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Selection and Evaluation of a Silver Nanoparticle Imaging Agent for Dual-Energy Mammography

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Selection and Evaluation of a Silver Nanoparticle Imaging Agent for Dual-Energy Mammography University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2014 Selection and Evaluation of a Silver Nanoparticle Imaging Agent for Dual-Energy Mammography Roshan Anuradha Karunamuni University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Biomedical Commons Recommended Citation Karunamuni, Roshan Anuradha, "Selection and Evaluation of a Silver Nanoparticle Imaging Agent for Dual- Energy Mammography" (2014). Publicly Accessible Penn Dissertations. 1326. https://repository.upenn.edu/edissertations/1326 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/1326 For more information, please contact [email protected]. Selection and Evaluation of a Silver Nanoparticle Imaging Agent for Dual-Energy Mammography Abstract Over the past decade, contrast-enhanced (CE) dual-energy (DE) x-ray breast imaging has emerged as an exciting, new modality to provide high quality anatomic and functional information of the breast. The combination of these data in a single imaging procedure represents a powerful tool for the detection and diagnosis of breast cancer. The most widely used implementation of CEDE imaging is k-edge imaging, whereby two x-ray spectra are placed on either side of the k-edge of the contrast material. Currently, CEDE imaging is performed with iodinated contrast agents. The lower energies used in clinical DE breast imaging systems compared to imaging systems for other organs suggest that an alternative material may be better suited. We developed an analytical model to compare the contrast of various elements in the periodic table. The model predicts that materials with atomic numbers from 42 to 52 should provide the best contrast in DE breast imaging while still providing high-quality anatomical images. Upon consideration, silver was chosen for more detailed study. Through simulation and experimental validation, we determined that not only does silver perform better than iodine when imaged at their respective optimal conditions, but silver is able to provide higher levels of contrast than iodine when imaged with current protocols that are optimal for iodine. Therefore, a silver agent could be translated to the clinic without modification of existing imaging systems or techniques. A prototype silver agent was designed. The agent consists of (i) a silver core for DE contrast, (ii) a silica shell to prevent the release of toxic silver cations, and (iii) a polyethylene glycol layer to improve the biocompatibility of the entire nanostructure. DE imaging with the particles showed a 9-fold increase in contrast when injected into mice, while displaying no acutely toxic effects. The prototype silica-silver nanoparticles represent a first step in developing a biologically stable contrast agent that is specifically suited for DE breast imaging. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Bioengineering First Advisor Andrew D. Maidment Keywords dual-energy, mammography, nanoparticle, silver Subject Categories Biomedical This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/1326 SELECTION AND EVALUATION OF A SILVER NANOPARTICLE IMAGING AGENT FOR DUAL-ENERGY MAMMOGRAPHY Roshan Karunamuni A DISSERTATION in Bioengineering Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2014 Supervisor of Dissertation: _______________________________________________ Andrew D.A. Maidment, Ph.D. Associate Professor of Radiology Graduate Group Chairperson: _______________________________________________ Jason A. Burdick, Ph.D. Professor of Bioengineering Dissertation Committee: Andrew Tsourkas, Ph.D. Jim Delikatny, Ph.D. Associate Professor of Bioengineering Associate Professor of Radiology David Cormode, Ph.D. Assistant Professor of Radiology ABSTRACT SELECTION AND EVALUATION OF A SILVER NANOPARTICLE IMAGING AGENT FOR DUAL-ENERGY MAMMOGRAPHY Roshan Karunamuni Andrew D.A. Maidment, Ph.D. Over the past decade, contrast-enhanced (CE) dual-energy (DE) x-ray breast imaging has emerged as an exciting, new modality to provide high quality anatomic and functional information of the breast. The combination of these data in a single imaging procedure represents a powerful tool for the detection and diagnosis of breast cancer. The most widely used implementation of CEDE imaging is k-edge imaging, whereby two x-ray spectra are placed on either side of the k-edge of the contrast material. Currently, CEDE imaging is performed with iodinated contrast agents. The lower energies used in clinical DE breast imaging systems compared to imaging systems for other organs suggest that an alternative material may be better suited. We developed an analytical model to compare the contrast of various elements in the periodic table. The model predicts that materials with atomic numbers from 42 to 52 should provide the best contrast in DE breast imaging while still providing high-quality anatomical images. Upon consideration, silver was chosen for more detailed study. Through simulation and experimental validation, we determined that not only does silver perform better than iodine when imaged at their respective optimal conditions, but silver is able to provide higher levels of contrast than iodine when imaged with current protocols that are optimal for iodine. Therefore, a silver agent could be translated to the clinic without modification of existing imaging systems or techniques. A prototype silver agent was designed. The agent consists of (i) a silver core for DE contrast, (ii) a silica shell to prevent the release of toxic silver cations, and (iii) a polyethylene glycol layer to improve the biocompatibility of the entire nanostructure. DE imaging with the particles showed a 9-fold increase in contrast when injected into mice, while displaying no acutely toxic effects. The prototype silica-silver nanoparticles represent a first step in developing a biologically stable contrast agent that is specifically suited for DE breast imaging. ii TABLE OF CONTENTS ABSTRACT ....................................................................................................................... ii LIST OF TABLES ........................................................................................................... vi LIST OF ILLUSTRATIONS ......................................................................................... vii CHAPTER 1 .......................................................................................................................1 1. HISTORICAL PERSPECTIVE ......................................................................................................... 1 1.1 Non K-edge Imaging ..................................................................................................................... 1 1.2 K-edge Imaging ............................................................................................................................. 3 1.3 Current K-edge imaging in Mammography ................................................................................... 6 2. INDUSTRIAL INNOVATION .......................................................................................................... 8 3. CLINICAL IMPACT ....................................................................................................................... 11 4. COMMERCIAL CONTRAST AGENTS ........................................................................................ 15 5. ALTERNATIVES TO IODINE CONTRAST AGENTS ................................................................ 20 6. PREFACE TO DISSERTATION .................................................................................................... 22 CHAPTER 2 .....................................................................................................................24 ABSTRACT .............................................................................................................................................. 24 1. INTRODUCTION ............................................................................................................................ 25 2. METHODS ...................................................................................................................................... 28 2.1. Formulation of DE Signal Intensity ................................................................................................ 28 2.2. Calculation of Weighting Factor, Contrast and Contrast to Noise Ratio ........................................ 29 3. RESULTS ........................................................................................................................................ 31 3.1. Energy Dependence of W, SC, and CNR ........................................................................................ 31 3.2. Maximum CNR for each material .................................................................................................. 35 3.3. Candidate contrast materials for CEDE breast imaging ................................................................. 37 4. DISCUSSION .................................................................................................................................. 39 5. CONCLUSIONS .............................................................................................................................. 41
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