Targeted delivery of antifungal drug loaded liposomes to control mucormycosis

项目总结 侵袭性真菌病(IFDS)每年导致数百万人死亡，而且难以治疗。 毛霉病是威胁生命的侵袭性真菌病的20%到30%的原因，一直以来 排在曲霉病和念珠菌病之后的第三大真菌病，折磨着近100万人 每年都有人。毛霉目的一种德尔根霉是大多数毛霉病的罪魁祸首。 患毛霉病风险最大的患者削弱了免疫系统，如艾滋病毒/艾滋病 病人。由于吸食毒品的个体数量增加，易受伤害的人口正在增加 用于干细胞或器官移植和医疗器械植入的免疫抑制药物。受感染的人 个人的医疗费用往往超过10万美元。脂质体两性霉素B(Amb)是最常见的 但Amb有严重的局限性，由于人体器官毒性，缺乏足够的治疗 在安全剂量下的杀菌效果和在有限的治疗期内的安全性，以及出现耐药真菌。 即使接受治疗，仍有大约30%至50%的死亡率。我们创造了一个变革性的 一种几乎任何抗真菌药物都可以专门输送到真菌细胞壁和/或其上的技术 分泌胞外多糖基质，使药效提高数量级。这项技术和 概念框架支持它满足显著改进抗真菌疗法的迫切需要。 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药物对真菌葡聚糖。脂质体包装的两性霉素B等抗真菌药物 与洗涤剂增溶药物相比，具有更长的半衰期和更低的输液毒性。 我们有非常有力的数据表明Dectin-1靶向两性霉素B脂质体的改善 脂质体Amb的结合效率是非靶向脂质体的1000倍，对R.delemar的杀伤率更高 效率很高。这一高风险高回报提案的交付成果包括(1)展示 DEC1-AMB-LLS和DEC1-AFG-11的Dectin-1靶向脂质体， 与非靶向载药相比，单独和联合在体外抑制和/或杀死R.delemar (2)证实DEC1-Amb-L1和DEC1-AFG-L1的增效作用 单独和联合治疗中性粒细胞减少的小鼠模型中的肺毛霉病 非靶向药物。我们相信这项研究将有助于治疗急性淋巴细胞白血病的显著范式转变。 IFDS在临床上的应用，将刺激抗真菌制药行业的新活动。 我们有一支成熟的科学家团队，已经将他们在不同科学领域的专业知识结合在一起。 进行这些实验所必需的。我们开发了一个快速创新的实验平台 并反复测试真菌细胞特异性靶向抗真菌药物，这些药物可能用于治疗不同的生命- 威胁着真菌感染。

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.