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 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 DHA 3 NP S (ED 90 7.82 ± 1.16 μmol×(kg×day) −1 ) had a superior antimalarial effect compared with that of control groups (ED 90 values of 14.68 ± 0.98 (DHA) and 14.34 ± 1.96 (AS) μmol×(kg×day) −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.
Artemisinin and its derivates (ARTs) exert antimalarial effect by virtue of unique endoperoxide bridge, which is generally considered to generate oxygen free radicals and then form carbon-centered free radicals to damage parasites. The known high level of glutathione (GSH) in parasites plays a key role in maintaining redox balance to protect parasites from oxidative stress damage, which may be a risk factor for the failure of ARTs-based combination therapy and drug resistance. Nevertheless, the highly reducing environment in cytoplasm of malaria parasites provides an available trigger for intracellular nanoparticle disassembly to responsively release drug. In this study, a reduction-responsive releasing dihydroartemisinin (DHA) prodrug (C 14 -SS-DHA) was synthesized by conjugating DHA and tetradecylamine (C 14 –NH 2 ) with disulfide bond (–SS–) as a linker. As a control, a DHA carbon-carbon bond (–CC–) prodrug (C 14 -CC-DHA) was synthesized using succinic anhydride as a –CC– linker. To note, DHA prodrugs were prepared as self-assembled nanoparticles (C 14 -SS-DHA NPs and C 14 -CC-DHA NPs). The size and zeta potential of C 14 -SS-DHA NPs were 121 ± 1.582 nm and −29 ± 0.635 mV, and those of C 14 -CC-DHA NPs were 137.5 ± 0.5132 nm and −41 ± 0.377 mV, respectively. The C 14 -SS-DHA NPs can release DHA in a reductive media in vitro . The pharmacokinetics study showed that the area under the curve ( AUC (0-t) ) of plasma concentration versus time of DHA from C 14 -SS-DHA NPs was 20737.2 ± 6028.3 h μg L −1 , which was much higher than that of C 14 -CC-DHA NPs (6254.5 ± 2578.8) or DHA solution (857.6 ± 103.7 h μg L −1 ). The pharmacodynamics study presented that the ED 90 of C 14 -SS-DHA NPs was 3.81 ± 0.35 μmol/kg, which was lower than that of C 14 -CC-DHA NPs (12.70 ± 1.63 μmol/kg)) or DHA solution (17.67 ± 3.38 μmol/kg). C 14 -SS-DHA NPs showed significantly higher systemic exposure and better antimalarial activity in comparison with C 14 -CC-DHA NPs or DHA solution ( P < 0.05).
危险品化学品经营许可证（带存储）