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

• 批准号: 10668509
• 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
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-20 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668509
• 关键词: 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; HIV/AIDS; Half-Life; Host Defense; Human; Immune system; Immunocompromised Host; Immunoliposome; Immunology; Immunosuppressive Agents; In Vitro; Individual; 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; Penetration; 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; dectin 1; drug efficacy; exosome; experimental study; fungicide; 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

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.

项目概要 侵袭性真菌病 (IFD) 每年导致数百万人死亡，并且难以治疗。 毛霉菌病导致 20% 至 30% 的危及生命的侵袭性真菌病病例，并且已被 是仅次于曲霉病和念珠菌病的第三大重要真菌病，影响近百万人 人每年。毛霉菌目中的一种，德雷根霉 (Rhizopus delemar) 是大多数毛霉菌病的罪魁祸首。 患毛霉菌病风险最高的患者免疫系统较弱，例如艾滋病毒/艾滋病 患者。由于服用药物的人数不断增加，弱势群体正在增加 用于干细胞或器官移植和医疗器械植入的免疫抑制药物。一个被感染的 个人的医疗费用往往超过10万美元。脂质体两性霉素 B (AmB) 是最常见的 但AmB由于对人体器官的毒性、缺乏足够的治疗手段而具有严重的局限性。 安全剂量下的杀菌效果和有限治疗期间的安全性，以及抗药性真菌的出现。 即使进行治疗，死亡率仍约为 30% 至 50%。我们创造了一个变革性的 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。这项技术和 概念框架支持它满足显着改进抗真菌治疗的迫切需求。 我们利用 C 型凝集素受体 Dectin-1 的碳水化合物识别域来靶向 脂质体包装的真菌葡聚糖抗真菌剂。脂质体包装的抗真菌药，例如两性霉素 B 穿透内皮，比洗涤剂溶解的药物具有更长的半衰期和更低的输注毒性。 我们有非常有力的数据表明，Dectin-1 靶向两性霉素 B 脂质体改善了 脂质体 AmB 的结合效率是非靶向脂质体的 1,000 倍，并且更能杀死 R. delemar 高效。这个高风险高回报提案的可交付成果包括（1）展示 Dectin-1 靶向脂质体装载有 AmB 或阿尼芬净 (AFG)、DEC1-AmB-LL 和 DEC1-AFG-LL， 与非靶向载药相比，单独或组合在体外抑制和/或杀死 R. delemar 脂质体或游离药物以及 (2) 证明 DEC1-AmB-LL 和 DEC1-AFG-LL 的增强功效 单独或联合治疗中性粒细胞减少小鼠模型中的肺毛霉菌病，与 非靶向药物。我们相信这项研究将有助于治疗所有疾病的显着范式转变 IFD进入临床，这将刺激抗真菌制药行业的新活动。 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 进行这些实验所必需的。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 威胁真菌感染。