1. Murine pharmacokinetics and antimalarial pharmacodynamics of dihydroartemisinin trimer self-assembled nanoparticles.
- Author
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Guo, Wenju, Li, Ning, Ren, Guolian, Wang, RongRong, Chai, Liqing, Li, Yujie, Wang, Xi, Yang, Qingshan, Wang, Ruili, Zhang, Guoshun, Yang, Liuqing, Yi, Bofang, and Zhang, Shuqiu
- Subjects
PHARMACODYNAMICS ,PHARMACOKINETICS ,PLASMODIUM yoelii ,NANOPARTICLES ,INTRAVENOUS therapy ,BIODEGRADABLE nanoparticles - Abstract
Currently, conjugation of artemisinin-derived dimers, trimers, and tetramers is a viable strategy for developing new effective antimalarial candidates. Furthermore, nanotechnology is an effective means to achieve intravenous administration of hydrophobic drugs. In this paper, an ester-linked dihydroartemisinin trimer (DHA
3 ) was synthesized and further prepared as self-assembled nanoparticles (DHA3 NPs) by a one-step nanoprecipitation method. The pharmacokinetics and antimalarial pharmacodynamics of DHA3 NPs were studied in rats and mice infected with Plasmodium yoelii BY265 (PyBY265). DHA3 NPs had a regular spherical shape with a uniform size distribution of 140.27 ± 3.59 nm, entrapment efficiency (EE) of 99.63 ± 0.17%, and drug loading efficiency (DL) of 79.62 ± 0.11%. The in vitro release characterization revealed that DHA3 NPs were easily hydrolysed into DHA in an esterase environment. The pharmacokinetics study demonstrated that the area under the concentration–time curve (AUC0-t ) of DHA in DHA3 NPs group was 2070.52 ± 578.76 h×ng×mL−1 , which was higher than that of DHA and artesunate (AS) control groups (AUC0-t values of 724.18 ± 94.32 and 448.40 ± 94.45 h×ng×mL−1 , respectively) (P < 0.05). The antimalarial pharmacodynamics in vivo suggested that DHA3 NPS (ED90 7.82 ± 1.16 μmol×(kg×day)−1 ) had a superior antimalarial effect compared with that of control groups (ED90 values of 14.68 ± 0.98 (DHA) and 14.34 ± 1.96 (AS) μmol×(kg×day)−1 ) (P < 0.05). In addition, DHA3 NPS reduced the recurrence ratio and improved the cure ratio and survival time. In summary, DHA3 NPs exhibited promising pharmacokinetic characteristics and antimalarial pharmacodynamics in vivo. [ABSTRACT FROM AUTHOR]- Published
- 2021
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