title: Nanostructured lipid carriers for incorporation of copper(II) complexes to be used againstMycobacterium tuberculosis.
abstract: Tuberculosis (TB) is a disease caused byMycobacterium tuberculosis. Cessation of treatment before the recommended conclusion may lead to the emergence of multidrug-resistant strains. The aim of this study was to develop nanostructured lipid carriers (NLCs) for use in the treatment ofM. tuberculosis. The NLCs comprised the following lipid phase: 2.07% polyoxyethylene 40 stearate, 2.05% caprylic/capric triglyceride, and 0.88% polyoxyl 40 hydrogenated castor oil; the following aqueous phase: 3.50% poloxamer 407 (F1-F6), and 0.50% cetyltrimethylammonium bromide (F7-F12); and incorporated the copper(II) complexes [CuCl2(INH)2]·H2O (1), [Cu(NCS)2(INH)2]·5H2O (2), and [Cu(NCO)2(INH)2]·4H2O (3) to form compounds F11.1, F11.2, and F11.3, respectively. The mean diameter of F11, F11.1, F11.2, and F11.3 ranged from 111.27±21.86 to 134.25±22.72 nm, 90.27±12.97 to 116.46±9.17 nm, 112.4±10.22 to 149.3±15.82 nm, and 78.65±6.00 to 122.00±8.70 nm, respectively. The polydispersity index values for the NLCs ranged from 0.13±0.01 to 0.30±0.09. The NLCs showed significant changes in zeta potential, except for F11.2, with F11, F11.1, F11.2, and F11.3 ranging from 18.87±4.04 to 23.25±1.13 mV, 17.03±1.77 to 21.42±1.87 mV, 20.51±1.88 to 22.60±3.44 mV, and 17.80±1.96 to 25.25±7.78 mV, respectively. Atomic force microscopy confirmed the formation of nanoscale spherical particle dispersions by the NLCs. Differential scanning calorimetry determined the melting points of the constituents of the NLCs. The in vitro activity of copper(II) complex-loaded NLCs againstM. tuberculosisH37Rvshowed an improvement in the anti-TB activity of 55.4, 27.1, and 41.1 times the activity for complexes 1, 2, and 3, respectively. An in vivo acute toxicity study of complex-loaded NLCs demonstrated their reduced toxicity. The results suggest that NLCs may be a powerful tool to optimize the activity of copper(II) complexes againstM. tuberculosis.
authors.affiliation: Department of Drugs and Medicines, Faculdade de Ciências Farmacêuticas, UNESP - Univ Estadual Paulista, Campus Araraquara, Araraquara, SP, Brazil.
authors.forename: Mariana R
authors.initials: MR
authors.lastname: Sato
authors.affiliation: Department of Drugs and Medicines, Faculdade de Ciências Farmacêuticas, UNESP - Univ Estadual Paulista, Campus Araraquara, Araraquara, SP, Brazil.
authors.forename: João A
authors.initials: JA
authors.lastname: Oshiro Junior
authors.affiliation: Department of Drugs and Medicines, Faculdade de Ciências Farmacêuticas, UNESP - Univ Estadual Paulista, Campus Araraquara, Araraquara, SP, Brazil.
authors.forename: Rachel Ta
authors.initials: RT
authors.lastname: Machado
authors.affiliation: Department of Biological Sciences, Faculdade de Ciências Farmacêuticas, UNESP - Univ Estadual Paulista, Campus Araraquara, Araraquara, SP, Brazil.
authors.forename: Paula C
authors.initials: PC
authors.lastname: de Souza
authors.affiliation: Department of Biological Sciences, Faculdade de Ciências Farmacêuticas, UNESP - Univ Estadual Paulista, Campus Araraquara, Araraquara, SP, Brazil.
authors.forename: Débora L
authors.initials: DL
authors.lastname: Campos
authors.affiliation: Department of Biological Sciences, Faculdade de Ciências Farmacêuticas, UNESP - Univ Estadual Paulista, Campus Araraquara, Araraquara, SP, Brazil.
authors.forename: Fernando R
authors.initials: FR
authors.lastname: Pavan
authors.affiliation: Department of Drugs and Medicines, Faculdade de Ciências Farmacêuticas, UNESP - Univ Estadual Paulista, Campus Araraquara, Araraquara, SP, Brazil.
authors.forename: Patricia B
authors.initials: PB
authors.lastname: da Silva
authors.affiliation: Department of Drugs and Medicines, Faculdade de Ciências Farmacêuticas, UNESP - Univ Estadual Paulista, Campus Araraquara, Araraquara, SP, Brazil.
authors.forename: Marlus
authors.initials: M
authors.lastname: Chorilli
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology; D003300:Copper / Q000008:administration & dosage* / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D008055:Lipids / Q000737:chemistry*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D049329:Nanostructures / Q000737:chemistry*; D009942:Organometallic Compounds / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D004337:Drug Carriers; D008055:Lipids; D009942:Organometallic Compounds; D003300:Copper
keywords: M. tuberculosis; copper(II) complex; in vitro activity; in vivo acute toxicity assay; nanostructured lipid carriers; tuberculosis