SBIR-STTR Award

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

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. A. fumigatus infection in HIV infected patients is most pertinent due to the exceptionally high mortality rate (>75% die within the first year of infection). 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 (AMB) but it is both highly nephrotoxic and insoluble. Its nephrotoxicity can be a significant contributing factor to mortality. Thus, AMB presents an array of challenges to its therapeutic application. 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 AMB 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 AMB (AmBisome), the minimal inhibitory concentration of ND-AMB against Aspergillus is 25-fold lower and in an animal model of disseminated Candidiasis, ND-AMB is effective at 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. Phase I results of this SBIR proposal demonstrated that ND-AMB could be lyophilized, milled into powder and reyhydrated without loss of biological activity, complex integrity or AMB toxicity attenuation. Therefore we hypothesize that NanoDisks are capable of effective pulmonary and systemic delivery via inhalation for the treatment of A. fumigatus pulmonary and systemically disseminated infection. We will examine the overall capability of ND-AMB as an inhaled therapy. Specifically, we will characterize ND-AMB's ability to enter the bloodstream after inhalation, its pharmacokinetic distribution, toxicity and efficacy in treating pulmonary and systemic fungal infection in murine model systems. We hope to replicate our success with AMB as a leishmaniasis therapy, wherein we converted AMB from a marginally effective treatment to a potent cure by reformulating AMB into ND-AMB. Results from this study are essential for the development of an improved inhalable AMB-based therapy for the treatment of aspergillosis; a serious health issue for HIV infected patients, wherein median survival is 3 months. With inhalable ND-AMB we believe we will bring to bear an effective cure to a disease, wherein mortality rates are extremely high (> 75%)