Inhalable nanomedicines for treatment of tuberculosis

摘要：耐多药结核病（TB）的快速传播是对全球公共卫生的重大威胁。据世卫组织统计，每年约有180万人死于结核病，估计每年有980万新感染病例，由于感染艾滋病毒/艾滋病的患者人数众多，这一情况进一步恶化。结核病的治疗时间很长（短期疗程为6个月），由于治疗不完全或不适当，会产生耐药生物（结核分枝杆菌）。博士学位的目标是开发一种雾化、可吸入的纳米药物，将一线抗结核药物嵌入抗菌银纳米颗粒（NPs）中，局部递送到宿主内的结核分枝杆菌，感染周围呼吸带的巨噬细胞。抗菌银NPs可以渗透结核分枝杆菌细胞包膜屏障以提高药物疗效——具有减少治疗所需药物剂量、避免全身副作用、提高患者依从性和减少多药耐药发展的临床潜力。该工程药物系统将由聚乳酸-羟基乙酸（PLGA）微粒包封平台组成，并装入AgNPs和一线抗生素（单独或联合）。早期的重点将放在一线抗生素上，但该平台将进行调整，以便以后纳入治疗耐药结核病的新兴药物。该学生将在人类肺泡感染结核分枝杆菌模型的独特体外共培养中测试纳米药物，以评估其有效性和安全性，以及它如何与宿主免疫系统相互作用，以促进成功的微生物杀死。该学生将开发气溶胶暴露系统，以在体外输送微粒药物配方；医疗药物输送设备——无论是雾化器还是干粉吸入器——将作为潜在的输送系统进行测试，用于临床实现治疗性吸入药物剂量。相关EPSRC研究领域：分析科学，粒子技术，传感器和仪器，临床技术（不包括成像）

Abstract: Date: 16/03/2022The rapid spread of multi drug-resistant tuberculosis (TB) is a major threat to global public health. According to WHO ~1.8 million people die every year of TB, with an estimated 9.8 million new infections per year, which is exacerbated due to the number of patients infected with HIV/AIDs. Treatment of TB is lengthy (6-months for the short course), with the development of drug resistant organisms (Mycobacterium tuberculosis (M.tb)) due to incomplete or inappropriate treatment. The aim of the PhD is to develop an aerosolised, inhalable nanomedicine that delivers first line anti-tuberculous drugs embedded within antibacterial silver (Ag) nanoparticles (NPs) locally to the M.tb inside the host, infected macrophages in the peripheral respiratory zone. The antibacterial Ag NPs can permeabilise the M.tb cell envelope barrier to increase drug efficacy - with clinical potential to reduce the drug doses needed for treatment, avoid systemic side effects and increase patient compliance and reduce development of multidrug resistance. The engineered drug system will consist of a poly(lactic-co-glycolic acid) (PLGA) microparticle-encapsulation platform into AgNPs and first-line antibiotics (alone and in combination) will be loaded. The early focus will be given to first-line antibiotics, however the platform will be tailored for later inclusion of emerging drugs that treat drug resistant TB. The student will test the nanodrug in unique in vitro human co-culture of models of the human alveolar unit infected with M.tb, to assess its efficacy and safety and how it interacts with the host's immune system to facilitate successful microbial killing. The student will develop aerosol exposure systems to deliver the microparticle-drug formulations in vitro; medical drug delivery devices - either nebulisers or dry-powder inhalers - will be tested as potential delivery systems for use in the clinic to achieve therapeutically inhaled drug doses.Relevant EPSRC research areas: Analytical science, Particle technology, Sensors and instrumentation, Clinical technologies (excluding imaging)