Dimeric artesunate-choline conjugate micelles coated with hyaluronic acid as a stable, safe and potent alternative anti-malarial injection of artesunate

• Published in: International journal of pharmaceutics 2021-11, Vol.609, p.121138-121138, Article 121138
• Main Authors: He, Wei, Du, Yawei, Li, Chuncao, Wang, Ji, Wang, Yang, Dogovski, Con, Hu, Rui, Tao, Zhiyong, Yao, Chen, Li, Xinsong
• Format: Article
• Language: English
• Subjects: Anti-malarial; Dimeric artesunate-choline conjugate; Hyaluronic acid; Nanocomplex
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2021.121138

Novel dimeric artesunate-choline conjugate (dACC) is synthesized, and its self-assembly could be neutralized by hyaluronic acid (dACC/HA nanocomplex), which is potent and safe compared with traditional artemisinins for malaria treatment. [Display omitted] Artesunate (ARS) is the only artemisinin-based intravenous drug approved for treatment of malaria in the clinic. ARS is rapidly metabolized in vivo to short lived (∼30–45 min) but fast acting, dihydroartemisinin (DHA). The short half-life of DHA necessitates multiple dose administration to circumvent the risk of recrudescence and development of artemisinin resistance. In this work, we report a stable, safe and potent alternative artemisinin-based injectable nanocomplex consisting of dimeric artesunate-choline conjugate (dACC) micelles coated with hyaluronic acid (HA). Firstly, dACC was synthesized by one-step esterification of two artesunate molecules with 3-(dimethylamino)-1,2-propanediol followed by quaternization. After that, dACC was self-assembled into cationic nanomicelles and further coated with anionic small molecular weight HA. The HA-coated dACC nanocomplex (dACC/HA nanocomplex) has a narrow size distribution of about 30 nm. Hemolytic toxicity and cytotoxicity studies revealed a favorable bio-safety profile. Finally, in vitro and in vivo studies showed the dACC/HA nanocomplex possess superior safety and antimalarial efficacy compared to ARS. Taken together, the dACC/HA nanocomplex is a promising injectable alternative to the traditional clinically used artesunate.