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

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，它通过受感染采采蝇的叮咬传播给人类。被叮咬后，受感染的人将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），一旦寄生虫从血液渗透到大脑就会发生。如果不治疗第2阶段HAT，受感染的人将会死亡。血脑屏障（BBB）使中枢神经系统阶段难以治疗，因为它阻止99%的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药物本身就是有毒的化合物，并且有严重的副作用。喷他脒是一种毒性较低的血液阶段药物，我们的研究表明，由于外排转运蛋白（一种从细胞中去除有毒物质的膜蛋白）的清除作用，喷他脒穿过血脑屏障的能力有限。此外，转运体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标是利用纳米技术改善喷他脒向大脑和寄生虫的输送，同时减少其副作用。在此过程中，我们将创造一种封装喷他脒的新配方。具体来说，我们将使用一种两亲性聚合物（一种由许多重复单元组成的长分子，包含亲水和憎水块），它可以自发地自组装成称为胶束的小聚集体。这些胶束可以用来包裹药物，从而延长其循环时间并保护药物。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，从而允许药物通过血脑屏障。这表明这种改进的药物配方有可能治疗2期疾病。最佳配方将通过反复筛选过程确定，该过程将利用来自各种生物物理、制药和生物学学科的一系列前沿研究技术。这项研究的最终产品将是一种配方，该配方将准备用于治疗二期HAT的临床前测试。

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.