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 (DHA(3)) was synthesized and further prepared as self-assembled nanoparticles (DHA(3)NPs) by a one-step nanoprecipitation method. The pharmacokinetics and antimalarial pharmacodynamics of DHA(3)NPs were studied in rats and mice infected with Plasmodium yoelii BY265 (PyBY265). DHA(3)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 DHA(3)NPs 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 DHA(3)NPs group was 2070.52 +/- 578.76 hxngxmL(-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 hxngxmL(-1), respectively) (P < 0.05). The antimalarial pharmacodynamics in vivo suggested that DHA(3)NP(S) (ED90 7.82 +/- 1.16 mu molx(kgxday)(-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) mu molx(kgxday)(-1)) (P < 0.05). In addition, DHA(3)NP(S) reduced the recurrence ratio and improved the cure ratio and survival time. In summary, DHA(3)NPs exhibited promising pharmacokinetic characteristics and antimalarial pharmacodynamics in vivo.