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On the Permeabilisation and Disruption of Cell Membranes by Ultrasound and Microbubbles

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On the Permeabilisation and Disruption of Cell Membranes by Ultrasound and Microbubbles On the Permeabilisation and Disruption of Cell Membranes by Ultrasound and Microbubbles By Raffi Karshafian A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Medical Biophysics University of Toronto Raffi Karshafian Doctor of Philosophy Thesis Department of Medical Biophysics, University of Toronto, Sunnybrook Health Sciences Centre, S639-2075 Bayview Avenue Toronto, Ontario M4N 3M5 Canada © Copyright by Raffi Karshafian 2010 ABSTRACT On the Permeabilisation and Disruption of Cell Membranes by Ultrasound and Microbubbles Raffi Karshafian Doctor of Philosophy Department of Medical Biophysics, University of Toronto, 2010 Therapeutic efficacy of drugs depends on their ability to reach the treatment target. Drugs that exert their effect within cells are constrained by an inability to cross the cell membrane. Methods are being developed to overcome this barrier including biochemical and biophysical strategies. The application of ultrasound with microbubbles increases the permeability of cell membranes allowing molecules, which otherwise would be excluded, to enter the intracellular space of cells; a phenomenon known as sonoporation. This thesis describes studies aimed at improving our understanding of the mechanism underpinning sonoporation and of the exposure parameters affecting sonoporation efficiency. Cancer cells (KHT-C) in suspension were exposed to ultrasound and microbubbles – total of 97 exposure conditions. The effects on cells were assessed through uptake of cell-impermeable molecules (10 kDa to 2 MDa FITC-dextran), cell viability and microscopic observations of the plasma membrane using flow cytometry, colony assay and electron microscopy techniques. Sonoporation was a result of the interaction of ultrasound and microbubbles with the cell membrane. Disruptions (30-100 nm) were generated on the cell membrane allowing cell impermeable molecules to cross the membrane. Molecules up to 2 MDa in size were delivered at high efficiency (~70% permeabilisation). Sonoporation was short lived; cells re-established their barrier function within one minute, which allowed compounds to remain inside the cell. Following uptake, cells remained viable; ~50% of sonoporated cells proliferated. Sonoporation efficiency depended on ultrasound and microbubble exposure conditions. Microbubble disruption was a necessary but insufficient indicator of ultrasound-induced permeabilisation. The exposure conditions can be tailored to achieve a desired effect; cell permeability of ~70% with ~25% cell death versus permeability of ~35% with ~2% cell death. In addition, sonoporation depended on position in the cell cycle. Cells in later stages were more prone to being permeabilised and killed by ultrasound and microbubbles. This study indicated that sonoporation can be controlled through exposure parameters and that molecular size may not be a limiting factor. However, the transient nature may necessitate that the drug be in close vicinity to target cells in sonoporation-mediated therapies. Future work will extend the investigation into in vivo models. ii To my wife Taleen and children Karnie, Tro and Meghrie To my parents, who gave up everything to give us a better life iii ACknowledgemenTS Dr. Peter N. Burns, my scientific mentor, provided an excellent environment to satisfy my scientific curiosity and the guidance in becoming an independent scientist, for which I am very grateful. I thank my supervisory committee members, Drs. Dick Hill, Kullervo Hynynen and Brian Wilson for their guidance and scientific discussions. Many colleagues including research engineers and graduate students provided support throughout my graduate years. Most notably, Ross Williams, Sanya Samac, Anoja Giles, Dr. Emmanuel Cherin, Dr. Peter D. Bevan and Kasia Harasiewicz. Steven Doyle (Microscopy Imaging Lab, University of Toronto) helped with electron microscopy preparations. I have also benefited from Drs. Gregory J. Czarnota and David E. Goertz scientific knowledge and insightful discussions. Finally, I am grateful for the continuous support from my family and friends throughout my academic path. This work was supported in part by the Canadian Institutes of Health Research (CIHR) Doctoral Award (3 years) and the Ontario Graduate Scholarship in Science and Technology (OGSST). iv TABle oF ConTenTS ABSTRACT ...................................................................................................................................ii Acknowledgements ....................................................................................................................... iv TABLE OF CONTENTS ............................................................................................................... v LIST OF TABLES ......................................................................................................................... x LIST OF FIGURES ...................................................................................................................... xi Chapter One Drug Delivery and Sonoporation 1.1 Introduction .............................................................................................................................. 1 1.2 The problems of anticancer therapeutic agents ........................................................................ 2 1.3 Biological barriers to anticancer agents ................................................................................... 2 1.3.1 Cell membrane barrier ...................................................................................................... 3 1.4 Delivery strategies for therapeutic agents ................................................................................ 4 1.4.1 Intracellular delivery strategies ......................................................................................... 4 1.5 Ultrasound and microbubbles in imaging and therapy ............................................................ 5 1.5.1 Physics of ultrasound ........................................................................................................ 5 1.5.2 Ultrasound in imaging and therapy ................................................................................... 6 1.5.3 Ultrasound microbubble contrast agents ........................................................................... 6 1.5.4 Ultrasound imaging with microbubbles ............................................................................ 8 1.5.5 Ultrasound therapy with microbubbles ............................................................................. 9 1.6 Sonoporation ............................................................................................................................ 9 1.6.1 Sonoporation Efficiency .................................................................................................. 10 1.6.2 Mechanism of Sonoporation ........................................................................................... 12 1.7 Sonoporation applications ...................................................................................................... 13 1.8 Thesis outline ......................................................................................................................... 14 Chapter Two Sonoporation by ultrasound-activated microbubble contrast agents: Effect of acoustic exposure parameters on cell membrane permeability and cell viability 2.0 Abstract .................................................................................................................................. 16 v 2.1 Introduction ............................................................................................................................ 16 2.2 Methods.................................................................................................................................. 17 2.2.1 In vitro cell model ........................................................................................................... 17 2.2.2 Ultrasound exposure system ........................................................................................... 18 2.2.3 Ultrasound microbubble agent ........................................................................................ 19 2.2.4 Microbubble size distribution: Coulter Counter ............................................................. 20 2.2.5 Reversible permeability and PI-viability: PR and VPI ...................................................... 20 2.2.6 Therapeutic Ratio: TRR ................................................................................................... 21 2.2.7 Experiments: Ultrasound exposure parameters .............................................................. 22 2.3 Results .................................................................................................................................... 24 2.3.1 Ultrasound exposure parameters ..................................................................................... 24 2.3.2 Optimisation of sonoporation: Therapeutic Ratio ........................................................... 30 2.3.3 Relationship between permeability and viability ............................................................ 34 2.3.4 Relationship between permeability and microbubble disruption .................................... 35 2.4 Discussion .............................................................................................................................. 36 2.4.1
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