Nanomedicine as a therapeutic approach against severe malaria, a proof of concept
Résumé
In 2018, children aged under 5 years accounted for 61% of all malaria deaths. The treatment of severe malaria is a major challenge. The medical care of severe malaria requires parenteral administration of quinine or artemisinin (ART) derivatives. The use of ART is limited by its poor aqueous solubility, short half-life and high first-pass metabolism. However, nanomedicine has significantly optimized the therapeutic efficacy of many active ingredients: doxorubicine (Myocet®), mifamuride (Mepac®), cytarabine (DepoCyte®), verteporfin (Visudyne®) or paclitaxel (Abraxane®). In this context, we have formulated original nanoparticles prepared by nanoprecipitation of bioesterified cyclodextrins (gamma-CD substituted with C10 alkyl chains), yielding either nanospheres or nanoreservoirs. Both nanosystems could associate ART with a 95% drug recovery, corresponding to drug levels of 0.4 and 1.6 mg/mL for nanospheres and nanoreservoirs, respectively and exhibited sustained release profiles over 96 h (nanoreservoirs) and 240 h (nanospheres). AR-loaded nanoparticles inhibited the growth of cultured Plasmodium falciparum, both multiresistant K1 and susceptible 3D7 strains with IC50 values 2.8 and 7.0 ng/mL, close to those of a reference ART solution. The in vitro plasma protein adsorption and phagocytosis by macrophage cells triggered by CD-C10 particles significantly decreased when they were decorated with amphiphilic PEGylated molecules (PEG1500 stearate, DMPE-mPEG2000, polysorbate 80). The resulting nanosystems were non-hemolytic and showed stealth properties after intravenous injection in mice, the residence time of DMPE-mPEG2000-decorated nanospheres reaching 24 h. Significantly enhanced pharmacokinetic parameters were obtained in healthy rats using a single dose (1.5 mg/kg or 2 mg/kg) of intravenously injected ART-loaded nanoparticles. The geometric mean exposures in plasma (AUC0-t) exhibited 2.35 and 3.26-fold increases with ART-loaded nanoreservoirs and nanospheres, respectively. The plasma half-life increased 4.00 and 6.25-fold and the clearance decreased up to 2.5 and 4.72-fold. These systems thus provide significant advantages for the intravenous treatment of severe malaria. Further studies should aim at consolidating these results with in vivo efficacy studies.