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.
Simultaneous detection and quantification of antimalarial drugs is important for evaluating the spread of their resistance. On the base of the target-induced assembly of branched DNA nanostructure signal amplification and different electrochemical coding tags at distinct potentials, an aptasensing method for multiplexed and highly sensitive detection of piperaquine (PQ) and mefloquine (MQ) antimalarial drugs is established. The target drugs associate with and switch the conformation of the aptamers to release free ssDNA trigger sequences, which initiate the self-assembly of many methylene blue (MB)- and ferrocene (Fc)-labeled auxiliary signal sequences to form branched nano-assemblies on electrode. The electrode-captured MB and Fc tags thus yield highly magnified current reponses at well-resolved potentials for simultaneously monitoring PQ and MQ with respective detection limits as low as 0.061 ng mL −1 (i.e., 0.114 nM) and 0.17 ng mL −1 (i.e., 0.449 nM). Moreover, the simultaneous detection of PQ and MQ in diluted human serum samples has also been verified by the developed sensor, revealing its potential for multiplexed monitoring of different drugs in connection with the corresponding aptamers for various application purposes.
Kejie Wang,Bingye Shi,Yihui Chen,Chunyan Hou,Xie Li,Xiaoqiang Qiao,Tingting Wang
Quinine, chloroquine, and hydroxychloroquine are effective antimalarial drugs that have shown antiviral activity against SARS-CoV-2 in initial in vitro studies. However, their excessive use can lead to adverse effects in humans. Therefore, rapid and accurate analysis of these inhibitors in whole blood samples is crucial for public health, although this presents significant challenges. In this study, perfluorooctyl-functionalized halloysite nanotubes were synthesized and used as sorbents for dispersive solid-phase extraction. The developed sorbents interacted with inhibitors through various mechanisms, including hydrophobic interactions, electrostatic interactions, F–π interactions, and hydrogen bonding. Notably, their adsorption capacity was twice that of unmodified halloysite nanotubes. By combining the perfluorooctyl-functionalized halloysite nanotubes-based dispersive solid-phase extraction method with liquid chromatography-tandem mass spectrometry, an analytical method was developed to determine concentrations of the three inhibitors in whole blood samples. Under optimized conditions, the limits of detection ranged from 1.2 to 2.1 ng/mL. The recoveries achieved 91.9%–101.5% for intra-day and 92.8%–101.2% for inter-day. The inter- and intra-day relative standard deviations were in the range of 0.6%–3.8% and 2.3%–8.1%, respectively. This study introduces a novel approach for developing sorbents to target drugs and presents an innovative analytical method for therapeutic monitoring. These advancements will facilitate the evaluation of the pharmacokinetics of these inhibitors in patients and support ongoing clinical trials.
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