Antifungal Liposomes Targeted to Cell Wall Mannans

侵袭性真菌病（IFD）每年导致数百万人死亡，并且难以治疗。 例如，白色念珠菌和新型隐球菌会导致危及生命的侵袭性念珠菌病， 隐球菌病。发生这些IFD风险最大的患者的免疫力较弱， 艾滋病病毒感染者等。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。念珠菌病患者或 隐球菌病可以用各种抗真菌药物治疗，但所有的抗真菌药物都有严重的局限性， 人体细胞和器官毒性，耐药真菌的出现，以及缺乏足够的杀真菌效果， 安全剂量即使使用目前的抗真菌治疗，这两种IFD也与显著的 医疗费用增加，住院时间延长，一年生存率仅为12%至90%，具体取决于 患者人群。我们的建议满足了改善抗真菌治疗的迫切需要。 厚的外细胞壁和分泌的细胞外基质，富含甘露聚糖、半乳甘露聚糖和 甘露糖蛋白有助于某些病原真菌，包括C.白色念珠菌和C.新型生物逃避宿主的防御的 哺乳动物淋巴细胞表面的C-型凝集素受体Dectin-2与甘露聚糖强烈结合， 真菌细胞壁、基质，并溶解到组织中以发出对感染的先天免疫应答的信号。我们有 强有力的初步数据显示截短的Dectin-2在脂质体膜中起作用。Dectin-2涂层 抗真菌药物负载的脂质体结合C.白色 和C.比未涂覆的脂质体更有效地杀死两个数量级的新形式， 数量级更高效。这一探索性提案的总体目标是证明Dectin- 2-与目前的抗真菌药物相比，靶向的抗真菌负载脂质体增加了抗真菌药物的功效 毒品特别是，我们将证明Dectin-2包被的载药脂质体具有增强的抗真菌作用。 活性向C.白色念珠菌和C.在体外培养新型念珠菌，并在体内有效治疗播散性念珠菌病 小鼠体内模型。 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 这些实验包括真菌生物学和病理学、免疫学和脂质体 生物化学、遗传学和蛋白质化学。本研究的成功完成将确立 的抗真菌药物输送，特别是真菌甘露聚糖，最终将改善患者的结果， 念珠菌病、曲霉病和隐球菌病。我们将开发一个实验平台， 创新和优化真菌甘露聚糖和生物膜靶向疗法，可用于治疗各种生命- 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. For instance, Candida albicans and Cryptococcus neoformans cause life-threatening invasive candidiasis and cryptococcosis, 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. Patients with candidiasis or cryptococcosis are treated with various antifungal drugs, but all antifungals have serious limitations due to human cell and organ toxicity, the emergence of resistant fungi, and the lack of sufficient fungicidal effect at safe doses. Even with the current antifungal therapies, these two IFDs are associated with dramatically increased medical costs, increased length of hospital stay, and one-year survival is only 12 to 90%, depending upon the patient population. Our proposal meets the critical need for improved antifungal therapeutics. A thick outer cell wall and secreted extracellular matrix rich in mannans, galactomannans, and mannoproteins help some pathogenic fungi including C. albicans and C. neoformans evade host defense. The C-type lectin receptor Dectin-2 on the surface of mammalian lymphocytes bind strongly to mannans in the fungal cell wall, matrix, and solubilized into tissue to signal an innate immune response to infection. We have strong preliminary data showing that truncated Dectin-2 functions in a liposomal membrane. Dectin-2-coated antifungal drug-loaded liposomes bind mannans in the cell-associated exopolysaccharide matrix of C. albicans and C. neoformans two orders of magnitude more efficiently than uncoated liposomes and kills both species an order of magnitude more efficiently. The overarching goal of this exploratory proposal is to demonstrate Dectin- 2-targeted antifungal loaded liposomes increase antifungal drug efficacy as compared to current antifungal drugs. In particular, we will show that Dectin-2-coated drug-loaded liposomes have enhanced antifungal activity toward C. albicans and C. neoformans in vitro and efficiently treat disseminated candidiasis in an in vivo mouse model. We have an established team of scientists already combining their expertise in diverse areas of science necessary to carry out these experiments including fungal biology and pathology, immunology and liposome biochemistry, genetics, and protein chemistry. Successful completion of this study will establish the feasibility of antifungal drug delivery specifically to fungal mannans that will ultimately improve outcomes of patients with candidiasis, aspergillosis, and cryptococcosis. We will have developed an experimental platform to rapidly innovate and optimize fungal mannan and biofilm targeted therapies that may be used to treat diverse life- threatening fungal infections and milder fungal infections of eyes, skin, toenails, and biomedical devices.