Efeito da dexametasona incorporada a nanopartículas poliméricas de poli (ácido lático-co-glicólico) (PLGA) na mucosite oral experimental
Oral mucositis (OM) is a frequent and limiting adverse reaction to cancer therapy, characterized by an intense inflammatory reaction and cumulative ulcer formation in the oral cavity. The aim of the present study was to evaluate the effect of dexamethasone (DEX) incorporated in polymeric nanopart...
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Quimioterapia Mucosite oral Dexametasona Nanopartículas de PLGA Vias de sinalizações |
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Quimioterapia Mucosite oral Dexametasona Nanopartículas de PLGA Vias de sinalizações Ribeiro, Susana Barbosa Efeito da dexametasona incorporada a nanopartículas poliméricas de poli (ácido lático-co-glicólico) (PLGA) na mucosite oral experimental |
| description |
Oral mucositis (OM) is a frequent and limiting adverse reaction to cancer therapy, characterized
by an intense inflammatory reaction and cumulative ulcer formation in the oral cavity. The aim
of the present study was to evaluate the effect of dexamethasone (DEX) incorporated in
polymeric nanoparticles (NP) of poly (lactic-co-glycolic acid) - PGLA - in the experimental
model of oral mucositis induced by 5-fluorouracil (5-FU) in Golden syrian hamsters. The
incorporation of DEX into the PLGA was performed using the solvent evaporation
emulsification technique, followed by characterization with determination of the zeta potential,
polydispersity index, particle size, atomic force microscopy, stability study, determination of
encapsulation efficiency and study of in vitro release. To induce the OM model, 5-FU was
administered intraperitoneally (i.p.) on the 1st (60mg/kg) and 2nd (40mg/kg) days of the
experiment, followed by mechanical trauma on the oral mucosa performed on the 4th day, under
effect anesthetic. The animals were distributed in the experimental groups: Normal, Mechanical
Trauma, 5-FU, DEX (0,25; 0,5 or 1mg/kg) and NP PLGA-DEX (0,1; 0,5 or 1mg/kg). On the
11th day of the experimental model, the animals were euthanized. Macroscopic,
histopathological analyzes, IL-1β and TNF-α quantification by ELISA, immunohistochemistry
for MMP-2, COX-2, TGF-β and NF-κB p65, MIF, immunofluorescence for NF-κB markers
were performed p65, SMAD 2/3 and p-SMAD 2/3, qRT-PCR assay to determine the gene
expression of GILZ, MKP1, NF-κB p65 and AKT. Dexamethasone 1mg/kg and NP PLGADEX 0,1mg/kg demonstrated anti-inflammatory effects in the experimental OM model, with a
significant reduction in macroscopic and histopathological scores (* p <0,05). Treatment with
DEX or NP PLGA-DEX attenuated the levels of the pro-inflammatory cytokines TNF-α and
IL-1β (* p <0,05), reduced the immunostaining for MMP-2, COX-2, TGF-β and NF-κB p65 (*
p <0,05), suppressed the protein expression of MIF, NF-κB p65, SMAD 2/3 and p-SMAD 2/3
(* p <0,05), inhibited gene expression for NF-κB p65 and AKT, and increased the mRNA to
GILZ and MKP1 (* p <0,05), compared to animals with untreated OM (group 5-FU). DEX
1mg/kg and the NP PLGA-DEX 0,1mg/kg formulation reduced inflammation in the 5-FUinduced oral mucositis model. The PLGA NP optimized the effect of DEX, since it was
effective with a reduced dose of glucocorticoid. |
| author2 |
Medeiros, Caroline Addison Carvalho Xavier de |
| author_facet |
Medeiros, Caroline Addison Carvalho Xavier de Ribeiro, Susana Barbosa |
| format |
doctoralThesis |
| author |
Ribeiro, Susana Barbosa |
| author_sort |
Ribeiro, Susana Barbosa |
| title |
Efeito da dexametasona incorporada a nanopartículas poliméricas de poli (ácido lático-co-glicólico) (PLGA) na mucosite oral experimental |
| title_short |
Efeito da dexametasona incorporada a nanopartículas poliméricas de poli (ácido lático-co-glicólico) (PLGA) na mucosite oral experimental |
| title_full |
Efeito da dexametasona incorporada a nanopartículas poliméricas de poli (ácido lático-co-glicólico) (PLGA) na mucosite oral experimental |
| title_fullStr |
Efeito da dexametasona incorporada a nanopartículas poliméricas de poli (ácido lático-co-glicólico) (PLGA) na mucosite oral experimental |
| title_full_unstemmed |
Efeito da dexametasona incorporada a nanopartículas poliméricas de poli (ácido lático-co-glicólico) (PLGA) na mucosite oral experimental |
| title_sort |
efeito da dexametasona incorporada a nanopartículas poliméricas de poli (ácido lático-co-glicólico) (plga) na mucosite oral experimental |
| publisher |
Universidade Federal do Rio Grande do Norte |
| publishDate |
2021 |
| url |
https://repositorio.ufrn.br/handle/123456789/32254 |
| work_keys_str_mv |
AT ribeirosusanabarbosa efeitodadexametasonaincorporadaananoparticulaspolimericasdepoliacidolaticocoglicolicoplganamucositeoralexperimental |
| _version_ |
1773962007098163200 |
| spelling |
ri-123456789-322542021-04-18T09:07:47Z Efeito da dexametasona incorporada a nanopartículas poliméricas de poli (ácido lático-co-glicólico) (PLGA) na mucosite oral experimental Ribeiro, Susana Barbosa Medeiros, Caroline Addison Carvalho Xavier de http://lattes.cnpq.br/6144871780056915 http://lattes.cnpq.br/2982271986555450 Maciel, Maria Aparecida Medeiros http://lattes.cnpq.br/5360188002708095 Oliveira, Riva de Paula http://lattes.cnpq.br/6790385939188325 Figueiredo, Jozi Godoy http://lattes.cnpq.br/9995009111225694 Leitão, Renata Ferreira de Carvalho http://lattes.cnpq.br/5213035069793195 Quimioterapia Mucosite oral Dexametasona Nanopartículas de PLGA Vias de sinalizações Oral mucositis (OM) is a frequent and limiting adverse reaction to cancer therapy, characterized by an intense inflammatory reaction and cumulative ulcer formation in the oral cavity. The aim of the present study was to evaluate the effect of dexamethasone (DEX) incorporated in polymeric nanoparticles (NP) of poly (lactic-co-glycolic acid) - PGLA - in the experimental model of oral mucositis induced by 5-fluorouracil (5-FU) in Golden syrian hamsters. The incorporation of DEX into the PLGA was performed using the solvent evaporation emulsification technique, followed by characterization with determination of the zeta potential, polydispersity index, particle size, atomic force microscopy, stability study, determination of encapsulation efficiency and study of in vitro release. To induce the OM model, 5-FU was administered intraperitoneally (i.p.) on the 1st (60mg/kg) and 2nd (40mg/kg) days of the experiment, followed by mechanical trauma on the oral mucosa performed on the 4th day, under effect anesthetic. The animals were distributed in the experimental groups: Normal, Mechanical Trauma, 5-FU, DEX (0,25; 0,5 or 1mg/kg) and NP PLGA-DEX (0,1; 0,5 or 1mg/kg). On the 11th day of the experimental model, the animals were euthanized. Macroscopic, histopathological analyzes, IL-1β and TNF-α quantification by ELISA, immunohistochemistry for MMP-2, COX-2, TGF-β and NF-κB p65, MIF, immunofluorescence for NF-κB markers were performed p65, SMAD 2/3 and p-SMAD 2/3, qRT-PCR assay to determine the gene expression of GILZ, MKP1, NF-κB p65 and AKT. Dexamethasone 1mg/kg and NP PLGADEX 0,1mg/kg demonstrated anti-inflammatory effects in the experimental OM model, with a significant reduction in macroscopic and histopathological scores (* p <0,05). Treatment with DEX or NP PLGA-DEX attenuated the levels of the pro-inflammatory cytokines TNF-α and IL-1β (* p <0,05), reduced the immunostaining for MMP-2, COX-2, TGF-β and NF-κB p65 (* p <0,05), suppressed the protein expression of MIF, NF-κB p65, SMAD 2/3 and p-SMAD 2/3 (* p <0,05), inhibited gene expression for NF-κB p65 and AKT, and increased the mRNA to GILZ and MKP1 (* p <0,05), compared to animals with untreated OM (group 5-FU). DEX 1mg/kg and the NP PLGA-DEX 0,1mg/kg formulation reduced inflammation in the 5-FUinduced oral mucositis model. The PLGA NP optimized the effect of DEX, since it was effective with a reduced dose of glucocorticoid. A mucosite oral (MO) é uma reação adversa frequente e limitante da terapia de combate ao câncer, caracterizada por intensa reação inflamatória e formação cumulativa de úlceras na cavidade oral. O objetivo do presente estudo foi avaliar o efeito da dexametasona (DEX) incorporada em nanopartícula (NP) polimérica do poli (ácido lático-co-glicólico) - PGLA - no modelo experimental de mucosite oral induzida por 5-fluorouracil (5-FU) em hamsters Golden syrian. A incorporação da DEX ao PLGA foi realizada pela técnica da emulsificação evaporação do solvente, seguida por caracterização com determinação do potencial zeta, índice de polidispersibilidade, tamanho de partículas, microscopia de força atômica, estudo de estabilidade, determinação da eficiência de encapsulação e estudo de liberação in vitro. Para induzir o modelo de MO, o 5-FU foi administrado por via intraperitoneal (i.p.) no 1º (60mg/kg) e 2º (40mg/kg) dias do experimento, com subsequentes escoriações na mucosa oral realizada no 4º dia, sob efeito anestésico. Os animais foram distribuídos nos grupos experimentais: Normal, Trauma Mecânico, 5-FU, DEX (0,25; 0,5 ou 1mg/kg) e NP PLGA-DEX (0,1; 0,5 ou 1mg/kg). No 11º dia do modelo experimental, os animais foram eutanasiados. Foram realizadas as análises macroscópica, histopatológica, quantificação de IL-1β e TNF-α por ELISA, imunohistoquímica para os marcadores MMP-2, COX-2, TGF-β e NF-κB p65, MIF, imunofluorescência para NF-κB p65, SMAD 2/3 e p-SMAD 2/3, ensaio de qRT-PCR para determinar a expressão gênica de GILZ, MKP1, NF-κB p65 e AKT. A dexametasona 1mg/kg e NP PLGA-DEX 0,1mg/kg demonstraram efeitos anti-inflamatórios no modelo de MO experimental, apresentando redução significativa dos escores macroscópicos e histopatológicos (*p<0,05). O tratamento com DEX ou com NP PLGA-DEX atenuou os níveis das citocinas pró-inflamatórias TNF-α e IL-1β (*p<0,05), reduziu a imunomarcação para MMP-2, COX-2, TGF-β e NF-κB p65 (*p<0,05), suprimiu a expressão proteica de MIF, NF-κB p65, SMAD 2/3 e p-SMAD 2/3 (*p<0,05), inibiu a expressão gênica para NF-κB p65 e AKT, e elevou o mRNA para GILZ e MKP1 (*p<0,05), comparada aos animais com MO não tratados (grupo 5-FU). A DEX 1mg/kg e a formulação NP PLGA-DEX 0,1mg/kg reduziram a inflamação no modelo de MO induzida por 5-FU. A NP de PLGA otimizou o efeito da DEX, uma vez que apresentou eficácia com dose reduzida do glicocorticoide. 2021-04-16T17:43:31Z 2021-04-16T17:43:31Z 2020-12-01 doctoralThesis RIBEIRO, Susana Barbosa. Efeito da dexametasona incorporada a nanopartículas poliméricas de poli (ácido lático-co-glicólico) (PLGA) na mucosite oral experimental. 2020. 101f. Tese (Doutorado em Biotecnologia) - Centro de Tecnologia, Universidade Federal do Rio Grande do Norte, Natal, 2020. https://repositorio.ufrn.br/handle/123456789/32254 pt_BR Acesso Aberto application/pdf Universidade Federal do Rio Grande do Norte Brasil UFRN PROGRAMA DE PÓS-GRADUAÇÃO EM BIOTECNOLOGIA |