AMB can be lyophilized and rehydrated without loss of biological activity or complex integrity, we hypothesize that NanoDisks are compatible with dry powder inhalation delivery. We propose to test the hypothesis that NDAMB can be formulated into an improved inhaleable treatment for A. fumigatus infection. We will examine the overall suitability of ND-AMB for inhalation administration, specifically, ND-AMB compatibility with inhaleable dry powder synthesis and the ability of ND-AMB to transit the alveolar epithelium.
