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

Abstract

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, 9 H -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, S mix (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 IC 50 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 (t max = 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.

The Development of the Innovative Synthesis Methodology of Albumin Nanoparticles Supported by Their Physicochemical, Cytotoxic and Hemolytic Evaluation

“…Thus, in order to gain further overview of possible cytotoxic effects of synthesized nanoparticles, an activity screen in normal human dermal fibroblasts representing healthy cells was performed. Fibroblasts cells are often selected as exemplary control lines to demonstrate safety for various types of formulations [ 50 , 51 , 52 ]. The impact of albumin particles (concentrations of 25, 50 and 100 µL/mL) on the viability of NHDF cells was measured with the MTT assay after incubation for 48 h. Results of the performed investigations are shown in Figure 10 .…”

Synthesis and Antiplasmodial Activity of Novel Bioinspired Imidazolidinedione Derivatives

“…Additionally, for each compound, the selectivity index (SI), namely the ratio between the IC 50 values on the human cells and that on the P. falciparum strains, was calculated and reported in Table 3 . For the cytotoxicity studies, we choose the HaCaT keratinocyte cell line, since skin cell lines are often used as a control human cell line for antimalarial agents [ 33 , 34 ]. The cytotoxicity test showed 50% inhibitory cellular cytotoxicity at a concentration range of 20,216.67 to 30,536.67 ng/mL, after 48 h. The calculated selectivity indexes for D10 were similar, in the range of 3.16–3.32 while, in the case of W2, they reached much higher values (4.02–8.34), which suggests they demonstrate significant selectivity towards W2, especially ( 5 ), in relation to the CQ-resistant strain.…”

Evaluation of the In Vitro Cytotoxic Activity of Caffeic Acid Derivatives and Liposomal Formulation against Pancreatic Cancer Cell Lines

“…Moreover, both compounds also showed specificity of action towards cancer cells, which was confirmed by their SI indexes. This desired cytotoxic effect, in addition to weaker activity towards normal healthy fibroblasts, which are widely used in the literature as a control cell line [ 83 , 84 ], suggests that CA derivatives could constitute very promising targets for PC treatment. What is worth emphasizing, the most active compound, namely 4-(2’, 3’, 4’-trihydroxyphenyl)-3 (E)-buten-2-one, numbered as compound ( 11 ), is a new compound described by us in patent application.…”