title: Phospholipid-modified PEI-based nanocarriers for in vivo siRNA therapeutics against multidrug-resistant tumors.
abstract: Multidrug resistance (MDR) mediated by P-glycoprotein overexpression in solid tumors is a major factor in the failure of many forms of chemotherapy. Here we evaluated phospholipid-modified, low-molecular-weight polyethylenimine (DOPE-PEI) nanocarriers for intravenous delivery of anti-P-pg siRNA to tumors with the final goal of modulating MDR in breast cancer. First, we studied the biodistribution of DOPE-PEI nanocarriers and the effect of PEG coating in a subcutaneous breast tumor model. Four hours postinjection, PEGylated carriers showed an 8% injected dose (ID) accumulation in solid tumor via the enhanced permeability and retention effect and 22% ID in serum due to a prolonged, PEG-mediated circulation. Second, we established the therapeutic efficacy and safety of DOPE-PEI/siRNA-mediated P-gp downregulation in combination with doxorubicin (Dox) chemotherapy in MCF-7/MDR xenografts. Weekly injection of siRNA nanopreparations and Dox for up to 5 weeks sensitized the tumors to otherwise non-effective doses of Dox and decreased the tumor volume by threefold vs controls. This therapeutic improvement in response to Dox was attributed to the significant, sequence-specific P-gp downregulation in excised tumors mediated by the DOPE-PEI formulations.
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Essex
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA.
authors.forename: Gemma
authors.initials: G
authors.lastname: Navarro
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA.
authors.forename: Pooja
authors.initials: P
authors.lastname: Sabhachandani
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA.
authors.forename: Aabha
authors.initials: A
authors.lastname: Chordia
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA.
authors.forename: Malav
authors.initials: M
authors.lastname: Trivedi
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Movassaghian
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA.
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Torchilin
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D064593:Heterografts; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage; D009369:Neoplasms / Q000188:drug therapy*; D010743:Phospholipids / Q000008:administration & dosage / Q000737:chemistry*; D011094:Polyethyleneimine / Q000008:administration & dosage / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D010743:Phospholipids; D034741:RNA, Small Interfering; D004317:Doxorubicin; D011094:Polyethyleneimine