Understanding the Benefits and Limitations of Magnetic Nanoparticle Heating for Improved Applications in Cancer Hyperthermia and Biomaterial Cryopreservation

Understanding the Benefits and Limitations of Magnetic Nanoparticle Heating for Improved Applications in Cancer Hyperthermia and Biomaterial Cryopreservation

Understanding the Benefits and Limitations of Magnetic Nanoparticle Heating for Improved Applications in Cancer Hyperthermia and Biomaterial Cryopreservation A DISSERTATION SUBMITTED TO THE FACULTY OF UNIVERSITY OF MINNESOTA BY Michael L. Etheridge IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY Advisor: John C. Bischof December 2013 © Michael L. Etheridge 2014 Acknowledgements This work would not have been possible without the support (both professional and personal) of a great number of people. First, I would like to thank my advisor, Professor John Bischof, for his guidance throughout this endeavor. I waded into the Ph.D. program because I wanted to be sure that I could find a project I cared about and an advisor that I respected and could learn from. I think I developed a lot during my time here in the Bioheat and Mass Transfer Lab, thanks in a large part to our candid (and sometimes “lively”) discussions. Although our approaches may have differed, I think it provided overall for a great process and I am very proud of my work here. One of the greatest opportunities (and challenges) of this project was the collaborative nature of this research. Specifically, I would like to thank Dr. Steven Girshick (Mechanical Engineering), Dr. Rhonda Franklin (Electrical and Computer Engineering), Dr. Michael Garwood (Center for Magnetic Resonance Research), Dr. Jack Hoopes (Dartmouth College), Dr. Christy Haynes (Chemistry), and Dr. Chris Hogan (Mechanical Engineering), for a wide variety of technical and general direction over the years. In addition, Katie Hurley, Dr. Jeunghwan Choi, Zhenpeng Qin, Chunlan Jiang, Dr. Ryan Chamberlain, Jinjin Zhang, Seongho Jeon, Steven Jackson, Dushyant Mehra, Connie Chung, Dr. Alicia Petryk, and Robby Stigliano, offered significant intellectual and experimental support at various points in my program. My program also offered the unique opportunity to work on a diverse team investigating the ethical and regulatory considerations involved with the use of developmental nanomaterials in medicine. I would like to thank Dr. Jeff McCullough and Susan Wolf, J.D., for this chance to gain a broader scientific perspective and for the financial support i during the first years of my program (National Institutes of Health (NIH) / National Human Genome Research Institute (NHGRI) grant #1-RC1-HG005338-01). Additional financial support was also provided by the Minnesota Futures Grant Program, the National Science Foundation (NSF/CBET #1066343 and # 1336659), and the University of Minnesota Institute for Engineering Medicine Seed Grant Program. Last, but certainly not least, I would like to thank my family and friends for helping me maintain some level of balance (and sanity) through it all. Thanks to my parents for everything they have given me. Thanks to my sisters and brothers (and by proxy, my nieces and nephews) for being there to make me laugh. Thanks to my friends for all the good times and for picking things up where they left off when I’d disappear for months at a time. And finally, thanks to my incredibly understanding girlfriend, Nikki Brubaker, for keeping my life exciting. ii Dedication I would like to dedicate this thesis to my incredible parents, David and Catherine Etheridge. Their hard work, endless support and encouragement, and caring for everyone around them, has set an amazing example to live by and I hope that they realize it is reflected in their children and family. iii Abstract Magnetic nanoparticles are gaining traction in a wide variety of biomedical applications, ranging from diagnosis to treatment. While these applications take advantage of a number of unique behaviors occurring at the nanoscale, including influences to biodistribution, cellular interactions, imaging contrast, and magnetic forces, the current work focused on the ability of magnetic nanoparticles to produce heat in the presence of an applied alternating magnetic field. Magnetic nanoparticle hyperthermia applications utilize this behavior to treat cancer and this approach has received clinical approval in the European Union, but significant developments are necessary for this technology to have a chance for wider-spread acceptance. Here then we begin by investigating some of the important limitations of the current technology. By characterizing the ability of superparamagnetic and ferromagnetic nanoparticles to heat under a range of applied fields, we are able to determine the optimal field settings for clinical application and make recommendations on the highest impact strategies to increase heating. In addition, we apply these experimentally determined limits to heating in a series of heat transfer models, to demonstrate the therapeutic impact of nanoparticle concentration, target volume, and delivery strategy. Next, we attempt to address one of the key questions facing the field- what is the impact of biological aggregation on heating? Controlled aggregate populations are produced and characterized in ionic and protein solutions and their heating is compared with nanoparticles incubated in cellular suspensions. Through this investigation we are able to demonstrate that aggregation is responsible for up to a 50% decrease in heating. However, more importantly, we are able to demonstrate that the observed reductions in iv heating correlate with reductions in longitudinal relaxation (T1) measured by sweep imaging with Fourier transformation (SWIFT) magnetic resonance imaging (MRI), providing a potential platform to account for these aggregation effects and directly predict heating in a clinical setting. Finally, we present a new application for magnetic nanoparticle heating, in the thawing of cryopreserved biomaterials. A number of groups have demonstrated the ability to rapidly cool and preserve tissues in the vitreous state, but crystallization and cracking failures occur upon the subsequent thaw. Magnetic nanoparticles offer a potential solution to these issues, through their ability to provide rapid, uniform heating, and we illustrate this through experiments in several cryoprotectant solutions and by modeling the effects of heating at the bulk and micro-scales. v Tables of Contents List of Tables ............................................................................................................... ix List of Figures ............................................................................................................. xi 0. Preface ..................................................................................................................... 1 1. Magnetic Nanoparticles for Cancer Therapy ...................................................... 4 1.1 Introduction ....................................................................................................... 4 1.2 Scientific Background ....................................................................................... 7 1.2.1 Physical Principles ................................................................................... 7 1.2.2 Effects of AC Magnetic Fields in Human Application: Calculations and Clinical Experience ........................................................................................ 8 1.2.3 Activation of Iron Oxide Nanoparticles in Alternating Magnetic Fields ... 11 1.2.4 Alternating Magnetic Field Generation .................................................... 23 1.3 Synthesis and Modification of Iron Oxide Nanoparticles ................................. 25 1.3.1 Synthesis and Core-Shell Structures ...................................................... 25 1.3.2 Characterization ....................................................................................... 29 1.4 Biological Effects .............................................................................................. 30 1.4.1 Effects of Nanoparticle Surface Coating ................................................. 30 1.4.2 Thermal Dose In Vitro .............................................................................. 34 1.4.3 Thermal Dose In Vivo .............................................................................. 35 1.5 Clinical Application in Cancer Therapy ............................................................ 39 1.5.1 Components of a Clinical MFH Thermotherapy System ........................ 39 1.5.2 Clinical Results ........................................................................................ 49 1.6 What Comes Next? ........................................................................................... 55 vi 2. Optimizing Magnetic Nanoparticle Based Thermal Therapies within the Physical Limits of Heating ...................................................................................................... 59 2.1 Introduction ....................................................................................................... 60 2.2 Methods ............................................................................................................ 63 2.2.1 Nanoparticles ........................................................................................... 63 2.2.2 Alternating Magnetic Field (AMF) ............................................................ 64 2.2.3 Measuring SAR ........................................................................................ 64 2.2.4 Theoretical Specific Absorption Rate ...................................................... 65 2.2.5 Measuring Heating in Microvolume Droplets .......................................... 66

View Full Text

Details

  • File Type
    pdf
  • Upload Time
    -
  • Content Languages
    English
  • Upload User
    Anonymous/Not logged-in
  • File Pages
    239 Page
  • File Size
    -

Download

Channel Download Status
Express Download Enable

Copyright

We respect the copyrights and intellectual property rights of all users. All uploaded documents are either original works of the uploader or authorized works of the rightful owners.

  • Not to be reproduced or distributed without explicit permission.
  • Not used for commercial purposes outside of approved use cases.
  • Not used to infringe on the rights of the original creators.
  • If you believe any content infringes your copyright, please contact us immediately.

Support

For help with questions, suggestions, or problems, please contact us