Jaromin Anna, Parapini Silvia, Basilico Nicoletta, Zaremba-Czogalla Magdalena, Lewińska Agnieszka, Zagórska Agnieszka, Walczak Maria, Tyliszczak Bożena, Grzeszczak Aleksandra, Łukaszewicz Marcin, Kaczmarek Łukasz, Gubernator Jerzy
Department of Lipids and Liposomes, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland.
Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy.
Bioact Mater. 2020 Oct 24;6(4):1163-1174. doi: 10.1016/j.bioactmat.2020.10.004. eCollection 2021 Apr.
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 . The most active compound, 9-3-azacarbazole (), 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, S (Tween 80 and Transcutol HP) and water. This formulation was further analyzed using transmission electron microscopy, dynamic light scattering and and studies. It was shown that droplets of the -loaded nanosystem were spherical, with satisfactory stability, without cytotoxicity towards fibroblasts and intestinal cell lines at concentrations corresponding to twice the IC for . Moreover, the nanoemulsion with this type of oil phase was internalized by Caco-2 cells. Additionally, pharmacokinetics demonstrated rapid absorption of compound (t = 5.0 min) after intragastric administration of -encapsulated nanoemulsion at a dose of 0.02 mg/kg in mice, with penetration of compound to deep compartments. The -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 . Our findings support a role for novel o/w nanoemulsions as delivery vehicles for antimalarial drugs.
由于出现了耐药性，替代疗法对于疟疾治疗是必要的。然而，许多有前景的抗疟化合物水溶性差，且缺乏合适的给药系统，这严重限制了它们的活性。为了解决这个问题，我们合成了一系列氮杂咔唑，并评估了它们对恶性疟原虫D10（氯喹敏感）和W2（氯喹耐药）菌株的抗疟活性。最具活性的化合物9-3-氮杂咔唑（）被包裹在一种新型的水包油纳米乳剂中，该纳米乳剂由从亚麻油中获得的多不饱和脂肪酸n-3和n-6的乙酯作为油相、S（吐温80和二甲基亚砜）和水组成。使用透射电子显微镜、动态光散射以及和研究对该制剂进行了进一步分析。结果表明，负载的纳米系统的液滴呈球形，具有令人满意的稳定性，在相当于的IC两倍的浓度下对成纤维细胞和肠道细胞系无细胞毒性。此外，这种油相类型的纳米乳剂被Caco-2细胞内化。此外，药代动力学表明，在小鼠中以0.02 mg/kg的剂量胃内给予包裹的纳米乳剂后，化合物（t = 5.0分钟）迅速吸收，化合物渗透到深部隔室。与未包裹的相比，发现包裹的纳米乳剂分别对寄生虫的D10和W2菌株的抑制效果高2.8倍和4.2倍。我们的研究结果支持新型水包油纳米乳剂作为抗疟药物给药载体的作用。
