Avaliação do potencial de curcumina incorporada em nanopartículas de sílica mesoporosas dispersas em hidrogel termorresponsivo no tratamento da doença de Alzheimer
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Data
2021-11-25
Autores
Ribeiro, Tais de Cassia
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Universidade Estadual Paulista (Unesp)
Resumo
A doença de Alzheimer (DA) é uma doença altamente incidente na população mundial, acometendo cerca de 44 milhões de pessoas, levando ao comprometimento cognitivo e comportamental. Atualmente, pode-se empregar no tratamento fármacos que visam o controle dos sintomas, dentre eles os inibidores da enzima acetilcolinesterase, que apresentam efeitos adversos bem pronunciados, dentre eles náuseas, vômitos, diarreia e hepatotoxicidade. A curcumina (CUR) é um composto natural que tem apresentado ação farmacológica nas principais causas associadas a DA, diminuindo a neuroinflamação e formação de radicais livres no cérebro, além de inibir as placas beta-amilóides e hiperfosforilação da proteína tau. No entanto, seu uso é limitado devido à sua insolubilidade em meio aquoso, baixa biodisponibilidade e instabilidade em meio biológico. A fim de superar essas limitações, sua incorporação em nanopartículas de sílica mesoporosas (NSMs) demonstra ser uma opção muito interessante, visto que estes sistemas podem oferecer proteção contra a degradação, melhorando assim sua estabilidade, biodisponibilidade, potencializando sua ação e exercendo um controle de sua liberação. A via nasal é uma via alternativa que pode promover a rápida absorção do fármaco, além de direcioná-lo ao cérebro, pela via bulbo-olfativa, evitando assim a metabolização pre-sistêmica. Porém, essa via possui mecanismos de depuração mucociliar, os quais podem eliminar rapidamente a formulação da cavidade nasal. Tais inconvenientes podem ser contornados empregando hidrogéis termorresponsivos (HT), com propriedades mucoadesivas, que podem promover o contato prolongado entre o nanossistema e os sítios de absorção da cavidade nasal, retardando a depuração mucociliar. O objetivo deste trabalho foi a obtenção e caracterização das NSMs acrescidas de CUR (NSMs@CUR) para incorporação em HT baseados em poloxamer (P-407) e quitosana (QS) (HP-407/QS) objetivando a administração nasal, com potencial aplicação no tratamento da DA. A caracterização físico-química dos nanossistemas foi realizada pela determinação do índice de polidispersão, carga superficial, mobilidade eletroforética, microscopia eletrônica de transmissão (MET), espectroscopia vibracional de adsorção na região do infravermelho (FTIR), ressonância magnética nuclear de sólidos (RMN), adsorção-dessorção de nitrogênio e análise termogravimétrica. Os HT foram caracterizados por ensaios reológicos, análise do perfil de textura e mucoadesão in vitro. Os resultados evidenciaram que o método de síntese foi eficiente permitindo a obtenção de NSMs esféricas, uniformes, com distribuição de tamanho homogênea, apresentando um arranjo hexagonal de poros com 7,2 nm de diâmetro médio, área superficial em torno de 745 m2 g-1, grupos hidroxilas disponíveis na superfície e ausência de matéria orgânica nos poros. Foi possível incorporar quantidades significativas de CUR, com EE% que variou de 62 a 91%. A encapsulação da CUR foi confirmada através o espectro de FTIR e análise térmica. O HP-407/QS apresentaram boas propriedade mecânicas, elevada força mucoadesiva, foram considerados termorresponsivos e adequados para possibilitar administração nasal. O HP-407/QS+CUR, NSM@CUR e HP-407/QS+NSM@CUR apresentaram liberação de 79,94 ± 3,6, 20,39 ± 1,33 e 15,74 ± 5,07 respectivamente, atuando como um sistema de liberação prolongada. Além disso, a elevada permeação (17 a 56%) da CUR a partir dos sistemas desenvolvidos revelam seu potencial para administração na mucosa nasal. O ensaio in vivo mostrou que as NSM@CUR bem como o HP-407/QS+NSM@CUR foram capazes de reverter o déficit cognitivo em camundongos, apresentando potencial no tratamento da DA. A partir dos resultados obtidos pode-se concluir que as NSM@CUR bem como os HP-407/QS+NSM@CUR desenvolvidos demostram ser uma abordagem muito promissora e inovadora para o tratamento da DA.
Alzheimer’s disease (AD) is a worldwide incident disease, affecting around 44 million people, leading to cognitive and behavioral impairments. Currently, it is possible to use drugs able to control symptoms, among of them there are the acetylcholinesterase enzyme inhibitors, which present significant collateral damages, including nausea, vomits, diarrhoea, and hepatotoxicity. Curcumin (CUR) is a natural compound that has been presenting pharmacological action over the mainly causes associated to AD, diminishing brain neuroinflammation and free radical formation, as well as inhibiting the amyloid plaques and the tau protein hyperphosphorylation. However, it has limited use due its low water solubility, low bioavailability and biological medium instability. In order to overcome these limitations, its incorporation in mesoporous silica nanoparticles (MSNs) shows itself as a very interesting option, since these systems can offer protection from the degradation, improving its release. The nasal route is an alternative route able to promote the fast drug absorption, besides directing it to the brain by the olfactory bulb route, avoiding the presystemic metabolization. Even so, this rout has mucociliary depuration mechanisms, which can quickly eliminate the formulation from the nasal cavity. These hindrances can be overcome employing termoresponsive hydrogels (TH) with mucoadhesive properties that can promote the prolonged contact between the nanosystem and the absorption sites, delaying the mucociliary depuration. The aim of this study was the obtainment and characterization of the CUR-loaded MSNs (MSNs@CUR) for the incorporation in Poloxamer (P-407) and chitosan-based (CH) THs aiming the nasal administration with potential application in the treatment of AD. The physicochemical characterization of the nanosystems was performed by the determination of polydispersive index, zeta potential, mean hydrodynamic diameter, transmission electron microscopy (TEM), Fourier-transform infrared vibrational spectroscopy (FT-IR), solid-state nuclear magnetic resonance (ssNMR), nitrogen adsorption-dessorption isotherm and thermogravimetric assay. The THs were characterized by rheological assays, texture profile analysis, and in vivo mucoadhesion. The results evidenced that the synthesis method was efficient, allowing the obtainment of spherical uniform MSNs, having homogeneous size distribution, showing hexagonal arrangement of pores with 7.2 nm mean diameter, surface area around 745 m².g-1, hydroxyl groups available in the surface and absence of organic material in the pores. It was possible to incorporate significant quantities of CUR, with encapsulation efficiency (EE %) varying from 62 to 91%. The CUR encapsulation was confirmed by the FT-IR spectra, thermal analysis and the mean hydrodynamic diameter measurement. The formulation HP-407/CH shown good mechanical properties, high mucoadhesive strength, being considered thermoresponsive and adequate to enable the nasal administration. The formulations HP-407/CH+Cur, MSN@CUR and HP- 407/CH+MSN@CUR showed release of 79.94±3.6%, 20.39±1.33%, and 15.74±5.07% of CUR, respectively, acting as prolonged release systems. Additionally, the high CUR permeation (17 to 56%) from the developed systems reveals their potential for the nasal mucosa administration. The in vivo assay showed that the MSN@CUR, as well as the HP-407/CH+MSN@CUR were able to revert the cognitive deficit in mice, presenting potential activity in AD treatment. According to the obtained results, it is able to conclude that the developed MSN@CUR, as well as HP-407/CH+MSN@CUR showed themselves as a very promising and innovative approach for the AD treatment.
Alzheimer’s disease (AD) is a worldwide incident disease, affecting around 44 million people, leading to cognitive and behavioral impairments. Currently, it is possible to use drugs able to control symptoms, among of them there are the acetylcholinesterase enzyme inhibitors, which present significant collateral damages, including nausea, vomits, diarrhoea, and hepatotoxicity. Curcumin (CUR) is a natural compound that has been presenting pharmacological action over the mainly causes associated to AD, diminishing brain neuroinflammation and free radical formation, as well as inhibiting the amyloid plaques and the tau protein hyperphosphorylation. However, it has limited use due its low water solubility, low bioavailability and biological medium instability. In order to overcome these limitations, its incorporation in mesoporous silica nanoparticles (MSNs) shows itself as a very interesting option, since these systems can offer protection from the degradation, improving its release. The nasal route is an alternative route able to promote the fast drug absorption, besides directing it to the brain by the olfactory bulb route, avoiding the presystemic metabolization. Even so, this rout has mucociliary depuration mechanisms, which can quickly eliminate the formulation from the nasal cavity. These hindrances can be overcome employing termoresponsive hydrogels (TH) with mucoadhesive properties that can promote the prolonged contact between the nanosystem and the absorption sites, delaying the mucociliary depuration. The aim of this study was the obtainment and characterization of the CUR-loaded MSNs (MSNs@CUR) for the incorporation in Poloxamer (P-407) and chitosan-based (CH) THs aiming the nasal administration with potential application in the treatment of AD. The physicochemical characterization of the nanosystems was performed by the determination of polydispersive index, zeta potential, mean hydrodynamic diameter, transmission electron microscopy (TEM), Fourier-transform infrared vibrational spectroscopy (FT-IR), solid-state nuclear magnetic resonance (ssNMR), nitrogen adsorption-dessorption isotherm and thermogravimetric assay. The THs were characterized by rheological assays, texture profile analysis, and in vivo mucoadhesion. The results evidenced that the synthesis method was efficient, allowing the obtainment of spherical uniform MSNs, having homogeneous size distribution, showing hexagonal arrangement of pores with 7.2 nm mean diameter, surface area around 745 m².g-1, hydroxyl groups available in the surface and absence of organic material in the pores. It was possible to incorporate significant quantities of CUR, with encapsulation efficiency (EE %) varying from 62 to 91%. The CUR encapsulation was confirmed by the FT-IR spectra, thermal analysis and the mean hydrodynamic diameter measurement. The formulation HP-407/CH shown good mechanical properties, high mucoadhesive strength, being considered thermoresponsive and adequate to enable the nasal administration. The formulations HP-407/CH+Cur, MSN@CUR and HP- 407/CH+MSN@CUR showed release of 79.94±3.6%, 20.39±1.33%, and 15.74±5.07% of CUR, respectively, acting as prolonged release systems. Additionally, the high CUR permeation (17 to 56%) from the developed systems reveals their potential for the nasal mucosa administration. The in vivo assay showed that the MSN@CUR, as well as the HP-407/CH+MSN@CUR were able to revert the cognitive deficit in mice, presenting potential activity in AD treatment. According to the obtained results, it is able to conclude that the developed MSN@CUR, as well as HP-407/CH+MSN@CUR showed themselves as a very promising and innovative approach for the AD treatment.
Descrição
Palavras-chave
Alzheime, Curcumina, Nanopartículas de sílica mesoporosas, Hidrogel termorresponsivo, mesoporous silica nanoparticles, termoresponsive hydrogel