title: siRNA therapy in cutaneous T-cell lymphoma cells using polymeric carriers.
abstract: Cutaneous T-cell lymphomas (CTCLs) arise from specific molecular aberrations that lead to uncontrolled cell proliferation. RNA interference (RNAi) with short interfering RNAs (siRNAs) is a feasible approach to interrupt aberrant signal processing in CTCL cells, but functional biomaterial carriers are needed to effectively deliver siRNAs intracellularly. Towards this goal, we explored the utility of lipid-substituted polyethylenimines (PEI) carriers in a cell model of CTCL. Using caprylic and linoleic acid substituted 2 kDa PEI (PEI-CA and PEI-LA, respectively), we showed effective delivery of siRNA to T-lymphocyte Hut78 and Jurkat cells, but silencing of a model protein (Green Fluorescent Protein, GFP) was possible only in the Hut78 cells. To enhance siRNA delivery to Hut78 cells, a high siRNA: carrier ratio used to assemble the complexes and centrifugation of cells in the presence of complexes were found effective. The toxicities of PEI-CA and PEI-LA were significantly lower than other commercial carriers, 25 kDa PEI and Lipofectamine(®) RNAiMAX. This might have contributed to reduced siRNA delivery efficiency of the latter carriers. Screening several endogenous targets led us to identify phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and cyclin-dependent kinase 18 (CDK18) as viable targets to induce siRNA-mediated cell growth inhibition. The results of this study identified promising polymeric carriers and molecular targets that could control proliferation of CTCL cells based on RNAi therapy.
authors.affiliation: Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2V2, Canada.
authors.forename: Başak
authors.initials: B
authors.lastname: Sahin
authors.affiliation: Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, Alberta T6G 2G6, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Fife
authors.affiliation: Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 1E2, Canada.
authors.forename: Manoj B
authors.initials: MB
authors.lastname: Parmar
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.affiliation: Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2V2, Canada.
authors.forename: Hilal
authors.initials: H
authors.lastname: Gul-Uludağ
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta T6G 2G6, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Weinfeld
authors.affiliation: Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, Alberta T6G 2G6, Canada; Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 1E2, Canada.
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Lavasanifar
authors.affiliation: Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2V2, Canada; Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, Alberta T6G 2G6, Canada; Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 1E2, Canada. Electronic address: hasan.uludag@ualberta.ca.
authors.forename: Hasan
authors.initials: H
authors.lastname: Uludağ
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry*; D020868:Gene Silencing; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D016410:Lymphoma, T-Cell, Cutaneous / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011094:Polyethyleneimine / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D034622:RNA Interference / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology*
chemical_list: D004337:Drug Carriers; D011108:Polymers; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D011094:Polyethyleneimine; D019869:Phosphatidylinositol 3-Kinases; D018844:Cyclin-Dependent Kinases; C089464:PCTAIRE-3 protein kinase
keywords: Cutaneous T-cell lymphoma; Lipophilic polymer; Non-viral delivery; PI3K silencing; siRNA therapy