Barcelona Institute for Global Health (ISGlobal, Hospital Clínic-Universitat de Barcelona), Rosselló 149-153, ES-08036 Barcelona, Spain; Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, ES-08028 Barcelona, Spain; Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, ES-08028 Barcelona, Spain.
Grup d'Enginyeria de Materials (GEMAT), Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, 08017 Barcelona, Spain.
J Control Release. 2021 Mar 10;331:364-375. doi: 10.1016/j.jconrel.2021.01.028. Epub 2021 Jan 23.
The current decline in antimalarial drug efficacy due to the evolution of resistant Plasmodium strains calls for new strategies capable of improving the bioavailability of antimalarials, especially of those whose lipophilic character imparts them a low solubility in biological fluids. Here we have designed, synthesized and characterized amphiphilic zwitterionic block copolymers forming nanoparticles capable of penetrating the intestinal epithelium that can be used for oral administration. Poly(butyl methacrylate-co-morpholinoethyl sulfobetaine methacrylate) (PBMA-MESBMA)-based nanoparticles exhibited a specific targeting to Plasmodium falciparum-infected vs. parasite-free red blood cells (74.8%/0.8% respectively), which was maintained upon encapsulation of the lipophilic antimalarial drug curcumin (82.6%/0.3%). The in vitro efficacy of curcumin upon encapsulation was maintained relative to the free compound, with an IC50 around 5 μM. In vivo assays indicated a significantly increased curcumin concentration in the blood of mice one hour after being orally fed PBMA-MESBMA-curcumin in comparison to the administration of free drug (18.7 vs. 2.1 ng/ml, respectively). At longer times, however, plasma curcumin concentration equaled between free and encapsulated drug, which was reflected in similar in vivo antimalarial activities in Plasmodium yoelii yoelii-infected mice. Microscopic analysis in blood samples of fluorescently labeled PBMA-MESBMA revealed the presence of the polymer inside P. yoelii yoelii-parasitized erythrocytes one hour after oral administration to infected animals.
由于抗疟药物耐药性疟原虫的进化，目前抗疟药物的疗效正在下降，这就需要新的策略来提高抗疟药物的生物利用度，特别是那些脂溶性差、在生物体液中溶解度低的药物。在这里，我们设计、合成并表征了两亲性两性离子嵌段共聚物，形成了能够穿透肠上皮的纳米颗粒，可用于口服给药。基于聚（甲基丙烯酸丁酯-co-吗啉乙基磺酸甜菜碱甲基丙烯酸酯）（PBMA-MESBMA）的纳米颗粒对感染疟原虫的红细胞（分别为 74.8%/0.8%）和未感染的红细胞（分别为 74.8%/0.8%）具有特异性靶向性，而当包裹脂溶性抗疟药物姜黄素后，这种靶向性仍然保持（分别为 82.6%/0.3%）。与游离化合物相比，姜黄素包封后的体外疗效得以维持，IC50 约为 5 μM。体内实验表明，与游离药物相比，口服给予 PBMA-MESBMA-姜黄素后，小鼠血液中的姜黄素浓度在一小时后显著增加（分别为 18.7 和 2.1 ng/ml）。然而，在较长时间内，游离药物和包封药物的血浆姜黄素浓度相等，这反映了在感染疟原虫的小鼠中，体内抗疟活性相似。在感染疟原虫的动物口服给药后一小时，对血液样本进行荧光标记的 PBMA-MESBMA 的显微镜分析显示，聚合物存在于 P. yoelii yoelii 寄生虫化的红细胞内。
