title: Investigating siRNA delivery to chronic myeloid leukemia K562 cells with lipophilic polymers for therapeutic BCR-ABL down-regulation.
abstract: RNAi represents a new alternative for treatment of chronic myeloid leukemia (CML) to overcome the difficulties of current drug treatments such as the acquired resistance. However, potent carriers that can overcome delivery barriers to RNAi agents and have therapeutic efficacy especially in difficult-to-transfect CML cells are needed. Here, we explored the use of lipid-modified polyethylenimines (PEI) of low molecular weights (0.6, 1.2 and 2.0kDa) in K562 cells and showed that the delivery efficiency was dependent on the type of lipid used for polymer modification, degree of lipid substitution and polymer molecular weight. Among the lipid-substituted polymers investigated, palmitic acid (PA)-substituted 1.2kDa PEI (~2 lipids/PEI) has proven to be highly efficient in delivering siRNA and silencing of the reporter gene green fluorescent protein (GFP). The silencing efficacy achieved with this polymer was found to be higher than the 25kDa PEI and is similar to commercial reagent Lipofectamine™ 2000. Moreover, when BCR-ABL protein was targeted in K562 cells, a reduction in the corresponding mRNA levels was observed, as well as an induction of early and late stage apoptosis. The results of this study demonstrated that PA-substitutions on low MW polymers could be useful for siRNA delivery in CML cells for therapeutic purposes.
authors.affiliation: Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2V2, Canada.
authors.forename: Juliana
authors.initials: J
authors.lastname: Valencia-Serna
authors.forename: Hilal
authors.initials: H
authors.lastname: Gul-Uludağ
authors.forename: Parvin
authors.initials: P
authors.lastname: Mahdipoor
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Jiang
authors.forename: Hasan
authors.initials: H
authors.lastname: Uludağ
mesh_terms: D015536:Down-Regulation; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000628:therapy*; D011094:Polyethyleneimine / Q000737:chemistry*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D014162:Transfection / Q000379:methods*
chemical_list: D034741:RNA, Small Interfering; D011094:Polyethyleneimine; D016044:Fusion Proteins, bcr-abl
keywords: CML; Cationic polymer; Chronic myeloid leukemia; GFP; Hydrophobic modification; LA; MFI; MW; PA; PEI; Polyethylenimine; RNA interference; RNAi; Transfection; chronic myeloid leukemia; green fluorescent protein; linoleic acid; mean fluorescence intensity; molecular weight; palmitic acid; polyethylenimine; short interfering RNA; siRNA; siRNA delivery