Azacarbazole n-3 and n-6 polyunsaturated fatty acids ethyl esters nanoemulsion with enhanced efficacy against Plasmodium falciparum  

作　　者：Anna Jaromin Silvia Parapini Nicoletta Basilico Magdalena Zaremba-Czogalla Agnieszka Lewi´nska Agnieszka Zag´orska Maria Walczak Bozena Tyliszczak Aleksandra Grzeszczak MarcinŁukaszewicz Łukasz Kaczmarek Jerzy Gubernator 

机构地区：[1]Department of Lipids and Liposomes,Faculty of Biotechnology,University of Wroclaw,Wroclaw,Poland [2]Dipartimento di Scienze Biomediche per la Salute,Universit`a degli Studi di Milano,Milan,Italy [3]Dipartimento di Scienze Biomediche,Chirurgiche e Odontoiatriche,Universit`a degli Studi di Milano,Milan,Italy [4]Faculty of Chemistry,University of Wroclaw,Wroclaw,Poland [5]Department of Medicinal Chemistry,Jagiellonian University Medical College,Cracow,Poland [6]Chair and Department of Toxicology,Jagiellonian University Medical College,Faculty of Pharmacy,Cracow,Poland [7]Instytute of Materials Science,Cracow University of Technology,Cracow,Poland [8]Department of Biotransformation,Faculty of Biotechnology,University of Wroclaw,Wroclaw,Poland [9]Pharmaceutical Research Institute,Warsaw,Poland

出　　处：《Bioactive Materials》2021年第4期1163-1174,共12页生物活性材料（英文）

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”.

摘　　要：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.

关 键 词：Azacarbazoles Flax oil n-3 and n-6 polyunsaturated fatty acids ethyl ESTERS NANOEMULSION P.falciparum MALARIA 

分 类 号：R531.3[医药卫生—内科学] R318[医药卫生—临床医学]