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-DHA NPs)，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-DHA NPs 在4 ℃贮存35 d，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-DHA NPs 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。
Abstract
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)mV, (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.
关键词
双氢青蒿素 /
前药 /
自组装纳米粒 /
抗疟活性
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Key words
dihydroartemisinin /
prodrug /
self-assembled nanoparticle /
antimalarial activity
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参考文献
[1] 付岩松, 李春宇, 钟 越, 等．双氢青蒿素的研究进展[J]．吉林医药学院学报, 2018, 39(4): 292-294．
[2] 陈 佩, 任国莲, 郭文菊, 等．还原响应的双氢青蒿素前药自组装纳米粒的制备与药动学评价[J]．中国药学杂志,2018, 53(17): 1477-1484．
[3] 杨培慧, 陈晓翔, 周志军．青蒿素与还原型谷胱甘肽相互作用的研究[J]．药物分析杂志, 2005, 25(11): 1353-1356．
[4] NAJER A, WU D, NUSSBAUMER M G, et al．An amphiphilic graft copolymer-based nanoparticle platform for reduction-responsive anticancer and antimalarial drug delivery [J]．Nanoscale, 2016, 8(31): 14858-14869．
[5] REN G, CHEN P, TANG J, et al．Construction and cellular uptake evaluation of redox-responsive docetaxel prodrug
self-assembled nanoparticles [J]．Drug Dev Ind Pharm,2018, 44(4): 598-607．
[6] BATTY K T, DAVIS T M, THU L T, et al．Selective highperformance liquid chromatographic determination of artesunate and alpha- and beta-dihydroartemisinin in patients with falciparum malaria [J]．J Chromatogr B Biomed Appl,1996, 677(2): 345-350．
[7] ASHTON M, GORDI T, TRINH N H, et al．Artemisinin pharmacokinetics in healthy adults after 250, 500 and 1 000 mg
single oral doses [J]．Biopharm Drug Dispos, 1998, 19(4):245-250．
[8] 吴 婧, 王锐利, 申薇薇, 等．高效液相-柱后衍生化法同时测定双氢青蒿素和哌喹[J]．中国药物与临床, 2009, 9(3):178-181．
[9] 王永利, 王立华, 夏明华, 等．低速离心法测定大黄酮脂质体包封率[J]．河北北方学院学报: 自然科学版, 2012,28(6): 30-32．
[10] 祝凡平．双氢青蒿素的体外稳定性及其时间依赖性药动学研究[D]．济南: 山东大学硕士学位论文, 2014．
[11] PETERS W, ROBINSON B L．The chemotherapy of rodent malaria．XLVII．Studies on pyronaridine and other Mannich base antimalarials [J]．Ann Trop Med Parasitol,1992, 86(5): 455-465．
[12] PETERS W．The chemotherapy of rodent malaria, XXII．The value of drug-resistant strains of P．berghei in screening
for blood schizontocidal activity [J]．Ann Trop Med Parasitol, 1975, 69(2): 155-171．
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脚注
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基金
国家自然科学基金面上项目——基于代谢机制靶向红细胞内疟原虫的青蒿素类药物纳米递药系统研究(81373364)、山西省应用基础研究计划项目——基于Tf修饰的肿瘤靶向及响应释放的青蒿素前药自组装纳米传递系统的研究(201701D221162)、山西省高等学校科技创新项目——肿瘤靶向与刺激响应释放的青蒿素前药固体脂质纳米递药系统的研究(201701D31111210)
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