title: siRNA-mediated down-regulation of P-glycoprotein in a Xenograft tumor model in NOD-SCID mice.
abstract: OBJECTIVE
  The efficacy of chemotherapy is decreased due to over-expression of the drug transporter P-glycoprotein (P-gp). This study was conducted to determine the feasibility of down-regulating tumor P-gp levels with non-viral siRNA delivery in order to sensitize the tumors to drug therapy.
  
  
  METHODS
  P-gp over-expressing MDA435/LCC6 MDR1 cells were used to establish xenografts in NOD-SCID mouse. Cationic polymers polyethylenimine (PEI) and stearic acid-substituted poly-L-lysine (PLL-StA) were formulated with P-gp- specific siRNAs and delivered intratumorally to explore the feasibility of P-gp down-regulation in tumors. Intravenous Doxil™ was administered to investigate tumor growth.
  
  
  RESULTS
  PEI and PLL-StA effectively delivered siRNA to MDA435/LCC6 MDR1 cells in vitro to reduce P-gp expression for 3 days. Intratumoral injection of siRNA with the carriers resulted in 60-80% and 20-32% of siRNA retention in tumors after 24 and 96 hr, respectively. This led to ~29.0% and ~61.5% P-gp down-regulation with PEI- and PLL-StA-mediated siRNA delivery, respectively. The P-gp down-regulation by intratumoral siRNA injection led to better response to systemic Doxil™ treatment, resulting in slowed tumor growth in originally doxorubicin-resistant tumors.
  
  
  CONCLUSIONS
  Effective P-gp down-regulation was feasible with polymeric siRNA delivery in a xenograft model, resulting in an enhanced response to the drug therapy.
authors.affiliation: Department of Biomedical Engineering, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Meysam
authors.initials: M
authors.lastname: Abbasi
authors.forename: Hamidreza Montazeri
authors.initials: HM
authors.lastname: Aliabadi
authors.forename: Elaine H
authors.initials: EH
authors.lastname: Moase
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Lavasanifar
authors.forename: Kamaljit
authors.initials: K
authors.lastname: Kaur
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
authors.forename: Charles
authors.initials: C
authors.lastname: Doillon
authors.forename: Hasan
authors.initials: H
authors.lastname: Uludağ
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D015536:Down-Regulation; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000008:administration & dosage; D016503:Drug Delivery Systems / Q000379:methods; D019008:Drug Resistance, Neoplasm; D005260:Female; D008239:Lysine / Q000008:administration & dosage; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D011094:Polyethyleneimine / Q000008:administration & dosage; D011108:Polymers / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics*; D013229:Stearic Acids / Q000008:administration & dosage; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D004337:Drug Carriers; D011108:Polymers; D034741:RNA, Small Interfering; D013229:Stearic Acids; C031183:stearic acid; D004317:Doxorubicin; D011094:Polyethyleneimine; D008239:Lysine