Faculty Articles

Title

Phospholipid-modified PEI-based nanocarriers for in vivo siRNA therapeutics against multidrug-resistant tumors.

Publication Title

Gene therapy

Volume

22

Issue

3

Publication Date / Copyright Date

3-1-2015

First Page

257

Last Page

266

Publisher

Nature Publishing Group

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.

Disciplines

Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences

Keywords

ATP Binding Cassette Transporter, Subfamily B, Animals, Antineoplastic Combined Chemotherapy Protocols, Cell Line, Tumor, Doxorubicin, Drug Delivery Systems, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Female, Heterografts, Mice, Inbred BALB C, Nanoparticles, Neoplasms, Phospholipids, Polyethyleneimine, RNA, Small Interfering

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