Targeted Pan-Antifungal Liposomes

靶向泛抗真菌脂质体

基本信息

批准号：
10445869
负责人：
Zachary Lewis
金额：
$ 50.48万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-17 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10445869
关键词：
Acquired Immunodeficiency Syndrome Address Affinity Allergic Bronchopulmonary Aspergillosis Amphotericin Amphotericin B Anidulafungin Antifungal Agents Antifungal Therapy Area Aspergillosis Aspergillus fumigatus Binding C Type Lectin Receptors C-Type Lectins Candida albicans Candida auris Candidiasis Carbohydrates Cause of Death Cell Wall Cells Cessation of life Clinical Cryptococcal Meningitis Cryptococcosis Cryptococcus neoformans Custom Data Detergents Devices Direct Costs Disease Disease model Dose Drug Controls Drug Delivery Systems Drug Industry Drug Targeting Drug resistance Endothelium Fluconazole Funding Mechanisms Fungal eye infections Glucans Goals HIV Seropositivity Health Hospital Costs Human Immune Immune system In Vitro Individual Industrial fungicide Infection Inflammatory Infusion procedures Lead Life Liposomes Lung Mannans Medical Care Costs Medical Device Microbial Biofilms Molds Mucormycosis Multiple Fungal Drug Resistance Mycoses Organ Organ Transplantation Outcome Patients Performance Pharmaceutical Preparations Pharmacotherapy Polyenes Pre-Clinical Model Proteins Psyche structure Refractory Resistance Rhizopus Risk Science Scientist Skin Stem cell transplant Structure of nail of toe System Systemic infection Technology Testing Therapeutic Time Tissues Toxic effect Transplant Recipients Treatment Failure Triazoles Vulnerable Populations Work Yeasts cancer therapy chronic infection dectin 1 design drug efficacy experience experimental study fungus high reward high risk immunosuppressed improved innovation innovative technologies member mortality mouse dectin-2 mouse model novel therapeutics pathogen pathogenic fungus patient population pre-clinical targeted treatment therapeutically effective treatment duration

项目摘要

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.

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。白色念珠菌，曲霉菌，新生虫和根瘤菌的念珠菌会导致寿命 - 威胁侵入性念珠菌病，肺曲霉病，隐球菌性脑膜炎和毛霉菌病，分别。开发这些IFD的风险最大的患者已经削弱了免疫系统，例如艾滋病毒阳性个体。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。在美国的医疗费用每年三个IFD超过50亿美元。感染者的医疗费用通常超过100,000美元。患者接受了各种抗真菌药物的治疗，但是所有抗真菌剂都因人类而受到严重限制器官毒性，在安全剂量下缺乏足够的杀真菌作用，安全限制治疗期以及抗真菌的出现。即使治疗，一年生存率也只有1％至90％，具体取决于患者人数。在过去的20年中，很少有新药被接受。我们创造了一个变革性的几乎所有抗真菌药物都可以专门运送到真菌细胞墙和/或它们的技术中分泌的外多糖物质通过数量级提高药物效率。这项技术和支持它的概念框架满足了对抗真菌疗法的重要需求。我们已经工作了C型杠杆受体Dectin-1和 dectin-2靶向真菌葡萄糖和曼纳斯的脂质体包装抗真菌抗体。抗真菌剂，例如包装在脂质体中的两性霉素B渗透到内皮，具有更长的半衰期，输注较少毒性比去污剂可溶性药物。我们的体外数据非常强，表明Dectin-1-和/或两性霉素B负载脂质体的Dectin-2靶向提高了对这四种潜水员真菌的结合效率物种在未靶向的脂质体上100倍，并杀死了三种10到100倍的物种。这这个高风险的高回报提案的可交付成果包括（1）证明Dectin-3结合其他Dectins扩展了真菌细胞靶向能力，（2）将技术推广到其他抗真菌剂，例如氟康唑和Anidulafungin，以及（3）组装临床前数据包表明靶向抗真菌释放的脂质体在侵入性小鼠模型中具有提高的效率念珠菌病，肺曲霉病，隐球菌脑膜炎和肺胶质细胞增多。我们相信我们将在抗真菌制药行业发生范式转变。我们有一个成熟的科学家团队已经将他们在科学潜水领域的专业知识结合在一起进行这些实验所必需的。我们已经开发了一个实验平台来快速创新并重复测试可用于治疗多样化寿命的抗真菌剂的真菌细胞特异性靶向威胁真菌感染和米勒真菌感染的眼睛，皮肤，脚趾甲和生物医学装置。