P-glycoprotein silencing with siRNA delivered by DOPEmodified PEI overcomes doxorubicin resistance in breast cancer cells

AIMS: Multidrug resistance (MDR) mediated by overexpression of drug efflux transporters such as P-glycoprotein (P-gp), is a major problem, limiting successful chemotherapy of breast cancer. The use of siRNA to inhibit P-gp expression in MDR tumors is an attractive strategy to improve the effectivene...

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Detalles Bibliográficos
Autores: Navarro, G. (Gemma)|||/items/94abbc78-6e7a-4ebb-9219-d275ee6eb0d6, Sawant, R.R. (Rupa R.)|||/items/57391339-1350-4fc8-b9be-5c5f7bc5a6a8, Biswas, S. (Swati)|||/items/28fbc029-f454-4c41-a134-3017db1fede3, Essex, S. (Sean)|||/items/2d430047-e270-4310-b45d-ba62c6eea344, Tros-de-Ilarduya, C. (Conchita)|||/items/0ea908a6-07d4-4f5d-9296-c9958c6349d0, Torchilin, V.P. (Vladimir P.)|||/items/4cf49c24-5332-4311-8c5c-a6a9e3d3f707
Tipo de recurso: artículo
Fecha de publicación:2012
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/36627
Acceso en línea:https://hdl.handle.net/10171/36627
Access Level:acceso abierto
Palabra clave:MCF-7 breast cancer cell
P-glycoprotein
Polyethylenimine
SiRNA delivery
Micelle-like nanoparticle
Multidrug resistance
Descripción
Sumario:AIMS: Multidrug resistance (MDR) mediated by overexpression of drug efflux transporters such as P-glycoprotein (P-gp), is a major problem, limiting successful chemotherapy of breast cancer. The use of siRNA to inhibit P-gp expression in MDR tumors is an attractive strategy to improve the effectiveness of anticancer drugs. METHOD: We have synthesized a novel conjugate between a phospholipid (dioleoylphosphatidylethanolamine) and polyethylenimine (PEI) for siRNA delivery, for the purpose of silencing P-gp to overcome doxorubicin resistance in MCF-7 human breast cancer cells. RESULTS: The dioleoylphosphatidylethanolamine-PEI conjugate enhanced the transfection efficacy of low-molecular-weight PEI, which was otherwise totally ineffective. In addition, the polyethylene glycol/lipid coating of the new complexes gave rise to small micelle-like nanoparticles with improved biocompatibility properties. Both coated and noncoated formulations delivered P-gp-specific siRNA to MDR cells. DISCUSSION: The combination of doxorubicin and P-gp silencing formulations led to a twofold increase of doxorubicin uptake and a significant improvement of the therapeutic effect of doxorubicin in resistant cells.

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