Targeted Pan-Antifungal Liposomes

侵袭性真菌病(IFDS)每年导致数百万人死亡，而且难以治疗。 白色念珠菌、烟曲霉、新生隐球菌和米根霉导致生命- 威胁侵袭性念珠菌病、肺曲霉菌病、隐球菌性脑膜炎和毛霉菌病， 分别进行了分析。罹患这些IFDS风险最大的患者免疫系统减弱，如 艾滋病毒阳性者。由于数量的增加，脆弱的人口正在增加 接受干细胞或器官移植的免疫抑制患者。在美国，这些产品的医疗成本 有三个IFDS每年超过50亿美元。感染者的医疗费用往往超过10万美元。 患者可以用各种抗真菌药物治疗，但由于人类的原因，所有的抗真菌药物都有严重的局限性。 器官毒性，在安全剂量和安全有限的治疗期限内缺乏足够的杀菌效果，以及 抗药性真菌的出现。即使接受治疗，一年的存活率也只有1%到90%，这取决于 病人群体。在过去的20年里，很少有新药被接受。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 支持它的概念框架满足了显著改进抗真菌疗法的关键需求。 我们利用了C型凝集素受体Dectin-1和Dectin-1的碳水化合物识别结构域 Dectin-2针对真菌葡聚糖和甘露聚糖的脂质体包装的抗真菌药物。抗真菌药物，如 脂质体包裹的两性霉素B可穿透血管内皮细胞，半衰期更长，输液量更少 毒性大于洗涤剂增溶药物。我们有非常强大的体外数据表明Dectin-1和/或 以Dectin-2为靶点的两性霉素B脂质体对4种不同真菌的结合效率 物种比非靶向脂质体高100倍，杀死三个物种的效率要高出10到100倍。这个 这一高风险高回报提案的可交付成果包括(1)证明Dectin-3结合 Other Dectins扩展了真菌细胞靶向能力，(2)将该技术推广到其他 抗真菌药，如氟康唑和阿尼达芬净，以及(3)组装临床前数据包 显示靶向抗真菌脂质体在侵袭性小鼠模型中的疗效增加 念珠菌病、肺曲霉菌病、隐球菌性脑膜炎和肺毛霉菌病。我们相信我们 将在抗真菌制药行业创造一种范式转变。 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- 眼睛、皮肤、脚趾甲和生物医学设备的威胁真菌感染和较轻微的真菌感染。

Invasive fungal diseases (IFDs) cause millions of deaths each year and they are refractory to treatment. Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans and Rhizopus oryzae cause life- threatening invasive candidiasis, pulmonary aspergillosis, cryptococcal meningitis, and murormycosis, respectively. Patients at the greatest risk of developing these IFDs have weakened immune systems such as HIV positive individuals. The vulnerable population is increasing due to increasing numbers of immunosuppressed individuals receiving stem cell or organ transplants. In the U.S. medical costs for these three IFDs exceed $5 billion dollar per year. An infected individual’s medical cost often exceed $100,000. Patients are treated with various antifungal drugs, but all antifungals have serious limitations due to human organ toxicity, the lack of sufficient fungicidal effect at safe doses and safely limited treatment periods, and the emergence of resistant fungi. Even with treatment, one-year survival is only 1% to 90%, depending upon the patient population. Few new drugs have gained acceptance in the last 20 years. 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 supporting it meet the critical need for dramatically improved antifungal therapeutics. We have employed the carbohydrate recognition domains of the C-type lectin receptors Dectin-1 and Dectin-2 to target liposomal packaged antifungals to fungal glucans and mannans. 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 in vitro data showing that Dectin-1- and/or Dectin-2-targeting of Amphotericin B-loaded liposomes improved binding efficiency to these four diverse fungal species 100-fold over untargeted liposomes and killed three species 10- to 100-times more efficiently. The deliverables of this high-risk high-reward proposal include (1) demonstrating that Dectin-3 in combination the other Dectins expands fungal cell targeting capabilities, (2) generalizing the technology to the delivery of other antifungals agents such as fluconazole and anidulafungin, and (3) assembling a preclinical data package showing that targeted antifungal-loaded liposomes have increased efficacy in mouse models of invasive candidiasis, pulmonary aspergillosis, cryptococcal meningitis, and pulmonary mucormycosis. We believe we will create a paradigm shift 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 and milder fungal infections of eyes, skin, toenails, and biomedical devices.