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

Int J Pharm. 2021 Nov 20;609:121138. doi: 10.1016/j.ijpharm.2021.121138. Epub 2021 Sep 27.

Abstract

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.

Keywords: Anti-malarial; Dimeric artesunate-choline conjugate; Hyaluronic acid; Nanocomplex.

MeSH terms

  • Antimalarials* / therapeutic use
  • Artesunate
  • Choline
  • Humans
  • Hyaluronic Acid / therapeutic use
  • Malaria, Falciparum* / drug therapy
  • Micelles

Substances

  • Antimalarials
  • Micelles
  • Artesunate
  • Hyaluronic Acid
  • Choline