P-glycoprotein silencing with siRNA delivered by DOPE-modified PEI overcomes doxorubicin resistance in breast cancer cells
- 1 January 2012
- journal article
- Published by Future Medicine Ltd in Nanomedicine
- Vol. 7 (1), 65-78
- https://doi.org/10.2217/nnm.11.93
Abstract
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.Keywords
This publication has 44 references indexed in Scilit:
- Phospholipid–polyethylenimine conjugate-based micelle-like nanoparticles for siRNA deliveryDrug Delivery and Translational Research, 2010
- Sequential treatment of drug-resistant tumors with RGD-modified liposomes containing siRNA or doxorubicinEuropean Journal of Pharmaceutics and Biopharmaceutics, 2010
- Perspectives of P-Glycoprotein Modulating Agents in Oncology and Neurodegenerative Diseases: Pharmaceutical, Biological, and Diagnostic PotentialsJournal of Medicinal Chemistry, 2009
- Hydrophobically Modified Oligoethylenimines as Highly Efficient Transfection Agents for siRNA DeliveryBioconjugate Chemistry, 2009
- The use of nanoparticle-mediated targeted gene silencing and drug delivery to overcome tumor drug resistanceBiomaterials, 2009
- Coexpression of invasive markers (uPA, CD44) and multiple drug-resistance proteins (MDR1, MRP2) is correlated with epithelial ovarian cancer progressionBritish Journal of Cancer, 2009
- Transfection Efficiency of 25-kDa PEI–Cholesterol Conjugates with Different Levels of ModificationJournal of Biomaterials Science, Polymer Edition, 2009
- Co-Delivery of siRNA and An Anticancer Drug for Treatment of Multidrug-Resistant CancerNanomedicine, 2008
- Self-assembling micelle-like nanoparticles based on phospholipid–polyethyleneimine conjugates for systemic gene deliveryJournal of Controlled Release, 2008
- Epigenetic mechanisms involved in differential MDR1mRNA expression between gastric and colon cancer cell lines and rationales for clinical chemotherapyBMC Gastroenterology, 2008