Estudo da biodistribuição e determinação da eliminação de nanopartículas magnéticas em tempos longos por biosusceptometria de corrente alternada
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Data
2020-02-19
Autores
Faria, João Victor Carneiro
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Universidade Estadual Paulista (Unesp)
Resumo
Nanopartículas magnéticas (NPMs) têm sido alvo de vários estudos por conta de sua versatilidade, que se destaca quando comparadas a outros materiais. NPMs apresentam tamanho reduzido, alta susceptibilidade magnética e devido a possibilidade de alteração química de revestimento, apresentam um alto poder teranóstico. Entretanto, antes de aplicá-los clinicamente é de extrema importância conhecer seus destinos e possibilidades de interação no organismo. A quantificação da biodistribuição de NPMs por meio de suas características intrínsecas ainda se mostra como um desafio. A Biosusceptometria de corrente alternada (BAC) é uma técnica biomagnética que atua detectando a quantidade de materiais magnéticos em ambientes biológicos. Essa técnica, em relação às demais presentes no mercado, apresenta baixo custo e portabilidade. Baseado na problemática em torno da detecção e quantificação de NPMs, nesse estudo foi analisada a biodistribuição e eliminação de NPMs de ferrita de manganês revestidas com citrato e albumina via sistema BAC. Para isso, foram utilizados 100 ratos Wistar, separados em 2 grupos experimentais (NPMs revestidas com albumina e citrato) e 10 subgrupos, variando o tempo de eutanásia dos animais (1, 4, 12, 24 e 48 horas e 5, 10, 15, 30 e 60 dias após a administração). Para análise da biodistribuição, foram coletados 5 órgãos de interesse: fígado, pulmão, baço, rins e coração, além do sangue e, para análise da eliminação, foram coletadas as fezes dos animais. Foi possível observar a maior captação pelo baço e fígado (1 hora após a administração, o fígado apresentou uma concentração de 0,782 ± 0,08 miligramas de NPMs por grama de tecido seco (mg/g) o baço 0,643 ± 0,06 mg/g de NPMs revestidas com citrato. Para NPMs revestidas com albumina, no fígado foi detectado uma concentração de 1,049 ± 0,05 mg/g de NPMs e, para o baço, 0,723 ± 0,06 mg/g de NPMs). Apesar da alta captação do baço, a partir de 30 dias não foi possível detectar NPMs revestidas com citrato nesse órgão. Em 60 dias foi comprovada a ausência de NPMs de ambos os revestimentos no baço e um decaimento significativo no fígado (0,01 ± 0,009 mg/g de NPMs para NPMs revestidas com citrato e 0,03 ± 0,01 mg/g de NPMs para NPMs revestidas com albumina) demostrando a existência de um mecanismo endógeno de metabolização e/ou agregação das NPMs. Através de um modelo farmacocinético, foi possível determinar o tempo de meia vida de distribuição e eliminação para fígado e baço, obtendo valores no fígado para NPMs revestidas com citrato de 1,95 minutos e 12,8 dias para distribuição e eliminação, respectivamente, e 1,85 minutos e 2,4 dias para NPMs revestidas com albumina. Já para o baço, para NPMs revestidas com citrato o tempo médio de distribuição foi de 36,4 minutos e de eliminação 1,4 dias, e para NPMs revestidas com albumina, 2 minutos e 2,6 dias respectivamente. Além da biodistribuição, foi possível determinar a eliminação de NPMs via fezes. O sistema BAC se mostrou eficiente para detecção de NPMs e estudos futuros serão realizados para melhor compreensão dos mecanismos de eliminação e/ou metabolização dessas partículas.
Magnetic nanoparticles (MNPs) have been widely used in several studies due to their high versatility compared to other materials. MNPs presents small size, high magnetic susceptibility and, due to the possibility of biochemical alteration of its surface, enables a high level of theranostics applications. However, before applying them clinically, it is of paramount importance understand its destinations and possibilities of interaction in the organism. The biodistribution quantification of NPMs through their intrinsic characteristics still is a challenge. Alternating current biosusceptometry (ACB) is a biomagnetic technique that acts detecting a quantity of magnetic materials in biological samples. In comparison with the other techniques, ACB presents low cost and portability. Based on the lack of accessible techniques to study biodistribution and elimination process of MNPs, this work aimed to analyze the biodistribution and determine the elimination of manganese ferrite magnetic nanoparticles coated with citrate and albumin via BAC system. For this work, we used 100 Wistar rats, separated into 2 experimental groups (MNPs coated with albumin and citrate) and 10 subgroups, changing the euthanasia time point (1, 4, 12, 24 and 48 hours and 5, 10, 15, 30 and 60 days after administration). For biodistribution analysis, we collected the blood and 5 organs of interest: liver, lung, spleen, kidneys and heart, and, for elimination analysis, we collected the animal’s feces. It was possible observe a higher uptake by the liver and the spleen due to their characteristics of retention and uptake (1 hour after administration, the liver showed a concentration of 0.782 ± 0.08 mg/g of citrate-coated MNPs e and the spleen 0.643 ± 0.06 mg/g of MNPs. For MNPs albumin-coated, in liver, we found a concentration of 1.049 ± 0.05 mg/g of MNPs was detected and, for the spleen, 0.723 ± 0.06 mg/g of MNPs). Despite the high uptake of the spleen, after 30 days it was not possible to detect NPMs coated with citrate in this organ. In 60 days, the absence of NPMs, from both coatings, in the spleen and a significant decay in the liver was shown (0.01 ± 0.009 mg/g of MNPs for citrate-coated MNPs and 0.03 ± 0.01 mg/g of MNPs for albumin-coated MNPs), demonstrating the presence of an endogenous mechanism of metabolism or aggregation of MNPs. Through a pharmacokinetic model, it was possible to determine the half-life of absorption and distribution for the liver and the spleen obtaining values in the liver for citrate-coated NPMs of 1.95 minutes and 12.8 days for absorption and elimination, respectively, and 1.85 minutes and 2.4 days for MNPs albumin-coated. For the spleen, citrate-coated MNPs showed an average time of absorption was 36.4 minutes and elimination 1.4 days, and for albumin-coated MNPs, 2 minutes and 2.6 days respectively. In addition to biodistribution, it was possible to determine the elimination of MNPs through feces. The ACB was efficient for the detection of MNPs and future studies will be carried out to better understand the mechanisms of removal or metabolizing of these particles inside the animal’s body
Magnetic nanoparticles (MNPs) have been widely used in several studies due to their high versatility compared to other materials. MNPs presents small size, high magnetic susceptibility and, due to the possibility of biochemical alteration of its surface, enables a high level of theranostics applications. However, before applying them clinically, it is of paramount importance understand its destinations and possibilities of interaction in the organism. The biodistribution quantification of NPMs through their intrinsic characteristics still is a challenge. Alternating current biosusceptometry (ACB) is a biomagnetic technique that acts detecting a quantity of magnetic materials in biological samples. In comparison with the other techniques, ACB presents low cost and portability. Based on the lack of accessible techniques to study biodistribution and elimination process of MNPs, this work aimed to analyze the biodistribution and determine the elimination of manganese ferrite magnetic nanoparticles coated with citrate and albumin via BAC system. For this work, we used 100 Wistar rats, separated into 2 experimental groups (MNPs coated with albumin and citrate) and 10 subgroups, changing the euthanasia time point (1, 4, 12, 24 and 48 hours and 5, 10, 15, 30 and 60 days after administration). For biodistribution analysis, we collected the blood and 5 organs of interest: liver, lung, spleen, kidneys and heart, and, for elimination analysis, we collected the animal’s feces. It was possible observe a higher uptake by the liver and the spleen due to their characteristics of retention and uptake (1 hour after administration, the liver showed a concentration of 0.782 ± 0.08 mg/g of citrate-coated MNPs e and the spleen 0.643 ± 0.06 mg/g of MNPs. For MNPs albumin-coated, in liver, we found a concentration of 1.049 ± 0.05 mg/g of MNPs was detected and, for the spleen, 0.723 ± 0.06 mg/g of MNPs). Despite the high uptake of the spleen, after 30 days it was not possible to detect NPMs coated with citrate in this organ. In 60 days, the absence of NPMs, from both coatings, in the spleen and a significant decay in the liver was shown (0.01 ± 0.009 mg/g of MNPs for citrate-coated MNPs and 0.03 ± 0.01 mg/g of MNPs for albumin-coated MNPs), demonstrating the presence of an endogenous mechanism of metabolism or aggregation of MNPs. Through a pharmacokinetic model, it was possible to determine the half-life of absorption and distribution for the liver and the spleen obtaining values in the liver for citrate-coated NPMs of 1.95 minutes and 12.8 days for absorption and elimination, respectively, and 1.85 minutes and 2.4 days for MNPs albumin-coated. For the spleen, citrate-coated MNPs showed an average time of absorption was 36.4 minutes and elimination 1.4 days, and for albumin-coated MNPs, 2 minutes and 2.6 days respectively. In addition to biodistribution, it was possible to determine the elimination of MNPs through feces. The ACB was efficient for the detection of MNPs and future studies will be carried out to better understand the mechanisms of removal or metabolizing of these particles inside the animal’s body
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Palavras-chave
Biosusceptometria de Corrente Alternada, Nanopartículas Magnéticas, Biomagnetismo, Biodistribuição, Eliminação, Alternate current biosusceptometry, Magnetic nanoparticles, Biomagnetism