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Doctoral Thesis
DOI
https://doi.org/10.11606/T.5.2021.tde-25072021-174251
Document
Author
Full name
Camila Inagaki de Albuquerque
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2021
Supervisor
Committee
Maranhao, Raul Cavalcante (President)
Drager, Luciano Ferreira
Chagas, Antonio Carlos Palandri
Rached, Fabiana Hanna
Title in Portuguese
Uso do quimioterápico daunorrubicina associado à nanoemulsões lipídicas no tratamento da aterosclerose experimental em coelho.
Keywords in Portuguese
Aterosclerose
coelhos
daunorrubicina
inflamação
nanopartículas
quimioterápicos
Abstract in Portuguese
As nanopartículas lipídicas (LDE) demonstraram eficácia como veículo de direcionamento de fármacos no tratamento de aterosclerose e câncer em pacientes e em modelo animal. A LDE é sintetizada em laboratório com estrutura e composição semelhantes à LDL e concentra-se em locais com altas taxas de proliferação celular, como nas lesões ateroscleróticas. O agente quimioterápico daunorrubicina (DNR) é antiproliferativo e citotóxico e em estudos anteriores foi associada a LDE em modelo de câncer murino, não apresentando toxicidade relevante. Coelhos New Zealand machos foram submetidos a uma dieta com colesterol 1% durante 8 semanas. Após 4 semanas do início da dieta, os animais foram divididos em: Grupo LDE-DNR (6mg/kg EV, n=9), tratados semanalmente com DNR associada à LDE; Grupo LDE (EV, n=7), tratados com apenas LDE. Além disso, foi utilizado um grupo Controle de 3 animais, os quais não foram submetidos a qualquer intervenção. Perfil lipídico e hematológico, consumo de ração, massa corporal e ecocardiograma foram avaliados antes do início da dieta rica em colesterol, no pré-tratamento e pós-tratamento. Morfometria e Western blot foram realizados em segmentos das aortas, qRT-PCR foi realizado em segmento da aorta e tecido cardíaco. No grupo LDE-DNR as lesões macroscópicas aórticas foram 50% menores. A expressão proteica dos marcadores relacionados à inflamação CD68, IL-6 e TNF-? foi menor no grupo LDE-DNR em relação ao grupo LDE. Fatores pró-apoptóticos BAX, caspase 3 e caspase 9 também foram menores em LDE-DNR quando comparado ao grupo LDE. A expressão proteica do fator de crescimento endotelial (VEGF) e da molécula de adesão celular vascular (VCAM) foi menor no grupo LDE-DNR quando comparado ao grupo LDE. As interleucinas (IL-18, IL-10 e IL-1?) não tiveram diferença na expressão gênica quando comparado os grupos LDE-DNR e LDE. Entretanto, expressão gênica dos marcadores MMP12, MCP-1 e VCAM-1 foram menores no grupo LDE-DNR quando comparado ao grupo LDE. Pela ecocardiografia observou-se nos grupos LDE e LDE-DNR que as funções sistólica e diastólica foram preservadas comparadas ao grupo controle e não houve diferença na massa cardíaca entre os 3 grupos. Os grupos estudados não apresentaram diferenças na ingestão de ração e peso corporal, e a LDE-DNR não apresentou toxicidade observável no hemograma, porém houve um aumento na enzima hepática AST no grupo LDE- DNR que começou no período de pré-tratamento e continuou até o fim do protocolo. O tratamento com LDE-DNR reduziu a inflamação e a morte celular na aorta além de não prejudicar a função cardíaca desses animais, e reduzir drasticamente as lesões ateroscleróticas do grupo tratado com a associação.
Title in English
Use of the chemotherapy drug daunorubicin associated with lipid nanoemulsions in the treatment of experimental atherosclerosis in rabbits.
Keywords in English
Atherosclerosis
Chemotherapy
daunorubicin
inflammation
nanoparticles
rabbits
Abstract in English
Lipid nanoparticles (LDE) have shown effectiveness as a vehicle for targeting chemotherapeutic drugs in treatment of atherosclerosis and cancer in patients and in animal model. LDE was synthesized in laboratory with a structure and composition similar to LDL and it is concentrated in places with high rates of cell proliferation, such as atherosclerotic lesions. Daunorubicin (DNR) is a chemotherapy drug that in previous studies has been associated with LDE to treat a murine cancer model, with no relevant toxicity. Male New Zealand rabbits were fed with 1% cholesterol diet for 8 weeks. After 4 weeks from the beginning of the diet, the animals were divided in three groups: LDE-DNR group (6mg/kg iv, n=9), treated weekly with DNR associated with LDE; LDE group (iv, n=7), treated with LDE only, and Control group (3 animals) that no intervention was performed. Lipid and hematological profile, chow consumption, body mass and echocardiography were evaluated in the baseline, pre-treatment and post-treatment periods. Morphometry, protein and gene expression were performed on segments of the aortas. Aortic lesions were 50% smaller in LDE-DNR group compared to the LDE group. Protein expression of markers related to inflammation CD68, IL-6 and TNF- ? were lower in the LDE-DNR group compared to the LDE group. Pro-apoptotic factors BAX, caspase 3 and caspase 9 were also lower in LDE-DNR when compared to the LDE group. Protein expression of VEGF and VCAM were lower in LDE-DNR group when compared to LDE group. In addition, gene expression of MMP12, VCAM-1 and MCP-1 were lower in LDE-DNR group when compared to LDE group. The gene expression of interleukins (IL-18, IL-10 e IL-1?) had no difference when compared LDE-DNR and LDE group. By echocardiography, it was observed in LDE and LDE-DNR groups that the systolic and diastolic functions were preserved and there was no difference in cardiac mass between the 3 groups. There was no difference in chow consumption and body weight, and the LDE-DNR did not show toxicity that could be observed in blood count, however, there was an increase in levels of liver enzyme AST in LDE-DNR group that started in pre-treatment period and continued until the end of the protocol. Treatment with LDE-DNR reduced inflammation and cell death in aorta and did not impair cardiac function of these animals. In addition, remarkably reduced atherosclerotic lesions.
 
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Publishing Date
2021-08-19
 
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