十八胺修饰的双氢青蒿素前药自组装纳米粒的制备及其抗疟活性评价

Preparation and Antimalarial Activity of Octadecylamine-modified Dihydroartemisinin Prodrug Self-assembled Nanoparticles

通过纳米沉淀法制备1种以二硫代二丙酸为连接臂、十八胺为载体的双氢青蒿素(DHA)前药自组装纳米粒(C18-SS-DHANPs),并考察其体外的还原敏感释药行为及在约氏疟鼠体内的抗疟活性。结果显示,制备得到的C18-SS-DHA NPs呈类球形,粒度分布均匀,平均粒径、多分散系数(PDI)、ζ电位、包封率和载药量分别为(117.4±1.8)nm、0.20±0.02、(-23.9±1.1)mV、(97.37±0.09)%和(81.14±0.08)%。C18-SS-DHANPs在4℃贮存35d,粒径及PDI无明显变化。采用Peters 4天抑制试验考察制品的抗疟活性。结果显示,疟鼠尾静脉注射给药后,C18-SS-DHANPs的ED50值为(0.03±0.01)μmol/kg,明显低于DHA溶液[(1.05±0.30)μmol/kg]和实验室前期制备的以二硫代甘醇酸为连接臂、十二醇为载体的DHA前药自组装纳米粒[(0.37±0.08)μmol/kg](P<0.05),可为新型青蒿素类衍生物的抗疟应用提供试验依据。

Dihydroartemisinin(DHA) prodrug self-assembled nanoparticles(C18-SS-DHA NPs) were prepared with 3,3’-dithiodipropionic acid as linker and octadecylamine as carrier by nanoprecipitation. The reductionsensitive release behavior in vitro and antimalarial activity of the NPs in a rodent malaria model(Plasmodium yoelii) were evaluated. The results showed that the C18-SS-DHA NPs had a spherical shape and well-proportioned distribution in particle size. The particle size, polydispersion index(PDI), ζ potential, encapsulation efficiency and drug loading of C18-SS-DHA NPs were(117.4±1.8)nm, 0.20±0.02,(-23.9±1.1)m V,(97.37±0.09)% and(81.14±0.08)%, respectively. And the C18-SS-DHA NPs stored at 4 ℃ for 35 d were rather stable according to the determination results of particle size and PDI. The Peters’ four-day suppression test was carried out to evaluate the antimalarial activities of DHA solution, the previously studied nanoparticles with dithioglycollic acid as linker and dodecanol as carrier, and C18-SS-DHA NPs. The results showed that the ED50 values of the above preparations were(1.05±0.30),(0.37±0.08) and(0.03±0.01)μmol/kg, respectively. Obviously, there were significant differences between the C18-SS-DHA NPs and DHA solution or the previously studied nanoparticles(P<0.05). The results above might provide experimental basis for antimalarial application of novel derivatives of artemisinin.