Label free electrochemical DNA and protein detection using ruthenium complexes and functional polyethylenedioxythiophenes

LABEL-FREE ELECTROCHEMICAL DNA AND PROTEIN DETECTION USING RUTHENIUM COMPLEXES AND FUNCTIONAL POLYETHYLENEDIOXYTHIOPHENES XIE HONG (M Sc., NUS) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2008 LIST OF PUBLICATIONS Tansil, N C.; Xie, H.; Xie, F.; Gao, Z Q., Direct detection of DNA with an electrocatalytic threading intercalator Analytical Chemistry 2005, 77, (1), 126-134 Tansil, N C.; Xie, F.; Xie, H.; Gao, Z Q., An ultrasensitive nucleic acid biosensor based on the catalytic oxidation of guanine by a novel redox threading intercalator Chemical Communications 2005, (8), 1064-1066 Xie, H.; Tansil, N C.; Gao, Z Q., A redox active and electrochemiluminescent threading bis-intercalator and its applications in DNA assays Frontiers in Bioscience 2006, 11, 1147-1157 Xie, H.; Yang, D W.; Heller, A.; Gao, Z Q., Electrocatalytic oxidation of guanine, guanosine, and guanosine monophosphate Biophysical Journal 2007, 92, (8), L70L72 Luo, S-C; Xie, H.; Chen, N Y.;Yu, H-h; Ying, J Y., Functional PEDOT thin film for electrochemical DNA biosensing and controlled cell adhesion To be submitted Xie, H.; Luo, S-C; Yu, H-h; Ying, J Y., Functional PEDOT nanowires for label-free protein detection To be submitted Patents and Technology Disclosures: Xie, H., Gao Z.Q., Xie, F., Determination of nucleic acid using electrocatalytic intercalators, WO 2006/025796, US 2006/0046254, Mar 2006 Yu, H-H, Ying, J Y-R., Luo, S-C, Xie, H., Chen, N.Y., polyethylenedioxythiophene (PEDOT) biointerfaces for DNA detection, IBN Technology Disclosure, Nov 2006 Yu, H-H., Ying, J Y-R, Xie, H., Kantchev, E A B, Luo, S-C., Non-fouling polyethylenedioxythiophene (PEDOT) biointerfaces for controlled adhesion of cells and proteins, IBN Technology Disclosure, Jun 2007 Conference Presentations: Xie, H.; Luo, S-C; Yu, H-h; Ying, J Y., Non-fouling PEDOT for controled cell adhesion, Oral presentation, NanoBioEurope 2008, Barcelona, 9-13 Jun 2008 Xie, H.; Luo, S-C; Chen, N Y.; Yu, H-h; Ying, J Y., Functional PEDOTs for electrochemical biosensors, Oral presentation, Regional Electrochemical Meeting of South-East Aisa 2008, Singapore, 5-7 Aug 2008 ACKNOWLEDGEMENTS It is a pleasure to thank many people who made this thesis possible I would like to start by thanking my advisor, Dr Hsiao-hua (Bruce) Yu, for his enthusiastic supervision; and my co-advisor, Dr Choon Hong Tan, for many valuable advices I would also like to thank my ex-advisors, Dr Zhiqiang Gao and Dr Daiwen Yang Although they are unable to guide me throughout my whole PhD work, I am grateful to their guidance and mentorship during my first year I am very grateful to Prof Jackie Y Ying and Ms Noreena AbuBarka for allowing me to pursue my dreams in Institute of Bioengineering and Nanotechnology (IBN) I truly appreciate their constant support over the years Without them, IBN would not be so successful today and I would not be able to finish my projects so smoothly My gratitude also extends to all IBN administrative staffs for their general support Many wonderful friends have kept me balanced and lighthearted through my graduate study They have contributed to this thesis along the way I would like to especially thank Dr Shyh-Chyang Luo, Zaoli Zhang, Natalia Tansil, Emril Ali, Naiyan Chen, Dr Eric Kantchev, Dr Shujun Gao, Dr Han Yu, Dr Hongwei Gu, Dr Alex Lin, Shawn Tan, Dr Jiang Jiang, Dr Majad Khan, James Hsieh, Guangrong Peh, Huilin Shao, Dr Peggy Chan and Lishan Wang I am thankful for their valuable discussions, assistance, friendship, and for making my stay in IBN enjoyable I would like to express my deepest gratitude to those who helped me get through the difficult times I thank you for all the emotional support, entertainment and caring you provided i Finally I am forever indebted to my family for their love and understanding I would like to thank my parents for their endless support when it was most needed This thesis is dedicated to you Last but not least, I would like to thank IBN, BMRC and A*Star for the funding ii TABLE OF CONTENTS List of Publications Acknowledgements Table of Contents Summary List of Abbreviations List of Figures, Schemes and Tables Introduction 1.1 Background 1.1.1 Electrochemical Biosensors 1.1.2 Label-Free Electrochemical/Electrical Assays 1.1.3 Electroactive Conducting Polymers for Biosensing .10 1.2 Motivation and Objectives .11 1.3 Scope 12 1.4 Thesis Outline 12 Ruthenium-Complexed Electroactive Intercalators for Label-Free DNA Detection 14 2.1 Introduction .14 2.2 Experimental .18 2.2.1 Materials and Reagents 18 2.2.2 Synthesis of Electroactive DNA Intercalators 19 2.2.3 Apparatus .22 2.2.4 Sensor Construction 23 2.3 Results and Discussion .25 iii 2.3.1 Synthesis and Characterization of Electroactive DNA Intercalators 25 2.3.2 Intercalation with DNA 29 2.3.3 Application for Label-free DNA Detection 33 2.4 Conclusions .43 Ruthenium-Based Polymer Complexes for Electrocatalytic Guanine Oxidation 44 3.1 Introduction .44 3.2 Experimental .46 3.2.1 Materials and Reagents 46 3.2.2 Synthesis of Ruthenium-complexed Redox Polymers 46 3.2.3 Preparation of Redox Polymer Modified Electrodes 49 3.2.4 Apparatus .49 3.3 Results and Discussion .50 3.3.1 Synthesis and Characterization of Redox Polymers 50 3.3.2 Redox Polymer Modified Electrode 53 3.3.3 Electrocatalytic Oxidation of Guanine on Modified Electrode 54 3.3.4 Redox Titration .56 3.3.5 Oxidation of Guanosine and Guanosine Monophosphate (GMP) .58 3.4 Conclusions .60 Nanostructured Functional Polyethylenedioxythiophenes (PEDOTs) 61 4.1 Introduction .61 4.1.1 Conducting Polymers 61 4.1.2 Nanostructured Conducting Polymers 63 4.1.3 Synthesis of 1-D Conducting Polymer Nanostructures 64 iv 4.1.4 1-D Polyethylenedioxythiophene (PEDOT) Nanostructures .65 4.2 Experimental .66 4.2.1 Materials and Reagents 66 4.2.2 Chemical Polymerization .67 4.2.3 Electrochemical Polymerization 68 4.2.4 Characterization 68 4.3 Results and Discussion .68 4.3.1 Surfactant Template-Guided Nanofiber Synthesis .68 4.3.2 Stepwise Electropolymerization 73 4.3.3 Electrical Field-Assisted Nanowire Growth 77 4.4 Conclusions .79 PEDOT Nanowires for Label-Free Protein Detection 81 5.1 Introduction .81 5.2 Experimental Section 83 5.2.1 Materials and Reagents 83 5.2.2 Device Fabrication and Nanowire Synthesis .83 5.2.3 Aptamer Immobilization and Protein Binding 84 5.2.4 Electrical Measurement 84 5.3 Results and Discussion .85 5.3.1 Device Characteristics 85 5.3.2 Biomolecule Conjugation .86 5.3.3 Protein Detection 88 5.3.4 1-D Nanostructure vs 2-D Film 91 5.4 Conclusions .93 v Functional PEDOT Nanobiointerface: Toward in vivo Applications 95 6.1 Introduction .95 6.2 Experimental .97 6.2.1 Materials and Reagents 97 6.2.2 Electropolymerization and Film Synthesis 98 6.2.3 Electrochemical Characterization 99 6.2.4 Polymer Film Analysis 99 6.2.5 Protein Adsorption 100 6.2.6 Cell Culture 100 6.3 Results and Discussions 102 6.3.1 Synthesis and Characterization of Functional PEDOT Thin Films 102 6.3.2 Biocompatibility of Functional PEDOT Thin Films 106 6.3.3 Adhesive and Non-adhesive PEDOT Nanobiointerfaces 107 6.3.4 Controlled Cell Patterning 110 6.3.5 Biotin-functionalized PEDOT Nanobiointerface 111 6.3.6 Peptide-functionalized PEDOT Nanobiointerface 115 6.4 Conclusions .120 Conclusions and Outlook 121 References vi SUMMARY This thesis presents our studies on the development of label-free electrochemical biosensors for DNA/protein detection The urgent need for the development of point-of-care devices for the detection of infectious agents and cancer-related biomarkers motivate us to keep searching for simple, fast, sensitive yet affordable analytical tools We have demonstrated two very different approaches for label-free DNA/protein detection with electrochemical transduction Rutheniumcomplexed electroactive DNA threading intercalators and aptamer-modified polyethylenedioxythiophene (PEDOT) nanowires were used as signal reporters for the corresponding binding events In part I, we studied label-free electrochemical DNA detection using ruthenium-complexed intercalators Two ruthenium-complexed electroactive DNA intercalators were synthesized, characterized, and their application for label-free DNA detection were investigated One based on electrochemiluminescence, and the other one based on electrocatalytic oxidation of guanine bases in the DNA sequences The electroactive intercalators are dual functional: selective binding of double-stranded DNA (ds-DNA) and generation of catalytic electrochemical signals This feature allows simple and sensitive detection Moreover, the oxidation potential of guanine base and its corresponding nucleoside and nucleotide under physiological buffer condition were determined experimentally first time by electrocatalytic oxidation titration using ruthenium-complexed redox polymer modified electrode In part II, we explored the use of a conducting polymer, functionalized polyethylenedioxythiophene (PEDOT), as an intrinsic transducer for label-free protein sensing Various approaches for the synthesis of 1-D PEDOT nanostructures were vii studied Functional PEDOT nanowires were directly synthesized across the electrode junction under the assistance of an external electric field Such PEDOT nanowires devices can be applied immediately after synthesis for field effect transistor (FET) based sensing, eliminating complicated post-synthesis alignment and assembly Label-free detection of a blood-clogging factor, thrombin, was demonstrated using aptamer-modified PEDOT nanowires In comparison with 2-D thin films, 1-D nanostructures are crucial for field effect transistor (FET) based sensing The PEDOT nanowire based sensing platform is applicable for label-free detection of DNA as well as proteins which their DNA aptamers are available Finally, we evaluated functional PEDOT thin films as tunable nanobiointerfaces for effective biomolecule immobilization and controlled cell adhesion, for future cell-based sensing and other in vivo applications Particularly, biotin-functionalized PEDOT surface and peptide-functionalized PEDOT surface were achieved through direct polymerization from mixed monomer solution and facile post-polymerization functionalization Specific protein adsorption and controlled cell attachment were demonstrated on these biologically-relevant functionalized PEDOT surfaces Similar modification is also feasible on nanostructured PEDOT surfaces, and we expect to see more exciting in vivo applications in the future viii 36 Kelley, S O.; Barton, J K.; Jackson, N M.; Hill, M G., Electrochemistry of methylene blue bound to a DNA-modified electrode Bioconjugate Chemistry 1997, 8, (1), 31-37 37 Wong, E L S.; Gooding, J J., Charge transfer through DNA: A selective electrochemical DNA biosensor Analytical Chemistry 2006, 78, (7), 2138-2144 38 Gooding, J J.; Chou, A.; Mearns, F J.; Wong, E.; Jericho, K L., The ion gating effect: using a 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