title: P-glycoprotein silencing with siRNA delivered by DOPE-modified PEI overcomes doxorubicin resistance in breast cancer cells.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.affiliation: Center for Pharmaceutical Biotechnology & Nanomedicine, Northeastern University, Boston, MA 02115, USA.
authors.forename: Gemma
authors.initials: G
authors.lastname: Navarro
authors.forename: Rupa R
authors.initials: RR
authors.lastname: Sawant
authors.forename: Swati
authors.initials: S
authors.lastname: Biswas
authors.forename: Sean
authors.initials: S
authors.lastname: Essex
authors.forename: Conchita
authors.initials: C
authors.lastname: Tros de Ilarduya
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Torchilin
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000378:metabolism / Q000627:therapeutic use*; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D058726:Nanoconjugates / Q000737:chemistry; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D058726:Nanoconjugates; D010714:Phosphatidylethanolamines; D034741:RNA, Small Interfering; C094877:dioleoyl phosphatidylethanolamine; D004317:Doxorubicin; D011094:Polyethyleneimine