Targeted delivery of antifungal drug loaded liposomes to control mucormycosis

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PROJECT SUMMARY Invasive fungal diseases (IFDs) cause millions of deaths each year and they are refractory to treatment. Mucormycosis is responsible for 20 to 30% of life threatening invasive fungal disease cases and has been ranked the third most important fungal disease after aspergillosis and candidiasis, afflicting close to one million people annually. One species of Mucorales, Rhizopus delemar is responsible for most cases of mucormycosis. Patients at the greatest risk of developing mucormycosis have weakened immune systems such as HIV/AIDS patients. The vulnerable population is increasing due to increasing numbers of individuals taking immunosuppressive drugs for stem cell or organ transplants and medical device implantation. An infected individual’s medical cost often exceed $100,000. Liposomal amphotericin B (AmB) is the most commonly prescribed treatment, but AmB has serious limitations due to human organ toxicity, the lack of sufficient fungicidal effect at safe doses and safety at limited treatment periods, and the emergence of resistant fungi. Even with treatment, there is still approximately a 30% to 50% mortality rate. We created a transformative technology in which almost any antifungal drug may be delivered specifically to the fungal cell wall and/or their secreted exopolysaccharide matrices to increase drug efficacy by orders of magnitude. This technology and the conceptual framework support it meeting the critical need for dramatically improved antifungal therapeutics. We have employed the carbohydrate recognition domain of the C-type lectin receptor Dectin-1 to target liposomal packaged antifungals to fungal glucans. Antifungals such as Amphotericin B packaged in liposome penetrate the endothelium, have longer half-lives and less infusion toxicity than detergent solubilized drugs. We have remarkably strong data showing that Dectin-1-targeted Amphotericin B-loaded liposomes improved the binding efficiency of liposomal AmB 1,000-fold over untargeted liposomes and killed R. delemar more efficiently. The deliverables of this high-risk high-reward proposal include (1) demonstrating the potential of Dectin-1 targeted liposomes loaded with AmB or Anidulafungin (AFG), DEC1-AmB-LLs and DEC1-AFG-LL, alone and in combination, to inhibit and/or kill R. delemar in vitro as compared to untargeted drug-loaded liposomes or free drugs and (2) to demonstrate the enhanced efficacy of DEC1-AmB-LL and DEC1-AFG-LL alone and in combination to treat pulmonary mucormycosis in a neutropenic mouse model, as compared to untargeted drugs. We believe this research will contribute to an eminent paradigm shift for the treatment of all IFDs in the clinic, which will stimulate new activity in the antifungal pharmaceutical industry. We have an established team of scientists already combining their expertise in diverse areas of science necessary to carry out these experiments. We have developed an experimental platform to rapidly innovate and reiteratively test fungal cell specific targeting of antifungals that may be used to treat diverse life- threatening fungal infections.