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Doctoral Thesis
DOI
10.11606/T.5.2011.tde-14062011-154226
Document
Author
Full name
Jorge Luis Maria Ruiz
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2011
Supervisor
Committee
Bydlowski, Sergio Paulo (President)
Bizzacchi, Joyce Maria Annichino
Oliveira, Cristiano Luis Pinto de
Pereira, Juliana
Souza, Heraldo Possolo de
Title in Portuguese
Caracterização de uma nanopartícula lipídica semelhante à LDL (LDE) como vetor para RNA de interferência
Keywords in Portuguese
Interferência de RNA
Lipídeos
Neoplasias
Resistência a múltiplos medicamentos
Terapia de genes
Vetores genéticos
Abstract in Portuguese
As nanopartículas são consideradas promissores vetores para a liberação eficaz e segura de ácidos nucléicos para tipos específicos de célula ou tecido, proporcionando uma alternativa aos vetores virais para terapia gênica. No entanto, com a maioria destes sistemas não torna possível a entrega de oligonucleotídeos nas células in vivo de forma especifica. O uso de uma nanoemulsão funcionalmente semelhante à lipoproteina de baixa densidade poderia resolver esse problema, pois esta particula é capaz de direcionar o transporte das moléculas para a internalização celular através de receptores de LDL. Aqui, descreve-se um sistema lipidico semelhante à lipoproteína de baixa densidade, LDE, capaz de direcionar e liberar RNA de interferência (RNAi) para as células tumorais in vitro e in vivo em um modelo celular que expressa resistência a múltiplas drogas (células de sarcoma uterino; MESSA/ Dx5). Estudou-se também as caracteristicas de captação do complexo LDE-RNAi e a regulação especifica do gene mdr-1. Os resultados sugerem que a LDE é estavel e liga-se com alta afinidade aos RNAis permitindo que eles entrem nas células tumorais, com localização citoplasmática. Em conclusão, a LDE, por direcionar o RNAi a receptores de LDL favorece o silenciamento do gene mdr-1 por RNAi nas células MES-SA/Dx5 aumentando sua sensibilidade a quimioterápicos
Title in English
Characterization of an lipid nanoparticle resembles LDL (LDE) with vector for interference RNA
Keywords in English
Gene therapy
Genetic vectors
Interference RNA
Lipids
Multiple drug resistance
Neoplasm
Abstract in English
Nanoparticles are considered promising vectors for efficient and safe delivery of nucleic acids to specific types of cell or tissue, providing an alternative to viral vectors for gene therapy. However, most of these systems cannot target and deliver oligonucleotides to specific cells in vivo. The use of nanoemulsion functionally resemble low density emulsion could solve this problem, once particle is capable of direct the molecules transport to the cell through internalization in LDL receptors. Here, we describe a lipid system similar to low density lipoprotein, LDE, capable of targeting and release small interfering RNA (siRNA) to tumor cells in vitro and in vivo in a cell model that expresses multidrug resistance (sarcoma uterine cell line; MES-SA/Dx5). Were also studied the characteristics of uptake of the complex LDE-siRNA, as well as the downregulation of mdr-1 gene. The results suggest that LDE is stable and bind with high affinity to siRNAs allowing them to enter tumor cells, with cytoplasmic localization enhanced. In conclusion, LDE, binds to siRNA through LDL receptors, and promotes mdr-1 silenciament by RNAi in MES-sa/Dx5 cells, increasing their sensitivity to chemotherapeutics agents
 
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Publishing Date
2011-06-20
 
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