title: Artemisinin and artemisinin plus curcumin liposomal formulations: enhanced antimalarial efficacy against Plasmodium berghei-infected mice.
abstract: The therapeutic efficacies of novel liposomal delivery systems based on artemisinin or artemisinin-based combination therapy with curcumin have been investigated and reported in this study. The developed liposomal formulations had proper characteristics as drug carriers for parental administration in terms of particle size, polydispersity, encapsulation efficacy and ζ-potential. Their physical and chemical stabilities were also evaluated. Furthermore, the in vivo antimalarial activity of artemisinin-based liposomal formulations was tested in Plasmodium berghei NK-65 infected mice, a suitable model for studying malaria because the infection presents structural, physiological and life cycle analogies with the human disease. Artemisinin, alone or in combination with curcumin, was encapsulated in conventional and PEGylated liposomes and its in vivo performance was assessed by comparison with the free drug. Mice were treated with artemisinin at the dosage of 50 mg/kg/days alone or plus curcumin as partner drug, administered at the dosage of 100 mg/kg/days. Artemisinin alone began to decrease parasitaemia levels only 7 days after the start of the treatment and it appeared to have a fluctuant trend in blood concentration which is reflected in the antimalarial effectiveness. By contrast, treatments with artemisinin-loaded conventional liposomes (A-CL), artemisinin-curcumin-loaded conventional liposomes (AC-CL), artemisinin-loaded PEGylated liposomes (A-PL), artemisinin-curcumin-loaded PEGylated liposomes (AC-PL) appeared to have an immediate antimalarial effect. Both nanoencapsulated artemisinin and artemisinin plus curcumin formulations cured all malaria-infected mice within the same post-inoculation period of time. Additionally, all formulations showed less variability in artemisinin plasma concentrations which suggested that A-CL, AC-CL, A-PL and AC-PL give a modified release of drug(s) and, as a consequence, a constant antimalarial effect during time. In particular, A-PL seems to give the most pronounced and statistically significant therapeutic effect in this murine model of malaria. The enhanced permanency in blood of A-PL suggests the use of these nanosystems as suitable passive targeted carriers for parasitic infections; this strong effect of formulation is added up to the mechanism of action of artemisinin which acts in the erythrocyte cycle stage of human host as a blood schizonticide.
authors.affiliation: Department of Pharmaceutical Sciences, University of Florence, Sesto Fiorentino, Italy. benedetta.isacchi@unifi.it
authors.forename: Benedetta
authors.initials: B
authors.lastname: Isacchi
authors.forename: Maria Camilla
authors.initials: MC
authors.lastname: Bergonzi
authors.forename: Margherita
authors.initials: M
authors.lastname: Grazioso
authors.forename: Chiara
authors.initials: C
authors.lastname: Righeschi
authors.forename: Alessia
authors.initials: A
authors.lastname: Pietretti
authors.forename: Carlo
authors.initials: C
authors.lastname: Severini
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Bilia
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000737:chemistry; D037621:Artemisinins / Q000008:administration & dosage* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003474:Curcumin / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D004355:Drug Stability; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D010316:Particle Size; D010962:Plasmodium berghei / Q000187:drug effects*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004337:Drug Carriers; D008081:Liposomes; D011092:Polyethylene Glycols; C031327:artemisinin; D003474:Curcumin