Murine pharmacokinetics and antimalarial pharmacodynamics of dihydroartemisinin trimer self-assembled nanoparticles

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 (AUC_0-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 (AUC_0-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 DHA₃NP_S (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, DHA₃NP_S reduced the recurrence ratio and improved the cure ratio and survival time. In summary, DHA₃NPs exhibited promising pharmacokinetic characteristics and antimalarial pharmacodynamics in vivo.