Development of Nanomedicines for Tuberculosis Treatment

结核病治疗纳米药物的开发

• 批准号: 9401746
• 负责人: Admire Dube
• 金额: $ 6.98万
• 依托单位: UNIVERSITY OF THE WESTERN CAPE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-22 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9401746
• 关键词: Africa; Africa South of the Sahara; Alveolar; Animal Model; Antimicrobial Resistance; Antitubercular Agents; Award; Biology; Buffaloes; Bypass; Cell model; Cells; Cessation of life; Chitosan; Clinical; Communicable Diseases; Competence; Complement; Data; Development; Drug Kinetics; Drug effect disorder; Educational process of instructing; Ensure; Environment; Generations; Glucans; Glycolates; Goals; Histopathology; Human; Immune; Immune system; Immunology; Immunotherapy; Incubated; Individual; Infectious Disease Immunology; Inflammatory; Innate Immune System; Institution; International; Intravenous; Investigation; Kinetics; Leadership; Learning; Ligands; Liver; Lung; Measures; Medical; Mentors; Mentorship; Methods; Modality; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium tuberculosis; Nanotechnology; Nitrogen; Organism; Oxygen; Pharmaceutical Preparations; Pharmacology; Population Density; Postdoctoral Fellow; Production; Public Health; Radial; Reporting; Research; Research Personnel; Resistance; Resources; Rifampicin resistance; Rifampin; Scientist; Series; Serum; South Africa; Spleen; Surface; TNF gene; Time; Training; Travel; Tuberculosis; Universities; Work; antimicrobial; bactericide; base; beta-Glucans; biosafety level 3 facility; career; chemokine; cytokine; cytotoxicity; design; drug development; drug discovery; frontier; improved; infectious disease treatment; innovation; isoniazid; killings; macrophage; microbial; mortality; nanomedicine; nanoparticle; novel therapeutics; pathogen; response; skills; synergism; tuberculosis drugs; tuberculosis treatment

1" Project Summary: 2" Sub-Saharan Africa, in particular South Africa is disproportionately challenged by a burden of deadly 3" infectious diseases including tuberculosis (TB). South Africa has the highest burden of TB in the world 4" (22.5% of the global burden). Furthermore, TB that is resistant to existing drugs is on the rise. However, 5" there are very few new drugs for TB in the drug discovery pipeline. Further, it is not encouraging to note 6" that in the current era of increasing antimicrobial resistance, new drugs are faced with a real threat of 7" pathogen resistance emerging soon after clinical use; as was recently observed with bedaquiline, 8" whereby resistance was detected 2 years after clinical use. The combination of increasing multidrug 9" resistance, global population density and international travel urgently calls for the development of 10" novel therapeutics for TB. Under this 5-year mentored K43 award, I intend to investigate a new 11" treatment modality that employs nanoparticles to activate the innate immune system for treatment of TB 12" (immuno-therapy). As a Postdoctoral fellow in nanomedicine at the University at Buffalo, we synthesized 13" nanoparticles functionalized with an immune modulating ligand (β-glucan), and demonstrated that these 14" nanoparticles could stimulate the TB host cells, i.e. macrophages, to produce cytokines and oxidative 15" species known to be critical to the eradication of the TB causative organism Mycobacterium tuberculosis 16" (M.tb). Under this award, I will determine whether this cellular response leads to death of M.tb in 17" macrophages and mice. This study will generate proof of concept data towards the development of this 18" new treatment modality. My prior training in nanomedicine was focused on the synthesis of nanoparticles 19" and how to characterize them. However, my career objective is to be a leader in the development of 20" nanomedicines for the treatment of infectious diseases. Therefore, I intend to undergo extensive training 21" in the biology and immunology of infectious diseases and pharmacokinetics, and to also improve my 22" research leadership skills. I will gain these skills through completing didactic and hands-on training 23" courses and group learning. I believe these additional skills will complement my current skills (in 24" nanoparticle synthesis), to equip me to rationally design nanomedicines and effectively collaborate with 25" infectious disease medical experts throughout my career. My mentorship team comprises established 26" researchers in TB biology and immunology and nanotechnology (South Africa mentors) and drug 27" development (US mentor). I will leverage the scarce resources such as biosafety level 3 facilities as well 28" as the excellent teaching and research environment at institutions in South Africa and the US, to 29" successfully complete my training and research goals. 30" 31"

1" 项目概要： 2" 撒哈拉以南非洲地区，特别是南非，面临着致命的挑战 3”传染病，包括结核病（TB）。南非是世界上结核病负担最高的国家 4”（占全球负担的 22.5%）。此外，对现有药物具有耐药性的结核病正在增加。然而， 5“药物发现管道中的结核病新药很少。此外，值得注意的是，这并不令人鼓舞 6”指出，在当今抗菌药物耐药性日益增加的时代，新药面临着真正的威胁 7" 临床使用后不久就出现了病原体耐药性；正如最近在贝达喹啉中观察到的那样， 8"因此临床使用2年后检测到耐药。增加多药联合 9》抵抗、全球人口密度和国际旅行迫切呼唤发展 10" 结核病新疗法。在这个为期 5 年的 K43 指导奖下，我打算研究一种新的 11" 治疗方式采用纳米颗粒激活先天免疫系统来治疗结核病 12”（免疫疗法）。作为布法罗大学纳米医学博士后研究员，我们合成了 13英寸纳米粒子用免疫调节配体（β-葡聚糖）进行功能化，并证明这些 14英寸纳米粒子可以刺激结核宿主细胞，即巨噬细胞，产生细胞因子和氧化 已知对根除结核病病原体结核分枝杆菌至关重要的 15" 物种 16" (M.tb)。根据这个奖项，我将确定这种细胞反应是否会导致 M.tb 死亡 17" 巨噬细胞和小鼠。这项研究将为该技术的开发生成概念验证数据 18“新的治疗方式。我之前在纳米医学方面的培训重点是纳米颗粒的合成 19”以及如何描述它们。然而，我的职业目标是成为发展的领导者 20英寸纳米药物用于治疗传染病。因此，我打算接受广泛的培训 21”在传染病的生物学和免疫学以及药代动力学方面，也提高了我的水平 22" 研究领导技能。我将通过完成教学和实践培训来获得这些技能 23”课程和小组学习。我相信这些额外的技能将补充我目前的技能（在 24“纳米粒子合成），使我能够合理设计纳米药物并有效地与 在我的整个职业生涯中，我都是 25 英寸的传染病医学专家。我的导师团队包括已建立的 26" 结核病生物学、免疫学、纳米技术（南非导师）和药物研究人员 27”开发（美国导师）。我也会利用生物安全3级设施等稀缺资源 28”作为南非和美国院校优良的教学和研究环境， 29”顺利完成了我的训练和研究目标。 30英寸 31英寸