title: Multiple siRNA delivery against cell cycle and anti-apoptosis proteins using lipid-substituted polyethylenimine in triple-negative breast cancer and nonmalignant cells.
abstract: Conventional breast cancer therapies have significant limitations that warrant a search for alternative therapies. Short-interfering RNA (siRNA), delivered by polymeric biomaterials and capable of silencing specific genes critical for growth of cancer cells, holds great promise as an effective, and more specific therapy. Here, we employed amphiphilic polymers and silenced the expression of two cell cycle proteins, TTK and CDC20, and the anti-apoptosis protein survivin to determine the efficacy of polymer-mediated siRNA treatment in breast cancer cells as well as side effects in nonmalignant cells in vitro. We first identified effective siRNA carriers by screening a library of lipid-substituted polyethylenimines (PEI), and PEI substituted with linoleic acid (LA) emerged as the most effective carrier for selected siRNAs. Combinations of TTK/CDC20 and CDC20/Survivin siRNAs decreased the growth of MDA-MB-231 cells significantly, while only TTK/CDC20 combination inhibited MCF7 cell growth. The effects of combinational siRNA therapy was higher when complexes were formulated at lower siRNA:polymer ratio (1:2) compared to higher ratio (1:8) in nonmalignant cells. The lead polymer (1.2PEI-LA6) showed differential transfection efficiency based on the cell-type transfected. We conclude that the lipid-substituted polymers could serve as a viable platform for delivery of multiple siRNAs against critical targets in breast cancer therapy. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 3031-3044, 2016.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Manoj B
authors.initials: MB
authors.lastname: Parmar
authors.affiliation: Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Bárbara E
authors.initials: BE
authors.lastname: Arteaga Ballesteros
authors.affiliation: Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Timothy
authors.initials: T
authors.lastname: Fu
authors.affiliation: Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Remant Bahadur
authors.initials: RB
authors.lastname: K C
authors.affiliation: School of Pharmacy, Chapman University, Irvine, California, USA.
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Montazeri Aliabadi
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Judith C
authors.initials: JC
authors.lastname: Hugh
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Raimar
authors.initials: R
authors.lastname: Löbenberg
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada. hasan.uludag@ualberta.ca.|Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, Alberta, Canada. hasan.uludag@ualberta.ca.|Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada. hasan.uludag@ualberta.ca.
authors.forename: Hasan
authors.initials: H
authors.lastname: Uludağ
mesh_terms: D064199:Cdc20 Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D008055:Lipids / Q000737:chemistry*; D011094:Polyethyleneimine / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D000067492:RNAi Therapeutics; D000077022:Survivin; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000628:therapy*
chemical_list: C107489:BIRC5 protein, human; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; D051034:Inhibitor of Apoptosis Proteins; D008055:Lipids; D034741:RNA, Small Interfering; D000077022:Survivin; C577488:CDC20 protein, human; D011094:Polyethyleneimine; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human
keywords: amphiphilic polymers; anti-apoptosis protein; breast cancer therapy; cell cycle protein; siRNA delivery