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.
AIMS: Multidrug resistance (MDR) mediated by overexpression of drug efflux transporters such as P-glycoprotein (n>an class="Gene">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-7humanbreast 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.
Authors: Miriam Rothdiener; Dafne Müller; Patricia Garrido Castro; Anja Scholz; Michael Schwemmlein; Georg Fey; Olaf Heidenreich; Roland E Kontermann Journal: J Control Release Date: 2010-02-22 Impact factor: 9.776
Authors: Young Tag Ko; Amit Kale; William C Hartner; Brigitte Papahadjopoulos-Sternberg; Vladimir P Torchilin Journal: J Control Release Date: 2008-10-07 Impact factor: 9.776
Authors: Rupa R Sawant; Shravan Kumar Sriraman; Gemma Navarro; Swati Biswas; Riddhi A Dalvi; Vladimir P Torchilin Journal: Biomaterials Date: 2012-02-25 Impact factor: 12.479