Targeted delivery of antifungal drug loaded liposomes to control mucormycosis

项目摘要 侵袭性真菌病（IFD）每年导致数百万人死亡，并且难以治疗。 毛霉菌病是造成20%至30%的危及生命的侵袭性真菌病病例的原因， 仅次于曲霉病和念珠菌病， 人每年。毛霉目的一个种，德氏根霉是大多数毛霉病的原因。 最有可能患毛霉菌病的患者免疫系统较弱，如艾滋病毒/艾滋病 患者由于越来越多的人服用避孕药， 用于干细胞或器官移植和医疗装置植入的免疫抑制药物。受感染 个人医疗费用往往超过10万美元。脂质体阿霉素B（AmB）是最常见的 处方治疗，但由于人体器官毒性，缺乏足够的 安全剂量下的杀真菌效果和有限治疗期的安全性，以及耐药真菌的出现。 即使经过治疗，仍有大约30%至50%的死亡率。我们创造了一个变革性的 该技术中几乎任何抗真菌药物都可以特异性地递送至真菌细胞壁和/或其细胞壁。 分泌的外泌多糖基质以将药物功效提高几个数量级。这种技术和 概念框架支持它满足显著改进的抗真菌治疗的关键需求。 我们利用C型凝集素受体Dectin-1的碳水化合物识别结构域来靶向 脂质体包装的抗真菌剂对真菌葡聚糖的作用。脂质体包装的两性霉素B等抗真菌药 渗透内皮，具有比去污剂溶解的药物更长的半衰期和更小的输注毒性。 我们有非常强有力的数据表明，Dectin-1靶向两性霉素B负载脂质体改善了 脂质体AmB的结合效率是非靶向脂质体的1，000倍，并杀死了R.德莱马尔更多 有效地这个高风险高回报的提案的交付成果包括：（1）展示 负载AmB或阿尼芬净（AFG）的Dectin-1靶向脂质体，DEC 1-AmB-LL和DEC 1-AFG-LL， 单独和组合抑制和/或杀死R.与非靶向载药相比，体外delemar 脂质体或游离药物，以及（2）证明DEC 1-AmB-LL和DEC 1-AFG-LL的增强功效 单独和组合治疗肺毛霉菌病的效果，与 非靶向药物我们相信，这项研究将有助于一个突出的范式转变，为所有的治疗 IFDs在临床上的应用，这将刺激抗真菌制药行业的新活动。 我们有一个成熟的科学家团队，他们已经结合了不同科学领域的专业知识 进行这些实验所必需的。我们开发了一个实验平台， 并粘附性地测试抗真菌剂的真菌细胞特异性靶向，所述抗真菌剂可用于治疗多种生命， 威胁真菌感染

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.