Estudo de caracterização do complexo tris-(1,10-fenantrolina)ferro(II) incorporado ao sistema lípidico nanoestruturado e sua atividade anti-Mycobacterium tuberculosis
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Data
2021-10-25
Autores
Machado, Rachel Temperani Amaral
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Universidade Estadual Paulista (Unesp)
Resumo
A tuberculose (TB), apresenta cerca de 10 milhões de casos por ano em todo o mundo. Além disso, as elevadas taxas de resistência às principais classes de antimicrobianos contribuem para que a TB se encontre entre os maiores causadores de morte por um agente infeccioso. Sendo assim, faz-se evidente a necessidade de controle e combate dessa doença que representa uma séria ameaça à saúde pública global. Para tanto, é preciso enfrentar o desafio do desenvolvimento de novos agentes ativos contra a TB. Nesse trabalho, o complexo metálico tris-(1,10-fenantrolina)ferro(II) ([Fe(fen)3]2+), foi selecionado para o estudo, visto que trabalhos anteriores do nosso grupo demonstraram que este complexo é um bom candidato contra TB. Além disso, quando incorporado a um sistema lipídico nanoestruturado (SLN) demonstrou boa biodisponibilidade oral. Diante desses fatos, o objetivo deste trabalho foi caracterizar o complexo incorporado ao SLN e verificar sua atividade anti-Mycobacterium. tuberculosis. A frequência de resistência do Mycobacterium tuberculosis a [Fe(fen)3]2+ é menor do que a de outros fármacos de primeira linha para o tratamento da tuberculose, como a rifampicina. Ele se mostrou específico na inibição de micobactérias. Foi possível obter sistemas lipídicos nanoestruturados constituídos de colesterol como fase oleosa, fosfatidilcolina de soja, oleato de sódio e Eumulgin® HRE 40 [óleo de rícino de polioxil 40 hidrogenado]; na proporção de 3: 6: 8, como tensoativo e tampão-fosfato pH 7,4 como fase aquosa (SLN) e incorporar com sucesso o complexo [Fe(fen)3]2+ ao mesmo (SLN+([Fe(fen)3]2+)). A formulação de SLN+[Fe(fen)3]2+ revelou-se estável por até 90 dias a 5ºC e também se apresentam estáveis após 24h em soluções de pHs que remetem os encontrados no estômago e no sangue, e em contato com meios de cultura utilizados em outras metodologias in vitro, comprovando a integridade das partículas durante estes ensaios. O SLN mostrou uma taxa de eficiência de encapsulamento próxima a 60% de [Fe(fen)3]2+. Partículas de SLN+[Fe(fen)3]2+ mostraram-se homogêneas (PdI = 0,17), apresentando carga superficial negativa de -34,7mV e tamanho médio de 163nm, definido pela técnica de espalhamento dinâmico de luz (DLS) e confirmado por microscopia eletrônica de transmissão (TEM), que também revelou sua morfologia esférica. [Fe(fen)3]2+ apresentou um valor de CIM90 de 4,17 µM na sua forma livre e 23,39 µM quando incorporado no SLN. Estudos futuros devem analisar o perfil de liberação in vitro, a atividade in vivo e segurança do SLN+[Fe(fen)3]2+ para entender se esta combinação tem potencial para prosseguir como candidato a contra a tuberculose.
Tuberculosis (TB) presents about 10 million cases per year worldwide. In addition, the high rates of resistance to the main classes of antimicrobials contribute to TB being among the biggest killers of an infectious agent. Thus, the need to control and combat this disease, which represents a serious threat to global public health, is evident. Therefore, it is necessary to face the challenge of developing new agents active against TB. In this work, the metallic complex tris-(1,10-phenanthroline)iron(II) ([Fe(phen)3]2+) was selected for the study, as previous works by our group demonstrated that this complex is a good candidate against TB. Furthermore, when loaded into a nanostructured lipid system (NLS) it demonstrated good oral bioavailability. Given these facts, the objective of this work was to characterize the complex incorporated into NLS and verify its anti-Mycobacterium tuberculosis activity. The frequency of resistance of Mycobacterium tuberculosis to [Fe(phen)3]2+ is lower than that of other first-line drugs for the treatment of tuberculosis, such as rifampicin. It has been shown to be specific in inhibiting mycobacteria. It was possible to obtain NLS consisting of cholesterol as the oil phase, soy phosphatidylcholine, sodium oleate and Eumulgin® HRE 40 [polyoxyl 40 hydrogenated castor oil]; in a ratio of 3: 6: 8, as surfactant and phosphate-buffer pH 7.4 as aqueous phase, and successfully load the complex [Fe(phen)3]2+ to it (NLS+[Fe(phen)3]2+). The NLS+[Fe(phen)3]2+ formulation proved to be stable for up to 90 days at 5°C and are also stable after 24 hours in solutions with pHs that match those found in the stomach and blood, and in contact with means of culture used in other in vitro methodologies, proving the integrity of the particles during these assays. NLS showed a entrapment efficiency rate close to 60% of [Fe(phen)3]2+. NLS+[Fe(phen)3]2+ particles were homogeneous (PdI = 0.17), with a negative surface charge of -34.7mV and average size of 163nm, defined by the dynamic light scattering (DLS) technique and confirmed by transmission electron microscopy (TEM), which also revealed its spherical morphology. [Fe(phen)3]2+ had a MIC90 value of 4.17 µM in its free form and 23.39 µM when incorporated into NLS. Future studies must analyze the in vitro release profile, and the in vivo activity and safety of NLS+[Fe(phen)3]2+ in order to fully understand whether this combination of the [Fe(phen)3]2+ and the NLS has the potential to proceed as a drug candidate against TB.
Tuberculosis (TB) presents about 10 million cases per year worldwide. In addition, the high rates of resistance to the main classes of antimicrobials contribute to TB being among the biggest killers of an infectious agent. Thus, the need to control and combat this disease, which represents a serious threat to global public health, is evident. Therefore, it is necessary to face the challenge of developing new agents active against TB. In this work, the metallic complex tris-(1,10-phenanthroline)iron(II) ([Fe(phen)3]2+) was selected for the study, as previous works by our group demonstrated that this complex is a good candidate against TB. Furthermore, when loaded into a nanostructured lipid system (NLS) it demonstrated good oral bioavailability. Given these facts, the objective of this work was to characterize the complex incorporated into NLS and verify its anti-Mycobacterium tuberculosis activity. The frequency of resistance of Mycobacterium tuberculosis to [Fe(phen)3]2+ is lower than that of other first-line drugs for the treatment of tuberculosis, such as rifampicin. It has been shown to be specific in inhibiting mycobacteria. It was possible to obtain NLS consisting of cholesterol as the oil phase, soy phosphatidylcholine, sodium oleate and Eumulgin® HRE 40 [polyoxyl 40 hydrogenated castor oil]; in a ratio of 3: 6: 8, as surfactant and phosphate-buffer pH 7.4 as aqueous phase, and successfully load the complex [Fe(phen)3]2+ to it (NLS+[Fe(phen)3]2+). The NLS+[Fe(phen)3]2+ formulation proved to be stable for up to 90 days at 5°C and are also stable after 24 hours in solutions with pHs that match those found in the stomach and blood, and in contact with means of culture used in other in vitro methodologies, proving the integrity of the particles during these assays. NLS showed a entrapment efficiency rate close to 60% of [Fe(phen)3]2+. NLS+[Fe(phen)3]2+ particles were homogeneous (PdI = 0.17), with a negative surface charge of -34.7mV and average size of 163nm, defined by the dynamic light scattering (DLS) technique and confirmed by transmission electron microscopy (TEM), which also revealed its spherical morphology. [Fe(phen)3]2+ had a MIC90 value of 4.17 µM in its free form and 23.39 µM when incorporated into NLS. Future studies must analyze the in vitro release profile, and the in vivo activity and safety of NLS+[Fe(phen)3]2+ in order to fully understand whether this combination of the [Fe(phen)3]2+ and the NLS has the potential to proceed as a drug candidate against TB.
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Palavras-chave
Mycobacterium tuberculosis, fenantrolina, tris1,10-fenantrolina-ferro(II), sistema lipídico nanoestruturado, novos antibióticos