Antifungal Liposomes Targeted to Cell Wall Mannans

针对细胞壁甘露聚糖的抗真菌脂质体

基本信息

批准号：
9979038
负责人：
Richard Brian Meagher
金额：
$ 22.65万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-20 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979038
关键词：
Aftercare Amphotericin B Anidulafungin Antifungal Agents Antifungal Therapy Area Aspergillosis Aspergillus Aspergillus fumigatus Binding Biochemical Biochemistry Biological Biology Brain C Type Lectin Receptors C-Type Lectins Candida Candida albicans Candidiasis Carbohydrates Caspofungin Cell Wall Cells Cessation of life Cryptococcal Meningitis Cryptococcosis Cryptococcus Cryptococcus neoformans Data Devices Disease Disseminated candidiasis Dose Drug Delivery Systems Drug Formulations Drug Targeting Engineering Extracellular Matrix Fluconazole Formulation Fungal eye infections Genetic Goals HIV Seropositivity Health Host Defense Human Hyphae Immune system Immunocompromised Host Immunoliposome Immunology In Vitro Individual Industrial fungicide Infection Innate Immune Response Kidney Length of Stay Life Lipids Liposomes Lymphocyte Mannans Medical Care Costs Medical Device Membrane Microbial Biofilms Mus Mycoses Organ Organ Transplantation Pathogenesis Pathology Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacotherapy Polyenes Protein Chemistry Proteins Refractory Resistance Risk Science Scientist Signal Transduction Skin Stem cell transplant Structure of nail of toe Surface Survival Rate Testing Therapeutic Thick Tissues Toxic effect Triazoles Vulnerable Populations Yeasts cancer therapy dimer drug efficacy drug standard exosome experimental study fungus galactomannan immunosuppressed improved improved outcome in vitro activity in vivo innovation mannoproteins monomer mouse dectin-2 mouse model pathogenic fungus patient population receptor targeted delivery targeted treatment

项目摘要

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.

侵入性真菌疾病（IFD）每年会导致数百万人死亡，并且对治疗难治性。例如，白色念珠菌和加密型新型人物会导致威胁生命的侵入性念珠菌病和分别是隐球菌病。开发这些IFD的风险最大的患者使免疫力减弱诸如艾滋病毒阳性个体之类的系统。由于数量增加，脆弱的人口正在增加接收干细胞或器官移植的免疫抑制个体。念珠菌病或通过各种抗真菌药物治疗隐球菌病，但由于人类细胞和器官毒性，抗性真菌的出现以及缺乏足够的杀真菌作用安全剂量。即使采用电流抗真菌疗法，这两个IFD也与医疗费用增加，住院时间增加，一年生存率仅为12至90％，具体取决于对患者人数。我们的建议满足了改善抗真菌疗法的关键需求。厚厚的外细胞壁和分泌的细胞外基质，富含Mannans，Galactomannans和甘露蛋白有助于一些致病的真菌，包括白色念珠菌和新甲状腺梭菌逃避宿主防御。这哺乳动物淋巴细胞表面上的C型凝集素受体Dectin-2与Mannans强烈结合真菌细胞壁，基质并溶解在组织中，以信号对感染的先天免疫反应。我们有强的初步数据表明，截短的Dectin-2在脂质体膜中的功能。 Dectin-2涂层抗真菌药物载的脂质体在白色念珠菌的细胞相关外多糖基质中结合甘露氏素和Neofors C. Neofans比未涂层的脂质体更有效地两个数量级，并杀死两个物种更有效的数量级。该探索性建议的总体目标是证明二生与电流抗真菌相比毒品。特别是，我们将证明Dectin-2涂层的药物脂质体具有增强的抗真菌剂在体外对白色念珠菌和新生梭菌的活性，并有效地治疗An中的传播念珠菌病体内鼠标模型。我们有一个成熟的科学家团队已经将他们在科学不同领域的专业知识结合在一起进行这些实验，包括真菌生物学和病理学，免疫学和脂质体所需生物化学，遗传学和蛋白质化学。这项研究的成功完成将确定可行性抗真菌药物的专门针对真菌曼纳斯的递送念珠菌病，曲霉病和隐球菌病。我们将开发一个实验平台来快速创新和优化真菌Mannan和生物膜有针对性的疗法，可用于治疗多样化的生活 - 威胁着真菌感染和眼睛，皮肤，脚趾甲和生物医学装置的真菌感染。