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.

Automated summary

The newly synthesized drug DHA(3)NPs exhibited promising pharmacokinetic characteristics and antimalarial pharmacodynamics in vivo, demonstrating good therapeutic potential in the treatment of malaria.