Development of System for Treatment of Tuberculosis

结核病在全世界造成惊人的死亡率负担，每年造成200万人死亡。为了治愈结核病，需要至少6个月的长期治疗，因为抗结核药物不能很好地渗透到巨噬细胞中，巨噬细胞是结核分枝杆菌的主要储存库。为了设计缩短治疗时间的抗结核药物，我们将使用微粒靶向将酶可切割的异烟肼和利福平的亲脂衍生物递送到感染的巨噬细胞。一旦进入巨噬细胞，微粒降解并释放亲脂性药物，然后通过结核分枝杆菌细胞的包膜运输。我们的具体目标是：1。合成异烟肼和利福平棕榈酸衍生物并进行表征。2. 测定这些衍生物的酯酶或酰胺酶水解速率。3. 评估这些衍生物杀灭结核分枝杆菌的能力。如果该提案成功，将提交II期提案进行额外的研究，以评估这些药物与微粒在体外和动物细胞培养系统中的结合。这个项目将探索一种策略的可行性，这种策略可以应用于治疗由许多细胞内生物引起的感染，包括病毒、真菌和寄生虫。拟议的商业应用：我们将在这个项目中开发的技术有可能显著改善巨噬细胞中病原体引起的疾病的治疗，如结核病和HIV感染。在结核病的治疗中，目前还没有酶可切割的亲脂药物靶向递送系统。这一策略有可能提高治疗效果，减少所需药物的剂量，减少治疗的副作用，提高患者的依从性，并尽量减少耐药性的产生。

Tuberculosis causes a staggering burden of mortality world-wide, killing 2 million people annually. To cure tuberculosis, prolonged therapy of at least 6 months is required, because antituberculosis drugs do not penetrate well into macrophages, which are a major reservoir of M. tuberculosis. To devise antituberculosis medications that will shorten the duration of therapy, we will use microparticles to target the delivery of enzyme-cleavable lipophilic derivatives of isoniazid and rifampin to infected macrophages. Once inside the macrophage, the microparticles degrade and release the lipophilic drugs, which are then transported across the M. tuberculosis cell envelope. Our specific aims are: 1. To synthesize and characterize palmitic acid derivatives of isoniazid and rifampin. 2. To determine the rates of esterase or amidase hydrolysis of these derivatives. 3. To evaluate the capacity of these derivatives to kill M. tuberculosis. If this proposal is successful, a phase II proposal will be submitted to perform additional studies to evaluate these agents combined with microparticles in cell culture systems in vitro and in animals. This project will explore the feasibility of a strategy that can be applied to the treatment of infection caused by many intracellular organisms, including viruses, fungi and parasites. PROPOSED COMMERCIAL APPLICATIONS: The technology we will develop in this program has the potential to significantly improve the treatment of diseases due to pathogens that reside in macrophages, such as tuberculosis and HIV infection. In the treatment of tuberculosis, targeted-delivery systems of enzyme- cleavable lipophilic drugs are presently not available. This strategy has the potential to increase the efficacy of treatment, reduce the dosage of drugs required, reduce side effects of treatment, improve patient compliance, and minimize development of drug resistance.