Targeted delivery of antifungal drug loaded liposomes to control mucormycosis

靶向递送抗真菌药物脂质体来控制毛霉菌病

基本信息

批准号：
10509943
负责人：
Richard Brian Meagher
金额：
$ 18.88万
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：
2022-07-20 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10509943
关键词：
AIDS/HIV problem Allergic Bronchopulmonary Aspergillosis Amphotericin B Anidulafungin Antifungal Agents Antifungal Therapy Area Aspergillosis Aspergillus fumigatus Binding Biochemical Biological Assay Biology Body part C Type Lectin Receptors C-Type Lectins Candida albicans Candidiasis Carbohydrates Cell Wall Cells Cessation of life Chemistry Clinic Cryptococcus neoformans DEC1 protein Data Detergents Diagnosis Disease Dose Drug Delivery Systems Drug Industry Drug Targeting Endothelium Excision Extracellular Matrix Faculty Fluorescence Microscopy Formulation Fungal Spores Future Genetic Glucans Growth Half-Life Host Defense Human Immune system Immunocompromised Host Immunoliposome Immunology Immunosuppressive Agents In Vitro Individual Industrial fungicide Infection Infusion procedures Inhalation Intravenous Kidney Life Liposomes Lung Medical Care Costs Medical Device Metabolic Mucor Mucorales Mucormycosis Mus Mycoses Organ Organ Transplantation Oropharyngeal Pathogenesis Patient-Focused Outcomes Patients Persons Pharmaceutical Preparations Polyenes Proteins Publications Refractory Reproduction spores Research Resistance Rhizopus Risk Safety Science Scientist Sinus Site Soil Stem cell transplant Survival Rate Systemic infection Technology Testing Therapeutic Thick Tissues Toxic effect Treatment Efficacy Universities Vulnerable Populations Work Zygomycosis dectin 1 drug efficacy exosome experimental study fungus high reward high risk implantation improved improved outcome innovation meetings mortality mouse dectin-2 mouse model nephrotoxicity open wound pathogen pathogenic fungus receptor targeted delivery targeted treatment translational study treatment duration

项目摘要

PROJECT SUMMARY Invasive fungal diseases (IFDs) cause millions of deaths each year and they are refractory to treatment. Mucormycosis is responsible for 20 to 30% of life threatening invasive fungal disease cases and has been ranked the third most important fungal disease after aspergillosis and candidiasis, afflicting close to one million people annually. One species of Mucorales, Rhizopus delemar is responsible for most cases of mucormycosis. Patients at the greatest risk of developing mucormycosis have weakened immune systems such as HIV/AIDS patients. The vulnerable population is increasing due to increasing numbers of individuals taking immunosuppressive drugs for stem cell or organ transplants and medical device implantation. An infected individual’s medical cost often exceed $100,000. Liposomal amphotericin B (AmB) is the most commonly prescribed treatment, but AmB has serious limitations due to human organ toxicity, the lack of sufficient fungicidal effect at safe doses and safety at limited treatment periods, and the emergence of resistant fungi. Even with treatment, there is still approximately a 30% to 50% mortality rate. 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 support it meeting the critical need for dramatically improved antifungal therapeutics. We have employed the carbohydrate recognition domain of the C-type lectin receptor Dectin-1 to target liposomal packaged antifungals to fungal glucans. 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 data showing that Dectin-1-targeted Amphotericin B-loaded liposomes improved the binding efficiency of liposomal AmB 1,000-fold over untargeted liposomes and killed R. delemar more efficiently. The deliverables of this high-risk high-reward proposal include (1) demonstrating the potential of Dectin-1 targeted liposomes loaded with AmB or Anidulafungin (AFG), DEC1-AmB-LLs and DEC1-AFG-LL, alone and in combination, to inhibit and/or kill R. delemar in vitro as compared to untargeted drug-loaded liposomes or free drugs and (2) to demonstrate the enhanced efficacy of DEC1-AmB-LL and DEC1-AFG-LL alone and in combination to treat pulmonary mucormycosis in a neutropenic mouse model, as compared to untargeted drugs. We believe this research will contribute to an eminent paradigm shift for the treatment of all IFDs in the clinic, which will stimulate new activity 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.

项目摘要侵入性真菌疾病（IFD）每年会导致数百万人死亡，并且对治疗难治性。粘膜菌病负责20％至30％的生命威胁侵入性真菌病病例，并且已经是排名曲霉病和念珠菌病后的第三大最重要的真菌疾病，苦难近一百万每年的人。一种粘膜，一种粘液菌，造成大多数粘膜菌病的原因。患有粘膜细胞增多的风险最大的患者削弱了免疫系统，例如HIV/AIDS 患者。脆弱的人群由于增加的个人数量而增加用于干细胞或器官移植和医疗装置植入的免疫抑制药物。感染个人的医疗费用通常超过100,000美元。脂质体两性霉素B（AMB）是最常见的处方治疗，但由于人体器官毒性，AMB存在严重的局限性，缺乏足够的在有限的治疗期间安全剂量和安全性的真菌作用，以及抗真菌的出现。即使有治疗，仍有大约30％至50％的死亡率。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。这项技术和概念框架支持它满足动态改进抗真菌疗法的关键需求。我们已经在C型杠杆受体Dectin-1的碳水化合物识别域工作以靶向真菌葡萄糖的脂质体包装抗真菌抗体。在脂质中包装的抗真菌剂，例如两性霉素B 与洗涤剂可溶性药物相比，穿透内皮的半衰期更长，输注毒性更少。我们的数据非常强，表明Dectin-1靶向两性霉素B负载的脂质体得到了改善脂质体AMB的结合效率1,000倍于未靶向的脂质体，并杀死R. Delemar More 有效。这个高风险高回报提案的可交付成果包括（1）证明的潜力 dectin-1靶向脂质体，装有AMB或Anidulafungin（AFG），DEC1-AMB-LLL和DEC1-AFG-LL，与未靶向的药物相比脂质体或免费药物以及（2）证明DEC1-AMB-LL和DEC1-AFG-LL的效率提高与中性小鼠模型中的肺胶质细胞病治疗肺胶质细胞的组合相比未靶向的药物。我们认为，这项研究将有助于对所有人的范式转变 IFD在诊所中，将刺激抗真菌制药行业的新活动。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。