In Vitro Activity of Copper(II) Complexes, Loaded or Unloaded into a Nanostructured Lipid System, against Mycobacterium tuberculosis

Abstract

Tuberculosis (TB) is an infectious disease caused mainly by the bacillus Mycobacterium tuberculosis (Mtb), presenting 9.5 million new cases and 1.5 million deaths in 2014. The aim of this study was to evaluate a nanostructured lipid system (NLS) composed of 10% phase oil (cholesterol), 10% surfactant (soy phosphatidylcholine, sodium oleate), and Eumulgin® HRE 40 ([castor oil polyoxyl-40-hydrogenated] in a proportion of 3:6:8), and an 80% aqueous phase (phosphate buffer pH = 7.4) as a tactic to enhance the in vitro anti-Mtb activity of the copper(II) complexes [CuCl2(INH)2]·H2O (1), [Cu(NCS)2(INH)2]·5H2O (2) and [Cu(NCO)2(INH)2]·4H2O (3). The Cu(II) complex-loaded NLS displayed sizes ranging from 169.5 ± 0.7095 to 211.1 ± 0.8963 nm, polydispersity index (PDI) varying from 0.135 ± 0.0130 to 0.236 ± 0.00100, and zeta potential ranging from −0.00690 ± 0.0896 to −8.43 ± 1.63 mV. Rheological analysis showed that the formulations behave as non-Newtonian fluids of the pseudoplastic and viscoelastic type. Antimycobacterial activities of the free complexes and NLS-loaded complexes against Mtb H37Rv ATCC 27294 were evaluated by the REMA methodology, and the selectivity index (SI) was calculated using the cytotoxicity index (IC50) against Vero (ATCC® CCL-81), J774A.1 (ATCC® TIB-67), and MRC-5 (ATCC® CCL-171) cell lines. The data suggest that the incorporation of the complexes into NLS improved the inhibitory action against Mtb by 52-, 27-, and 4.7-fold and the SI values by 173-, 43-, and 7-fold for the compounds 1, 2 and 3, respectively. The incorporation of the complexes 1, 2 and 3 into the NLS also resulted in a significant decrease of toxicity towards an alternative model (Artemia salina L.). These findings suggest that the NLS may be considered as a platform for incorporation of metallic complexes aimed at the treatment of TB.

Nanostructured lipid carriers for incorporation of copper(II) complexes to be used against <em>Mycobacterium tuberculosis</em>

“…Silva et al15,17 performed cytotoxicity assays (IC 50 ) of complexes 1, 2, and 3 using Vero (ATCC ® CCL-81), J774A.1 (ATCC ® TIB-67), and MRC-5 (ATCC ® CCL-171) cell lines. No toxic effects of the complexes were identified.…”

“…Evaluation of the antimicrobial activity showed the activity and selectivity of the copper(II) complexes against bacteria, such as Staphylococcus aureus and Escherichia coli , were increased after the incorporation of the complexes into these systems, by analysis of cellular viability 15. Another study conducted by the same group showed that the copper(II) complexes loaded into nanostructured lipid systems also exhibited increased activity against M. tuberculosis 17. Therefore, research into nanostructured systems has intensified in order to improve the solubility of copper(II) complexes and achieve controlled release 18…”

Incorporation of Nonyl 3,4-Dihydroxybenzoate Into Nanostructured Lipid Systems: Effective Alternative for Maintaining Anti-Dermatophytic and Antibiofilm Activities and Reducing Toxicity at High Concentrations

“…The lower the PDI, the greater the uniformity of the particles (Goyal et al, 2012). For the zeta potential, the negative charge obtained comes from the components of the formulations, such as cholesterol, which in its structure has a free hydroxyl group [OH −] − and soy phosphatidylcholine, which has free ester groups [−OC = O −] − (Silva et al, 2016).…”

Copper Coordination Compounds as Biologically Active Agents

“…(Figure 34). The nano-sized drug delivery systems increased their antimycobacterial activity, decreased cytotoxicity against the Vero cell line, and consequently improved the selectivity index [122]. (Figure 34).…”

“…Fei et al [125] reported two copper (II) complexes, compounds 119 and 120, based on dehydroabietic acid (DHA), the main component of traditional Chinese medicine rosin (Figure 35 (Figure 34). The nano-sized drug delivery systems increased their antimycobacterial activity, decreased cytotoxicity against the Vero cell line, and consequently improved the selectivity index [122]. A recent study on the cyto-genotoxicity of Cu(II) compounds 116-118 with INH was conducted by Fregonezi et al and also concluding that the compounds show no cytotoxicity in therapeutic doses [123].…”