Targeted delivery of TB therapeutics

项目摘要： 结核病(TB)每年造成约1000万新病例，并且仍然是主要疾病之一。 传染性死亡的原因。虽然目前的“短”化疗方案总体上是有效的，但它必须是 而抗性无性系的进化是很常见的。药物的治疗选择- 耐药感染需要使用效果较差或毒性较大的制剂。目前的证据表明，有限的 结核肉芽肿内的药物暴露是造成这些缺陷的原因。因此，集中治疗结核病的药物 在肉芽肿内一直是一个长期的目标，可以加强细菌清除，减少 出现耐药性，并促进二线药物的使用，这些药物受到其系统性的限制 毒性。我们集团开发了一种灵活的交付平台技术，用于高效地封装 葡聚糖颗粒(GP)中的化合物，通过葡聚糖受体被巨噬细胞贪婪地摄取， 有选择地将货物定向到这些细胞。使用这个策略，我们发现我们可以有效地将两者集中在一起 异烟肼和氯法齐明在体外感染结核分枝杆菌感染的巨噬细胞，使这些药物的效力增加多达 100倍。我们现在计划通过优化更多药物的包装和输送来扩大这些研究 使用体外巨噬细胞模型，并进行原理动物研究以确定我们是否可以 有效地将药物靶向感染部位，增强细菌杀灭作用。如果成功，这个探索性项目 将为一个有可能改变结核病治疗的长期项目奠定基础。

Project Abstract: Tuberculosis (TB) causes an estimated 10 million new cases each year and remains one of the leading causes of infectious death. While the current “short” chemotherapy regimen is generally effective, it must be delivered for an extended period and the evolution of resistant clones is common. Treatment options for drug- resistant infections requires the use of less effective or more toxic agents. Current evidence suggests that limited drug exposure within the TB granuloma is responsible for these deficiencies. Thus, concentrating TB drugs within the granuloma has been a long-standing goal that could enhance bacterial clearance, reduce the emergence of drug resistance, and facilitate the use of second-line drugs that are limited by their systemic toxicity. Our group has developed a flexible delivery platform technology for the high efficiency encapsulation of compounds within glucan particles (GP), which are avidly taken up by macrophages via glucan receptors, selectively targeting cargo to these cells. Using this strategy, we found that we can efficiently concentrate both isoniazid and clofazimine in Mtb-infected macrophages ex vivo, increasing the potency of these drugs by up to 100-fold. We now plan to expand these studies by optimizing the encapsulation and delivery of additional drugs using the ex vivo macrophage model, and perform a proof of principle animal study to determine if we can effectively target drugs to the site of infection and enhance bacterial killing. If successful, this exploratory project will lay the groundwork for a longer-term project with the potential to transform TB therapy.