Drug reformulation for a neglected disease. The NANOHAT project to develop a safer more effective sleeping sickness drug.
Drug reformulation for a neglected disease. The NANOHAT project to develop a safer more effective sleeping sickness drug.
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DOI：
10.1371/journal.pntd.0009276
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发表时间：
2021-04
影响因子：
3.8
通讯作者：
Thomas SA
中科院分区：
文献类型：
--
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
人类非洲锥虫病（HAT或昏睡病）是由寄生虫布氏锥虫引起的。这种疾病有两个阶段，一个是被感染的采采蝇叮咬后的血淋巴阶段，接着是寄生虫穿透大脑的中枢神经系统阶段，如果不治疗会导致死亡。由于血脑屏障，治疗是阶段特异性的，毒性较小的药物如用于治疗阶段1的喷他脒。我们的研究计划的目的是开发一种喷他脒的静脉注射制剂，使CNS暴露增加约10-100倍，从而对2期HAT模型有效。这一候选靶点符合被忽视疾病药物的初步建议。为此，我们评估了喷他脒与普朗尼克胶束制剂的理化和结构特征（聚环氧乙烷和聚环氧丙烷的三嵌段共聚物），用于体外功效和毒性评价的选定候选物，体外和体内制剂子集的定量喷他脒CNS递送，并开发了一种戊烷脒-普朗尼克制剂，用于使用体内单剂量脑渗透研究进行进一步评价。针对40个CNS靶点筛选喷他脒未发现任何重大神经毒性问题，然而，喷他脒对咪唑啉2受体具有高亲和力。喷他脒导致MIN 6 β细胞胰岛素分泌减少可能继发于喷他脒介导的β细胞咪唑啉受体活化和细胞活力受损。Pluronic F68（0.01%w/v）-喷他脒制剂对胰岛素分泌的抑制作用与单独的喷他脒相似，并且在体外具有相加的杀锥虫作用。然而，所有Pluronics试验（P85、P105和F68）均未显著增强喷他脒的脑暴露。这些结果与进一步开发嵌段共聚物作为纳米载体，改善BBB药物渗透和了解喷他脒的副作用有关。昏睡病或人类非洲锥虫病（HAT）是一种由寄生虫引起的疾病，通过感染的采采蝇叮咬传播给人类。疾病有两个阶段：第一阶段是血液阶段，第二阶段影响大脑。如果不治疗是致命的。血脑屏障（BBB）使大脑阶段难以治疗，因为它阻止了99%的药物从血液进入大脑。那些进入大脑的抗HAT药物是有毒的，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，由于被称为转运蛋白的蛋白质清除，它穿过BBB的能力有限。本研究的目的是使用Pluronic改善喷他脒向靶部位的递送，同时减少其副作用。Pluronic是一种聚合物，可以组装成胶束并包裹药物。我们的研究表明，所选的普朗尼克并没有增加喷他脒的脑内释放。然而.与未配制的喷他脒相比，普朗尼克-喷他脒制剂具有杀锥虫活性，不会增加安全性问题。
Human African trypanosomiasis (HAT or sleeping sickness) is caused by the parasite Trypanosoma brucei sspp. The disease has two stages, a haemolymphatic stage after the bite of an infected tsetse fly, followed by a central nervous system stage where the parasite penetrates the brain, causing death if untreated. Treatment is stage-specific, due to the blood-brain barrier, with less toxic drugs such as pentamidine used to treat stage 1. The objective of our research programme was to develop an intravenous formulation of pentamidine which increases CNS exposure by some 10–100 fold, leading to efficacy against a model of stage 2 HAT. This target candidate profile is in line with drugs for neglected diseases inititative recommendations. To do this, we evaluated the physicochemical and structural characteristics of formulations of pentamidine with Pluronic micelles (triblock-copolymers of polyethylene-oxide and polypropylene oxide), selected candidates for efficacy and toxicity evaluation in vitro, quantified pentamidine CNS delivery of a sub-set of formulations in vitro and in vivo, and progressed one pentamidine-Pluronic formulation for further evaluation using an in vivo single dose brain penetration study. Screening pentamidine against 40 CNS targets did not reveal any major neurotoxicity concerns, however, pentamidine had a high affinity for the imidazoline2 receptor. The reduction in insulin secretion in MIN6 β-cells by pentamidine may be secondary to pentamidine-mediated activation of β-cell imidazoline receptors and impairment of cell viability. Pluronic F68 (0.01%w/v)-pentamidine formulation had a similar inhibitory effect on insulin secretion as pentamidine alone and an additive trypanocidal effect in vitro. However, all Pluronics tested (P85, P105 and F68) did not significantly enhance brain exposure of pentamidine. These results are relevant to further developing block-copolymers as nanocarriers, improving BBB drug penetration and understanding the side effects of pentamidine. Sleeping sickness or human African Trypanosomiasis (HAT) is a disease caused by a parasite, which is transferred to humans by the bite of an infected tsetse fly. There are two disease stages: the first stage is the blood-based stage of the disease and the second stage affects the brain. It is fatal if left untreated. The blood-brain barrier (BBB) makes the brain stage difficult to treat because it prevents 99% of all drugs from entering the brain from the blood. Those anti-HAT drugs that do enter the brain are toxic 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 proteins called transporters. The objective of this study was to use Pluronic to improve pentamidine delivery to target sites, whilst reducing its side effects. Pluronic is a polymer, which can assemble into micelles and encapsulate the drug. Thus, prolonging its circulation time and protecting it. Our study indicated that the selected Pluronics did not increase the brain delivery of pentamidine. However. Pluronic-pentamidine formulations were identified that harboured trypanocidal activity and did not increase safety concerns compared to unformulated pentamidine.
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