Samarwadee Plianwong1,2, Bindu Thapa3, Remant Bahadur Kc1, Cezary Kucharski1, Theerasak Rojanarata2, Hasan Uludağ4,5,6,7. 1. Department of Chemical & Material Engineering, Faculty of Engineering, University of Alberta, Edmonton, Canada. 2. Faculty of Pharmacy, Silpakorn University, Bangkok, Thailand. 3. Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Canada. 4. Department of Chemical & Material Engineering, Faculty of Engineering, University of Alberta, Edmonton, Canada. hasan.uludag@ualberta.ca. 5. Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Canada. hasan.uludag@ualberta.ca. 6. Department of Biomedical Engineering, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada. hasan.uludag@ualberta.ca. 7. Chemical & Materials Engineering Department, 2-021 RTF, University of Alberta, Edmonton, Alberta, Canada. hasan.uludag@ualberta.ca.
Abstract
PURPOSE: Short interfering RNA (siRNA) therapy promises a new era in treatment of breast cancers but effective delivery systems are needed for clinical use. Since silencing complementary targets may offer improved efficacy, this study was undertaken to identify non-viral carriers for combinatorial siRNA delivery for more effective therapy. METHODS: A library of lipid-substituted polymers from low molecular weight polyethyleneimine (PEI), linoleic acid (LA) and α-linoleic acid (αLA) with amide or thioester linkages was prepared and investigated for delivering Mcl-1, survivin and STAT5A siRNAs in breast cancer cells. RESULTS: The effective polymers formed 80-190 nm particles with similar zeta-potentials, but the serum stability was greater for complexes formed with amide-linked lipid conjugates. The LA and αLA substitutions, with the low molecular weight PEI (1.2 kDa and 2.0 kDa) were able to deliver siRNA effectively to cells and retarded the growth of breast cancer cells. The amide-linked lipid substituents showed higher cellular delivery of siRNA as compared to thioester linkages. Upon combinational delivery of siRNAs, growth of MCF-7 cells was inhibited to a greater extent with 2.0PEI-LA9 mediated delivery of Mcl-1 combined survivin siRNAs as compared to individual siRNAs. The qRT-PCR analysis confirmed the decrease in mRNA levels of target genes with specific siRNAs and 2.0PEI-LA9 was the most effective polymer for delivering siRNAs (either single or in combination). CONCLUSIONS: This study yielded effective siRNA carriers for combinational delivery of siRNAs. Careful choice of siRNA combinations will be critical since targeting individual genes might alter the expression of other critical mediators.
PURPOSE: Short interfering RNA (siRNA) therapy promises a new era in treatment of breast cancers but effective delivery systems are needed for clinical use. Since silencing complementary targets may offer improved efficacy, this study was undertaken to identify non-viral carriers for combinatorial siRNA delivery for more effective therapy. METHODS: A library of lipid-substituted polymers from low molecular weight polyethyleneimine (PEI), linoleic acid (LA) and α-linoleic acid (αLA) with amide or thioester linkages was prepared and investigated for delivering Mcl-1, survivin and STAT5A siRNAs in breast cancer cells. RESULTS: The effective polymers formed 80-190 nm particles with similar zeta-potentials, but the serum stability was greater for complexes formed with amide-linked lipid conjugates. The LA and αLA substitutions, with the low molecular weight PEI (1.2 kDa and 2.0 kDa) were able to deliver siRNA effectively to cells and retarded the growth of breast cancer cells. The amide-linked lipid substituents showed higher cellular delivery of siRNA as compared to thioester linkages. Upon combinational delivery of siRNAs, growth of MCF-7 cells was inhibited to a greater extent with 2.0PEI-LA9 mediated delivery of Mcl-1 combined survivin siRNAs as compared to individual siRNAs. The qRT-PCR analysis confirmed the decrease in mRNA levels of target genes with specific siRNAs and 2.0PEI-LA9 was the most effective polymer for delivering siRNAs (either single or in combination). CONCLUSIONS: This study yielded effective siRNA carriers for combinational delivery of siRNAs. Careful choice of siRNA combinations will be critical since targeting individual genes might alter the expression of other critical mediators.
Authors: Manoj B Parmar; Hamidreza Montazeri Aliabadi; Parvin Mahdipoor; Cezary Kucharski; Robert Maranchuk; Judith C Hugh; Hasan Uludağ Journal: Front Bioeng Biotechnol Date: 2015-02-16
Authors: Mahsa Mohseni; Cezary Kucharski; Remant Bahadur K C; Mohammad Nasrullah; Xiaoyan Jiang; Hasan Uludağ; Joseph Brandwein Journal: PLoS One Date: 2021-06-22 Impact factor: 3.240