CHEMICAL DRUG-ASSISTED GENE TRANSFER: A SENSIBLE APPROACH TO IMPROVE TRANSGENE EXPRESSION IN THE CENTRAL NERVOUS SYSTEM GUO HAIYAN NATIONAL UNIVERSITY OF SINGAPORE 2006 CHEMICAL DRUG-ASSISTED GENE TRANSFER: A SENSIBLE APPROACH TO IMPROVE TRANSGENE EXPRESSION IN THE CENTRAL NERVOUS SYSTEM GUO HAIYAN (B.M., PRC) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF BIOLOGICAL SCIENCES NATIONAL UNIVERSITY OF SINGAPORE & INSTITUTE OF BIOENGINEERING AND NANOTECHNOLOGY 2006 ACKNOWLEDGMENT I would like to express my sincere thanks and appreciation to my supervisor A/P Wang Shu, for his full support, invaluable guidance, and excellent advice on my research work, as well as his kind understanding and encouragement during my depression period when my work was not going well Without his great help my work would not be done smoothly I also want to sincerely thank my co-supervisor, A/P Lim Tit Meng, for his invaluable support, suggestions and encouragement on my research projects, and for his bright and optimistic smiles which really relieved my stress and strengthened my confidence My sincere thanks also go to A/P Sheu Fwu Shan and Dr Lim Kah Leong, for their sparking ideas and suggestions in our journal club which benefit me a lot Also I would sincerely thank all my dear lab members in IBN and DBS labs for their support and contributions to my work, especially Dr Jurvansuu Jaana, who is my excellent consultant on my experiments and thesis writing; also Dr Wang Xu, Dr Tang Guping, Dr Wang Chaoyang for their special technique support on my projects; and Dr The Hui Leng Christina, who is always there helping around and fully supports me without any hesitation; and Dr Leong Sai Mum who is always giving me valuable advice on my experiments and thesis I I would like to thank my dear parents and husband, who are always standing behind supporting and encouraging me, and whatever they could to help me Special thanks also go to my other friends in NUS and IBN for their kind concerns and moral support II PUBLICATIONS International journals Guo, H Y., S Wang “Enhanced Baculovirus-Mediated p53 Gene Therapy by A Histone Deacetylase Inhibitor, Sodium Butyrate, for Glioblastoma.” (manuscript) Guo, H Y., J M Zeng, W M Fan, S Wang “Downregualtion of Multidrug Transporter P-Glycoprotein Increases Polyethylenimine-Mediated Gene Expression in Tumor Cells.” (manuscript) Wang, C Y., F Li, Y Yang, H Y Guo, C X Wu and S Wang (2006) "Recombinant baculovirus containing the diphtheria toxin A gene for malignant glioma therapy." Cancer Res 66(11): 5798-806 Tang, G P., H Y Guo, F Alexis, X Wang, S Zeng, T M Lim, J Ding, Y Y Yang and S Wang (2006) "Low molecular weight polyethylenimines linked by beta-cyclodextrin for gene transfer into the nervous system." J Gene Med 8(6): 736-44 Wang, C Y., H Y Guo, T M Lim, Y K Ng, H P Neo, P Y Hwang, W C Yee and S Wang (2005) "Improved neuronal transgene expression from an AAV-2 vector with a hybrid CMV enhancer/PDGF-beta promoter." J Gene Med 7(7): 945-55 III Li, Y., X Wang, H Y Guo and S Wang (2004) "Axonal transport of recombinant baculovirus vectors." Mol Ther 10(6): 1121-9 Conferences Guo, H Y., S Wang Enhanced Baculovirus Mediated Gene Therapy by Histone Deacetylase Inhibitor for Glioma (oral presentation) Institute of Bioengineering &Nanotechnology Postgraduate Student Symposium, June 2006, Singapore Guo, H Y., J M Zeng, W M Fan, S Wang Downregulation of Multidrug Transporter P-glycoprotein Increases Polyethylenimine-mediated Gene Expression in Tumor Cells (Poster) Institute of Bioengineering &Nanotechnology Research Symposium, September 2005, Singapore Guo, H Y., C Y Wang, S Wang Neuronal Specific Gene Delivery with A Chimeric CMV IE/PDGF Promoter in A Rat Model (Poster) The 4th Sino-Singapore Conference in Biotechnology November 2003, Singapore Guo, H Y., C Y Wang, S Wang Neuronal Specific Gene Delivery with A Chimeric CMV IE/PDGF Promoter in A Rat Model (Oral Presentation) 8th Biological Sciences Graduate Congress December 2003, Singapore IV CONTENTS PAGE ACKNOWLEDGEMENT I PUBLICATIONS III TABLE OF CONTENTS V SUMMARY IX LIST OF FIGURES XI ABBREVIATION XIII Chapter Introduction 1.1 Current progress in gene therapy 1.2 Gene delivery vectors in central nervous system (CNS) 1.2.1 Non-viral vectors 1.2.1.1 Naked DNA 1.2.1.2 Cationic lipids 1.2.1.3 Cationic polymers 1.2.1.4 Chemical modifications of PEI to facilitate gene delivery 1.2.1.4.1 Polyethylene glycol (PEG) modified PEI 1.2.1.4.2 Ligands modified PEI 1.2.1.4.3 Cross-linking of PEI 10 1.2.1.5 PEI-mediated gene delivery to tumor cells 1.2.2 Viral vectors 1.2.2.1 Adenovirus (Ad) 13 17 18 V 1.2.2.2 Adeno-associated virus (AAV) 18 1.2.2.3 Retrovirus 19 1.2.2.4 Baculovirus 19 1.2.3 Epigenetic gene regulation by chemical compounds, histone deacetylase inhibitors 1.3 Objective of current study 22 24 Chapter Low Molecular Weight Polyethylenimines Modified by β-Cyclodextrin for Improved Gene Delivery 27 2.1 Introduction 28 2.2 Materials and Methods 30 2.2.1 Materials 31 2.2.2 Preparation of PEI 600-CyD copolymer 31 2.2.3 Reporter plasmid and polymer /DNA complexes 31 2.2.4 MTT cytotoxicity assay 32 2.2.5 Gene transfection assay 32 2.3 Results 2.3.1 Effects of PEI600-CyD copolymer on cell survival 35 35 2.3.2 Gene expression mediated by PEI600-CyD copolymer In vitro 35 2.3.3 Gene expression mediated by PEI600-CyD copolymer In vivo 2.4 Discussion 35 43 Chapter Down-regulation of P-Glycoprotein Increases VI Polyethylenimine-mediated Gene Expression 50 3.1 Introduction 51 3.2 Materials and Methods 55 3.2.1 Cell lines and culture 55 3.2.2 Preparation of PEI/DNA complexes 56 3.2.3 Gene delivery in vitro and luciferase activity assay 56 3.2.4 Rhodamine efflux analysis 57 3.2.5 siRNA preparation and transfection 57 3.2.6 Reverse transcription-polymerase chain reaction (RT-PCR) 58 3.2.7 Western blotting 58 3.3 Results 59 3.3.1 Effect of verapamil on PEI-mediated gene delivery in drug resistant tumor cell lines 59 3.3.2 PEI-mediated gene delivery in PGP-positive and PGP-negative tumor cells 60 3.3.3 PEI /DNA complexes inhibit rhodamine 123 efflux in PGP-positive tumor cells 61 3.3.4 PEI-mediated gene delivery efficiency in PGP down-regulated tumor cells 62 3.4 Discussion 72 Chapter A Histone Deacetylase Inhibitor Improves Baculovirus-mediated Gene Therapy in Malignant Gliomas 77 4.1 Introduction 78 VII 4.2 Materials and Methods 83 4.2.1 Cell lines and culture 83 4.2.2 Baculovirus vectors 83 4.2.3 Baculovirus transduction 85 4.2.4 Luciferase activity assay 85 4.2.5 Western blotting 86 4.2.6 Immunohistochemistry 86 4.2.7 MTT cytotoxicity assay 87 4.2.8 TUNEL staining 87 4.2.9 Flow cytometry 87 4.2.10 In vivo study 88 4.3 Results 89 4.3.1 Sodium butyrate improved baculovirus-mediated transgene expression in cultured glioma cells 89 4.3.2 Cytotoxicity of baculovirus-mediated p53 and/or sodium butyrate in vitro 93 4.3.3 Apoptosis in U251 cells treated with baculovirus-mediated p53 and /or sodium butyrate 94 4.3.4 Enhanced antitumor effect in vivo by combination of and sodium butyrate therapy 96 4.4 Discussion 115 Chapter 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APPROACH TO IMPROVE TRANSGENE EXPRESSION IN THE CENTRAL NERVOUS SYSTEM GUO HAIYAN (B.M., PRC) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR... or interfere with disease-causing processes(Factor, 2001) The original goal of gene therapy was to correct a genetic disorder by inserting a functional gene into an organism to replace an inherited