Title: Artesunate-heparin conjugate based nanocapsules with improved
pharmacokinetics to combat malaria
Authors: Muhammad Ismail, Yawei Du, Longbing Ling, Xinsong Li*
Journal: International Journal of Pharmaceutics
Accepted,2019
Abstract
10 Artesunate-heparin conjugate (ART-HEP) based nanocapsules as drug delivery vehicle was
developed for intracellular release of ART in malaria therapy. Owing both hydrophobic and
hydrophilic moieties, the conjugate was successfully self-assembled into artesunate-heparin
nanocapsules (ART-HEP-NCPs) with lower critical micelle concentration (CMC) of about 20
μg/mL. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) revealed
15 that ART-HEP-NCPs has an average hydrodynamic diameter of 112.1 nm with a negatively
charged surface (-11.2 mV) and typical micellar nanostructure, respectively. Interestingly, such
modification achieved high drug loading efficiency (DLE) of ART (29.3 wt.%), which is
significantly higher than already reported conventional ART-loaded nanoparticles. The
nanocapsules demonstrated lower in vitro ART release under neutral physiological environment
20 (33.81%) but higher release rate was observed in simulated acidic microenvironment (92.74%) in
70 h test. This behavior of ART-HEP-NCPs will facilitate the intracellular release of ART under
slightly acidic parasitic food vacuole for effective antimalarial effect. Storage stability and
hemolytic studies exhibited that ART-HEP based nanocapsules were stable and safe for
intravenous (i.v) injection. Notably, ART-HEP-NCPs has promising internalization into
25 Plasmodium infected red blood cells (iRBCs) and also displayed in vitro inhibitory effect against
P. falciparum 3D7 with half-maximal inhibitory concentration (IC50) of 10.16 nM, which was
slightly higher than free ART (IC50 6.27 nM). This expected slightly lower inhibitory effect of
polymeric prodrug could be ascribed to the gradual release of ART from the polymer chain over
time. More importantly, the in vivo pharmacokinetics study indicated that the nanoscale
30 characteristic of nanocapsules substantially contributed to the extended circulation of ART in
blood. In conclusion, such multifunctional ART-HEP-NCPs with higher ART loading and
extended half-life could be a promising platform for targeted antimalarial drug delivery.