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、新型隐球菌和米根霉导致生命威胁性侵袭性念珠菌病、肺曲霉病、隐球菌性脑膜炎和毛霉菌病，患这些 IFD 的风险最大的患者的免疫系统较弱，例如由于艾滋病毒呈阳性的人数不断增加，弱势群体也在不断增加。在美国接受干细胞或器官移植的免疫抑制个体的医疗费用。三个 IFD 每年超过 50 亿美元。感染者的医疗费用通常超过 10 万美元。患者接受各种抗真菌药物治疗，但所有抗真菌药物都由于人类的原因而存在严重的局限性。器官毒性，在安全剂量和安全有限的治疗期限下缺乏足够的杀菌作用，以及即使经过治疗，一年的存活率也只有 1% 到 90%，具体取决于情况。过去 20 年来，很少有新药获得患者群体的认可。几乎所有抗真菌药物都可以特异性递送至真菌细胞壁和/或其细胞的技术分泌的胞外多糖基质可将药物功效提高几个数量级。支持它的概念框架满足了显着改进抗真菌治疗的迫切需要。我们利用了 C 型凝集素受体 Dectin-1 的碳水化合物识别域和 Dectin-2 将脂质体包装的抗真菌药物靶向真菌葡聚糖和甘露聚糖，例如抗真菌药物。脂质体包装的两性霉素B可穿透内皮，半衰期更长，输注量更少我们有非常有力的体外数据表明 Dectin-1- 和/或 Dectin-2 靶向两性霉素 B 脂质体提高了与这四种不同真菌的结合效率杀灭物种的效率比非靶向脂质体高 100 倍，杀死 3 个物种的效率高出 10 至 100 倍。该高风险高回报提案的可交付成果包括 (1) 证明 Dectin-3 结合了 other Dectins 扩展了真菌细胞靶向能力，（2）将该技术推广到其他药物的递送抗真菌药物，例如氟康唑和阿尼芬净，以及 (3) 组装临床前数据包表明负载抗真菌药物的靶向脂质体在侵袭性小鼠模型中具有更高的功效我们相信，念珠菌病、肺曲霉病、隐球菌性脑膜炎和肺毛霉菌病。将创造抗真菌制药行业的范式转变。我们拥有一支成熟的科学家团队，他们已经将不同科学领域的专业知识结合起来我们开发了一个实验平台来快速创新。并反复测试可用于治疗多种生命的抗真菌药物的真菌细胞特异性靶向眼睛、皮肤、脚趾甲和生物医学设备的威胁性真菌感染和轻度真菌感染。