NANOHAT: Development of a safer and more effective sleeping sickness drug.

NANOHAT：开发一种更安全、更有效的昏睡病药物。

• 批准号: MR/K015451/1
• 负责人: Sarah Thomas
• 金额: $ 87.85万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK015451%2F1
• 关键词: NANOHAT; Development; safer; more; effective

Sleeping sickness or human African Trypanosomiasis (HAT) is a potentially fatal disease caused by the parasite, which is transferred to humans by the bite of an infected tsetse fly. After being bitten, the infected human will experience two stages of disease: the first stage is the blood-based stage of the disease and the second stage affects the central nervous system (CNS), which occurs once the parasite penetrates the brain from the blood. The infected human will die if Stage 2 HAT is left untreated. The blood-brain barrier (BBB) makes the CNS stage difficult to treat because it prevents 99% of all known drugs from entering the brain from the blood, including some anti-HAT drugs. Those anti-HAT drugs that do enter the brain are toxic compounds in their own right and have serious side effects. Pentamidine is a less toxic blood stage drug, which our research has shown has a limited ability to cross the BBB due to its removal by efflux transporters, which are membrane proteins that remove toxic substances from cells. Furthermore transporters are considered essential in the mode of action of pentamidine against the parasites that cause HAT. The objective of this multi-disciplinary study is to use nanotechnology to both improve the delivery of pentamidine to the brain and into the parasite, whilst reducing its side effects. In doing so, we will create a novel formulation that will encapsulate pentamidine. Specifically, we will use an amphiphilic polymer (a long molecule composed of many repeating units, bearing water-loving and water-hating blocks), which spontaneously self-assembles into small aggregates called micelles. These micelles can be used to encapsulate the drug, thus prolonging its circulation time and protecting it. In addition, these specific polymers (namely, Pluronics) have been shown to interact with efflux transporters and thus allow passage of the drug across the BBB. This indicates that this improved drug formulation has potential to treat Stage 2 disease. The optimal formulation will be determined using an iterative screening process that will utilise a series of cutting-edge research techniques from various biophysical, pharmaceutical and biological disciplines. The end product of this research will be a formulation which will be ready to be taken to pre-clinical testing for the treatment of Stage 2 HAT.

昏睡病或人类非洲锥虫病（HAT）是一种由寄生虫引起的潜在致命疾病，通过感染的采采蝇叮咬传播给人类。被叮咬后，受感染的人会经历两个阶段的疾病：第一阶段是疾病的血液阶段，第二阶段影响中枢神经系统（CNS），一旦寄生虫从血液中穿透大脑，就会发生这种情况。如果第二阶段HAT不治疗，受感染的人会死亡。血脑屏障（BBB）使CNS阶段难以治疗，因为它阻止了99%的所有已知药物从血液进入大脑，包括一些抗HAT药物。那些进入大脑的抗HAT药物本身就是有毒化合物，具有严重的副作用。喷他脒是一种毒性较低的血液阶段药物，我们的研究表明，由于其被外排转运蛋白（从细胞中清除有毒物质的膜蛋白）清除，因此其穿过BBB的能力有限。此外，转运蛋白被认为在喷他脒对抗引起HAT的寄生虫的作用模式中是必不可少的。这项多学科研究的目的是使用纳米技术来改善喷他脒向大脑和寄生虫的输送，同时减少其副作用。在这样做的过程中，我们将创造一种新的配方，将包封喷他脒。具体来说，我们将使用一种两亲性聚合物（由许多重复单元组成的长分子，带有亲水和憎水嵌段），它自发地自组装成称为胶束的小聚集体。这些胶束可用于包裹药物，从而延长其循环时间并保护它。此外，这些特定的聚合物（即Pluronics）已被证明与外排转运蛋白相互作用，从而允许药物穿过BBB。这表明这种改进的药物制剂具有治疗2期疾病的潜力。最佳配方将使用迭代筛选过程确定，该过程将利用来自各种生物物理学，制药学和生物学学科的一系列尖端研究技术。本研究的最终产品将是一种制剂，可用于临床前试验，用于治疗2期HAT。

项目成果

Delivery of antihuman African trypanosomiasis drugs across the blood-brain and blood-CSF barriers.

• DOI: 10.1016/bs.apha.2014.06.003
• 发表时间: 2014
• 期刊: Advances in pharmacology
• 作者: Gayathri N Sekhar;Christopher P. Watson;M. Fidanboylu;Lisa Sanderson;S. Thomas

Organic cation transporter 1 (OCT1) is involved in pentamidine transport at the human and mouse blood-brain barrier (BBB).

• DOI: 10.1371/journal.pone.0173474
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Sekhar GN;Georgian AR;Sanderson L;Vizcay-Barrena G;Brown RC;Muresan P;Fleck RA;Thomas SA
• 通讯作者: Thomas SA

Drug reformulation for a neglected disease. The NANOHAT project to develop a safer more effective sleeping sickness drug.

• DOI: 10.1371/journal.pntd.0009276
• 发表时间: 2021-04
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Sanderson L;da Silva M;Sekhar GN;Brown RC;Burrell-Saward H;Fidanboylu M;Liu B;Dailey LA;Dreiss CA;Lorenz C;Christie M;Persaud SJ;Yardley V;Croft SL;Valero M;Thomas SA
• 通讯作者: Thomas SA

Drug reformulation for a neglected disease. The NANOHAT project to develop a safer more effective sleeping sickness drug

针对被忽视的疾病重新配制药物。

• DOI: 10.1101/573329
• 发表时间: 2019
• 作者: Sanderson L