Most drugs currently entering the clinical pipeline for severe malaria therapeutics are of lipophilic nature, with a relatively poor solubility in plasma and large biodistribution volumes. Low amounts of these compounds do consequently accumulate in circulating Plasmodium-infected red blood cells, exhibiting limited antiparasitic activity. These drawbacks can in principle be satisfactorily dealt with by stably encapsulating drugs in targeted nanocarriers. Here this approach has been adapted for its use in immunocompetent mice infected by the Plasmodium yoelii 17XL lethal strain, selected as a model for human blood infections by Plasmodium falciparum. Using immunoliposomes targeted against a surface protein characteristic of the murine erythroid lineage, the protocol has been applied to two novel antimalarial lipophilic drug candidates, an aminoquinoline and an aminoalcohol. Large encapsulation yields of >90% were obtained using a citrate-buffered pH gradient method and the resulting immunoliposomes reached in vivo erythrocyte targeting and retention efficacies of >80%. In P. yoelii-infected mice, the immunoliposomized aminoquinoline succeeded in decreasing blood parasitemia from severe to uncomplicated malaria parasite densities (i.e. from ≥25% to ca. 5%), whereas the same amount of drug encapsulated in non-targeted liposomes had no significant effect on parasite growth. Pharmacokinetic analysis indicated that this good performance was obtained with a rapid clearance of immunoliposomes from the circulation (blood half-life of ca. 2 h), indicating a potential for improvement of the proposed model.

中文翻译：

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免疫PEG脂质体可在恶性疟疾鼠模型中将新型亲脂性药物靶向递送至红细胞

目前进入重症疟疾治疗的临床管线的大多数药物都是亲脂性的，在血浆中的溶解度相对较差，生物分布量较大。因此，少量这些化合物确实会在循环的疟原虫感染的红细胞中积聚，表现出有限的抗寄生虫活性。通过将药物稳定地包封在靶向的纳米载体中，原则上可以令人满意地解决这些缺点。在这里，此方法已适应其在受约氏疟原虫17XL致死菌株感染的免疫能力强的小鼠中的使用，该致死菌株被选为恶性疟原虫感染人类血液的模型。使用针对鼠类红细胞谱系特征性表面蛋白的免疫脂质体，该方案已应用于两种新型抗疟亲脂性药物候选物，一种氨基喹啉和一种氨基醇。使用柠檬酸缓冲的pH梯度方法获得了大于90％的大包封率，并且所得的免疫脂质体达到了体内红细胞靶向和保留效率> 80％的水平。在约埃里体育感染小鼠后，免疫脂质体化的氨基喹啉成功地将血液寄生虫病从严重的疟原虫密度降低到了简单的疟原虫密度（即从≥25％降低到大约5％），而相同剂量的非靶向脂质体中封装的药物对寄生虫没有显着影响生长。药代动力学分析表明，通过从循环中快速清除免疫脂质体（血液半衰期约为2小时）获得了这种良好的性能，表明该模型有改进的潜力。