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: Sean Essex, Gemma Navarro, Pooja Sabhachandani, Aabha Chordia, Malav Trivedi, Sara Movassaghian, Vladimir P Torchilin
• Journal: Gene therapy (Gene Ther) Vol. 22 Issue 3 Pg. 257-266 (Mar 2015) ISSN: 1476-5462 [Electronic] England
• PMID: 25354685 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B
• Phospholipids
• RNA, Small Interfering
• Doxorubicin
• Polyethyleneimine

Topics

• ATP Binding Cassette Transporter, Subfamily B (metabolism)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Cell Line, Tumor
• Doxorubicin (administration & dosage)
• Drug Delivery Systems
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Female
• Heterografts
• Mice, Inbred BALB C
• Nanoparticles (administration & dosage)
• Neoplasms (drug therapy)
• Phospholipids (administration & dosage, chemistry)
• Polyethyleneimine (administration & dosage, chemistry)
• RNA, Small Interfering (administration & dosage)