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Master's Dissertation
DOI
10.11606/D.9.2016.tde-04082016-092244
Document
Author
Full name
Marina Cecília Spatti
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2016
Supervisor
Committee
Farsky, Sandra Helena Poliselli (President)
Uchiyama, Mayara Klimuk
Martins, Tereza da Silva
Title in Portuguese
Efeito de nanoemulsão contendo oleato de paclitaxel em glioblastoma murino: estudos in vivo e in vitro
Keywords in Portuguese
Eficácia terapêutica
GL261
Nanotecnologia
Toxicidade
Abstract in Portuguese
O glioblastoma multiforme (GBM) é um tipo de câncer grave que acomete o sistema nervoso central (SNC), e a sobrevida dos pacientes é de aproximadamente 12 meses. O tratamento com o quimioterápico paclitaxel (PTX) reduz o GBM experimental e humano. No entanto, sua utilização é limitada pelas reações adversas graves que acarreta. A nanoemulsão rica em colesterol (LDE), a qual mimetiza a lipoproteína de baixa densidade, tem sido empregada como um sistema de entrega de fármacos eficiente em alguns casos de tumores. No presente trabalho visou-se avaliar a eficácia do oleato de PTX (OPTX), um derivado mais lipofílico do que o PTX, associado a LDE (LDE-OPTX) em ensaios in vitro e in vivo. Inicialmente, células tumorais da linhagem de glioblastoma murino GL261 foram incubadas com PTX em solução ou com LDE-OPTX, nas concentrações de 1 ou 10 µM. Os resultados obtidos mostraram que o tratamento in vitro com PTX e o LDE-OPTX causa toxicidade in vitro em células GL261 pela redução da proliferação e indução de apoptose, e que ainda reduz a secreção de MCP-1 (proteína quimiotáxica de monócitos). Os ensaios in vivo mostraram a toxicidade intensa do PTX comercial, uma vez que os animais com GBM não sobreviveram ao tratamento com 75mg/Kg, i.p., a cada 3 dias, e foram a óbito a partir do oitavo dia de tratamento. Diferentemente, os animais tratados com a mesma dose de LDE-OPTX sobreviveram ao tratamento, sem sinais de toxicidade, mas os dados obtidos mostraram que este protocolo de tratamento não foi eficaz para redução do volume tumoral. Assim, os animais com GBM passaram a ser tratados com doses diárias, i.p., de 15 mg/kg de PTX ou de 75mg/Kg de LDE-OPTX. Os resultados obtidos mostraram a ineficácia e eficácia dos tratamentos com PTX e LDE-OPTX, respectivamente, em reduzir o GBM; no entanto os animais tratados com LDE-OPTX apresentaram redução no peso corporal e no número de linfócitos circulantes. Em conjunto, os dados obtidos mostram a habilidade de preparação LDE-OPTX causar toxicidade in vitro nas células GL261 e sua eficácia terapêutica em dose elevada, em reduzir o GBM em modelo murino.
Title in English
Effect nanoemulsion containing paclitaxel oleato in murine glioblastoma: in vivo and in vitro studies.
Keywords in English
GL261
Nanotechnology
Therapeutic efficacy
Toxicity
Abstract in English
Glioblastoma multiforme (GBM) is a type of severe cancer that affects the central nervous system, and patient survival is about12 months. The treatment with the chemotherapeutic paclitaxel (PTX) reduces the experimental and human GBM, however, their use is limited by side effects. The lipid nanoemulsion (LDE), that is mimetic to low density protein, has been employed as an efficient drug nanocarrier to treat cancer. Therefore, the present study aimed to assess the effectiveness of the oleate PTX (OPTX), a more lipophilic derivative of PTX, associated to (LDE), in in vitro and in vivo studies. Initially, glioblastoma murine strain GL261 was incubated with commercial PTX solution or LDE-OPTX at concentrations of 1 or 10 µM. Data obtained showed that treatment with PTX or LDE-OPTX caused in vitro toxicity to GL261 cells, by reducing the proliferation and inducing apoptosis. Moreover, both treatments reduced the secretion of monocyte chemotacticprotein-1 (MCP-1). In vivo experiments showed the severe toxicity of commercial PTX, as mice with GBM did not survive to the treatment with 75mg/kg, i.p., each 3 days, and died after 8 days of treatment. Conversely, animals treated with the same schedule of treatment with LDE-OPTX survived until the end of treatment, without any toxicity signal. Nevertheless, the treatment was not effective to reduce the GBM volume. Hence, other sets of animals with GBM were treated with daily i.p. dose of 15mg/kg of PTX or 75mg/kg of LDE-OPTX. Data obtained showed the inefficacy and efficacy of PTX and LDE-OPTX treatments, respectively, to reduce the volume of GBM. Nevertheless, mice treated with LDE-OPTX lost weight and lower number of circulating lymphocytes. Together, our data show the ability of LDE-OPTX treatment cause in vitro toxicity on GL261 cells e the in vivo therapeutic efficacy of higher doses on GBM murine model.
 
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Publishing Date
2016-08-16
 
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