内皮细胞膜纳米给药体系联合MDR1抑制剂靶向iRBC逆转恶性疟原虫DHA抗性研究

As the first-line antimalarial drug, Artemisinin (ART) -based combination therapy (ACTs) has emerged resistance in Southeast Asia and Africa. Our previous study and clinical observations support this view. Reversal of ART and its derivatives resistance in Plasmodium falciparum is an effective strategy for malaria control. In this study, dihydroartemisinin (DHA)-resistant lines of P. falciparum are induced and cultured in vitro. The inhibitor targeting multidrug resistance protein 1 in P. falciparum dihydroartemisinin (DHA)-resistant lines is screened by susceptibility testing and cytotoxicity test in vitro. Then, nanoscaled antimalarial carrier system containing DHA and optimized inhibitor is constructed based on the membrane of cultured human vascular endothelial cells (ECs). Reversal of DHA resistance in infected erythrocytes of P. falciparum DHA resistant strains by the targeting drug delivery system is evaluated in vitro. It offers a scientific solution to resolving the ART resistance of P. falciparum, which has important theoretical and social significance.

作为一线抗疟药，以青蒿素(ART)为基础的联合疗法(ACTs)已在东南亚和非洲出现抗性，我们前期研究与临床观察也支持该观点。若能逆转ART及其衍生物抗性将为疟疾防治提供一种解决方案。本课题拟以恶性疟原虫为研究对象，体外培育双氢青蒿素(DHA)抗性系；以体外药敏试验结合细胞毒性试验筛选作用于DHA抗性株多药耐药蛋白1的抑制剂；以人脑微血管内皮细胞膜为材料，包封DHA和抑制剂，构建纳米给药体系，靶向作用于DHA抗性株的感染红细胞以达到逆转DHA抗性之目的。该项目的实施将为解决恶性疟原虫ART抗性提供科学依据，具有重要的理论意义和社会意义。

恶性疟原虫青蒿素耐药严重阻碍着全球疟疾防治进程。作为一线抗疟药，以青蒿素(ART)为基础的联合疗法(ACTs)已在东南亚和非洲出现抗性。若能逆转ART及其衍生物抗性将为疟疾防治提供一种解决方案。本课题分别以恶性疟原虫和伯氏疟原虫为研究对象，体外和体内培育双氢青蒿素(DHA)抗性虫株；基于同源建模与分子对接筛选多药耐药蛋白1的抑制剂；分别以人和小鼠脑微血管内皮细胞膜为材料，包封DHA和抑制剂，构建纳米给药体系，评价其靶向作用于DHA耐药恶性疟原虫感染的红细胞情况。随后，基于鼠疟模型评价仿生纳米载药体系治疗鼠脑型疟情况。通过上述研究，获得了恶性疟原虫和伯氏疟原虫耐药虫株，筛选到合适的抑制剂，成功构建了纳米载药体系并对进行了表征和应用评价。该课题通过交叉学科研究为耐药性疟疾的治疗提供了一种全新的研究思路。项目所产生的成果，指导着疟疾患者的临床用药。该项目的实施为解决恶性疟原虫ART抗性提供科学依据，具有重要的理论意义和社会意义。