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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 (DHA3) was synthesized and further prepared as self-assembled nanoparticles (DHA3NPs) by a one-step nanoprecipitation method. The pharmacokinetics and antimalarial pharmacodynamics of DHA3NPs were studied in rats and mice infected with Plasmodium yoelii BY265 (PyBY265). DHA3NPs 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 DHA3NPs 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 DHA3NPs 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 DHA3NPS (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, DHA3NPS reduced the recurrence ratio and improved the cure ratio and survival time. In summary, DHA3NPs exhibited promising pharmacokinetic characteristics and antimalarial pharmacodynamics in vivo. [ABSTRACT FROM AUTHOR]

The dihydroartemisinin-derived dimer (DHA dimer) was synthesized, and its antimalarial activities were evaluated both in vitro and in vivo. The dimer IC50 value of 0.51 ± 0.12 nM in vitro was significantly lower than that of DHA at 1.81 ± 0.70 nM. The dimer ED50 values were 0.44 ± 0.03 and 0.18 ± 0.03 mg/(kg·day) in vivo for intragastric (i.g.) and intravenous (i.v.) groups, respectively, to Plasmodium yoelii rodent malaria. It also performed better relative to those of DHA which had ED50 values of 0.76 ± 0.03 mg/(kg·day) (i.g.) and 0.32 ± 0.03 mg/(kg·day) (i.v.). Moreover, the recrudescence rate, negative conversion rate, and cure rate of the dimer showed superior performance. Furthermore, the metabolites and major metabolic pathways of the dimer in rats were preliminarily investigated using the HPLC-HRMSn method. Twenty-seven metabolites, including DHA, 11 metabolites of DHA, and 15 other novel metabolites, were detected in rats after i.g. administration of dimer. The metabolic pathways of the 15 novel metabolites were inferred: deoxygenation, hydroxylation, and hydroxylation with dehydration. [ABSTRACT FROM AUTHOR]