Alternative therapies are necessary for the treatment of malaria due to emerging drug resistance.However,many promising antimalarial compounds have poor water solubility and suffer from the lack of suitable delivery s...Alternative therapies are necessary for the treatment of malaria due to emerging drug resistance.However,many promising antimalarial compounds have poor water solubility and suffer from the lack of suitable delivery systems,which seriously limits their activity.To address this problem,we synthesized a series of azacarbazoles that were evaluated for antimalarial activity against D10(chloroquine-sensitive)and W2(chloroquine-resistant)strains of P.falciparum.The most active compound,9H-3-azacarbazole(3),was encapsulated in a novel o/w nanoemulsion consisting of ethyl esters of polyunsaturated fatty acids n-3 and n-6 obtained from flax oil as the oil phase,Smix(Tween 80 and Transcutol HP)and water.This formulation was further analyzed using transmission electron microscopy,dynamic light scattering and in vitro and in vivo studies.It was shown that droplets of the 3-loaded nanosystem were spherical,with satisfactory stability,without cytotoxicity towards fibroblasts and intestinal cell lines at concentrations corresponding to twice the IC50 for P.falciparum.Moreover,the nanoemulsion with this type of oil phase was internalized by Caco-2 cells.Additionally,pharmacokinetics demonstrated rapid absorption of compound 3(tmax=5.0 min)after intragastric administration of 3-encapsulated nanoemulsion at a dose of 0.02 mg/kg in mice,with penetration of compound 3 to deep compartments.The 3-encapsulated nanoemulsion was found to be 2.8 and 4.2 times more effective in inhibiting the D10 and W2 strains of the parasite,respectively,compared to non-encapsulated 3.Our findings support a role for novel o/w nanoemulsions as delivery vehicles for antimalarial drugs.展开更多
基金the statutory activity of subsidy from the Polish Ministry of Science and Higher Education for the Faculty of Biotechnology and Faculty of Chemistry of the University of Wroclaw and by Ministero dell’Istruzione,dell’Universit`a e della Ricerca[PRIN 2015.4JRJPP_004].Publication costs were supported by Wroclaw Center of Biotechnology program“The Leading National Research Center(KNOW)for years 2014-2018”.
文摘Alternative therapies are necessary for the treatment of malaria due to emerging drug resistance.However,many promising antimalarial compounds have poor water solubility and suffer from the lack of suitable delivery systems,which seriously limits their activity.To address this problem,we synthesized a series of azacarbazoles that were evaluated for antimalarial activity against D10(chloroquine-sensitive)and W2(chloroquine-resistant)strains of P.falciparum.The most active compound,9H-3-azacarbazole(3),was encapsulated in a novel o/w nanoemulsion consisting of ethyl esters of polyunsaturated fatty acids n-3 and n-6 obtained from flax oil as the oil phase,Smix(Tween 80 and Transcutol HP)and water.This formulation was further analyzed using transmission electron microscopy,dynamic light scattering and in vitro and in vivo studies.It was shown that droplets of the 3-loaded nanosystem were spherical,with satisfactory stability,without cytotoxicity towards fibroblasts and intestinal cell lines at concentrations corresponding to twice the IC50 for P.falciparum.Moreover,the nanoemulsion with this type of oil phase was internalized by Caco-2 cells.Additionally,pharmacokinetics demonstrated rapid absorption of compound 3(tmax=5.0 min)after intragastric administration of 3-encapsulated nanoemulsion at a dose of 0.02 mg/kg in mice,with penetration of compound 3 to deep compartments.The 3-encapsulated nanoemulsion was found to be 2.8 and 4.2 times more effective in inhibiting the D10 and W2 strains of the parasite,respectively,compared to non-encapsulated 3.Our findings support a role for novel o/w nanoemulsions as delivery vehicles for antimalarial drugs.
