Targeted delivery of TB therapeutics

结核病治疗的靶向递送

• 批准号: 10319612
• 负责人: CHRISTOPHER M SASSETTI
• 金额: $ 20.94万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-17 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319612
• 关键词: Animals; Bacteria; Cells; Cessation of life; Chemistry; Chemotherapy-Oncologic Procedure; Complex; DNA; Data; Drug Exposure; Drug Formulations; Drug Targeting; Drug resistance; Drug usage; Effectiveness; Encapsulated; Evolution; Glucans; Goals; Granuloma; Growth; Hydrophobicity; Infection; Lead; Lung; Lymphocyte; Methods; Modeling; Modernization; Mus; Mycobacterium tuberculosis; Necrosis; Phagocytosis; Pharmaceutical Preparations; Prodrugs; Proteins; Recurrent disease; Regimen; Resistance; Signal Transduction; Site; Small Interfering RNA; Stimulus; Structure; System; Technology; Therapeutic; Toxic effect; Tuberculosis; Zebrafish; base; controlled release; flexibility; high throughput screening; histological image; hydrophilicity; improved; in vitro activity; in vivo; isoniazid; macrophage; mouse model; mycobacterial; nonhuman primate; particle; prevent; receptor; scaffold; small molecule; systemic toxicity; targeted delivery; tuberculosis drugs; tuberculosis granuloma; tuberculosis treatment

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.

项目摘要： 据估计，结核病每年造成1000万新病例， 感染性死亡的原因。虽然目前的“短”化疗方案一般是有效的，但它必须 在很长一段时间内，抗性克隆的进化是常见的。药物的治疗选择- 耐药性感染需要使用效力较低或毒性较大的药剂。目前的证据表明， TB肉芽肿内的药物暴露是造成这些缺陷的原因。因此，集中结核病药物 长期以来，在肉芽肿内的药物治疗一直是一个长期的目标，可以提高细菌清除率，减少 耐药性的出现，并促进使用二线药物，这是有限的，其全身 毒性我们的团队开发了一种灵活的交付平台技术，用于高效封装 葡聚糖颗粒（GP）内的化合物，其通过葡聚糖受体被巨噬细胞贪婪地摄取， 选择性地将货物定向到这些细胞。使用这种策略，我们发现我们可以有效地集中两者 异烟肼和氯法齐明在结核分枝杆菌感染的巨噬细胞中的体外作用，使这些药物的效力增加高达 一百倍我们现在计划通过优化额外药物的封装和递送来扩展这些研究 使用离体巨噬细胞模型，并进行原理动物研究的证明，以确定我们是否可以 有效地将药物靶向感染部位并增强细菌杀灭。如果成功，这个探索性的项目 将为一个有可能改变结核病治疗的长期项目奠定基础。