Targeted Pan-Antifungal Liposomes

侵袭性真菌病（IFD）每年导致数百万人死亡，并且难以治疗。 白色念珠菌，烟曲霉，新型隐球菌和根霉引起生命- 威胁侵袭性念珠菌病、肺曲霉病、隐球菌脑膜炎和壁霉菌病， 分别发生这些IFD风险最大的患者的免疫系统较弱， 艾滋病毒阳性者。由于越来越多的人， 接受干细胞或器官移植的免疫抑制个体。在美国， 三个综合融资方案每年超过50亿美元。一个感染者的医疗费用往往超过10万美元。 患者接受各种抗真菌药物治疗，但由于人体免疫力，所有抗真菌药物都有严重局限性。 器官毒性，在安全剂量下缺乏足够的杀真菌作用和安全有限的治疗期，以及 耐药真菌的出现。即使接受治疗，一年生存率也只有1%到90%，这取决于患者的年龄。 患者人群。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 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 支持它的概念框架满足了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和Dectin-2的碳水化合物识别结构域， Dectin-2靶向脂质体包装的抗真菌剂，以真菌葡聚糖和甘露聚糖。抗真菌药物，如 脂质体包裹的两性霉素B能穿透内皮，半衰期长，输注量少 比洗涤剂溶解的药物毒性。我们具有非常强的体外数据，表明Dectin-1-和/或Dectin-2-在体内表达。 Dectin-2-靶向两性霉素B负载的脂质体提高了与这四种不同真菌的结合效率 这些脂质体比非靶向脂质体更有效地杀死三种物种100倍，并且更有效地杀死三种物种10至100倍。的 这一高风险高回报提案的可交付成果包括：（1）证明Dectin-3与 其他Dectins扩展了真菌细胞靶向能力，（2）将该技术推广到其他Dectins的递送， 抗真菌剂如氟康唑和阿尼芬净，和（3）组装临床前数据包 显示靶向抗真菌负载脂质体在侵袭性肿瘤小鼠模型中具有增加的功效， 念珠菌病、肺曲霉病、隐球菌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个范式转变。 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， 威胁性真菌感染和眼睛、皮肤、脚趾甲和生物医学设备的轻度真菌感染。

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.