Radiopharmaceuticals for Therapy

F. F. (Russ) Knapp • Ashutosh Dash

Radiopharmaceuticals for Therapy

ISBN 978-81-322-2606-2 ISBN 978-81-322-2607-9 (eBook) DOI 10.1007/978-81-322-2607-9

Library of Congress Control Number: 2015960843

Springer New Delhi Heidelberg New York Dordrecht London © Springer India 2016 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made.

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Springer (India) Pvt. Ltd. is part of Springer Science+Business Media (www.springer.com)

F. F. (Russ) Knapp Nuclear Security and Isotope Division Oak Ridge National Laboratory OAK RIDGE USA

Ashutosh Dash Isotope Production and Applications Division Bhabha Atomic Research Centre Mumbai India

www.springer.com

The authors dedicate this book to their families, mentors, and colleagues who have so strongly affected their professional careers. Russ Knapp offers his dedication to his parents, who inspired and supported a strong interest in science at an early age; to his wife and best friend Toni, who for over 50 years encouraged and, even in many cases, tolerated his professional work; and to their children Michael and Gina, who have made his more important personal life such a joy. He also expresses his personal thanks to his deceased important friend, Mr. A. P. Callahan, who as a mentor and colleague had taught him so much about science and life. Ashutosh Dash gives his dedication to his wife Sarita and son Shaswat, who stood by him through thick and thin, lifted him up when he was low, pushed him forward at diffi cult times, and never complained at all when times were diffi cult. Through lonely and diffi cult times, they gave him strength and encouraged him. He also expresses his personal thanks to Dr. Russ Knapp for believing, encouraging, understanding, and tolerating through the whole process of completing this book.

vii

The use of radioactivity for treatment of disease is more than a century old and began with the use of naturally occurring radium-226 in the early part of the twentieth century. However, the fi eld of radionuclide therapy (RNT) had not progressed as rapidly as probably anticipated due to the early failure due to absence of suitable targeting mechanisms. The use of artifi cially produced phosphorus-32 for the treatment of polycythemia vera beginning in the 1930s was a positive step which had stimulated the growth of this fi eld. The major breakthrough for RNT, however, was the use of iodine-131 for the treatment of thyroid cancer which began in 1946. The uptake of radioactive iodide anions is governed by a well-defi ned mechanism involving the sodium iodide symporter protein and is the most basic and fi nest example of molecular nuclear medicine. Normal thyroid tissue takes up around 30 % of ingested iodine, which represents the highest targeting that a drug can achieve. Iodine-131 continues to be widely used post surgically for the ablation of remnant cancer cells. Although a variety of radiopharmaceuticals were sub-sequently introduced in later years for treatment of some types of cancer and for palliation of pain due to bone metastases, widespread/routine use has not yet gained broad acceptability. Generally, the majority of the patients who have undergone unsuccessful treatment by alternative nonradioactive strate-gies who have few other options for success are often referred for nuclear medicine RNT as a last resort and mainly for palliative therapy. In fact, none of the other therapeutic radiopharmaceuticals introduced in the last century have been anywhere nearly successful like the use of iodine-131 for the treat-ment of thyroid cancer.

In this regard, introduction of peptide receptor radionuclide therapy (PRRNT) in the beginning of the current millennium for the treatment of neuroendocrine tumors (NETs) with beta-emitting is an important seminal exception. PRRNT utilizes low molecular weight radiolabeled peptides tar-geting to specifi c cell surface receptors which are very often upregulated on cancer cells. Although several radioisotopes have been identifi ed that are used for PRRNT, lutetium-177 and yttrium-90 are two key examples as radionu-clides used for both PRRNT and radioactive antibody targeting. Currently, PRRNT using somatostatin analog peptides is the most effi cacious mode of therapy for the treatment of inoperable NETs. However, NETs are tumors with relatively low incidence, and hence the total number of patients benefi t-ted is still very small. Another important developing theme is the use of alpha-emitting radioisotopes for therapy, and the commercialization and

Fore word

viii

routine clinical introduction of the Xofi go® (radium-223 chloride) for the treatment of castration-resistant prostate cancer is an important advance for the therapeutic arena.

However, the real success of PRRNT, as an example, will be demonstrated when suitable radiopharmaceuticals are developed for the treatment for major cancer entities, and success in this direction is already on the horizon. The pharmacophore, N-acetyl aspartyl glutamate (NAAG), radiolabeled with 68 Ga, for instance, is providing excellent PET images of patients presenting with prostate cancer. Adenocarcinoma of the prostate gland overexpresses prostate-specifi c membrane antigen (PSMA) which is targeted by NAAG. Because this is a small peptide, the radioactivity not attached to the targeted cancer cells is rapidly excreted, thereby providing excellent PET images of the cancer-affected areas. Lutetium-177-labeled NAAG is also under evaluation for the treatment of prostate cancer, and the male patient population who can benefi t from this PET technology is very large and is expected to dramatically change the trajectory of targeted therapy.

Growth in the development of therapeutic radiopharmaceuticals is linked to advances in many related disciplines, and molecular biology identifi es suit-able targets for different types of cancer. An in-depth understanding of the biochemical reactions occurring within the body is important to provide information which will help identify new targets. Once suitable target- seeking molecules are identifi ed, subsequent detailed research is required to develop a successful therapeutic radiopharmaceutical. These efforts include an evalu-ation for modifi cation of the target-seeking pharmacophore to provide suit-able radiolabeling without compromising the affi nity to the target. In addition, both in vitro and in vivo biological studies are required to demonstrate the targeting property, and preclinical evaluation and fi nally the demonstration of the clinical effi cacy must be established. A major goal which presents these challenges is the subsequent use in humans. Current regulations in most countries mandate that a radiopharmaceutical undergoes the same phase 0, I, II, and III studies before its market introduction as a product. Compliance with these regulatory requirements is diffi cult for a commercial radiopharma-ceutical manufacturer to justify, since the modest market volume for thera-peutic radiopharmaceuticals will often not qualify the high investment required for a clinical trial. The usual short shelf lives of radiopharmaceuti-cals do not allow large-scale manufacturing, and it is diffi cult for patent hold-ers to overcome the competition of use of generic radiopharmaceutical products. Hence, most discoveries in the therapeutic radiopharmaceutical arena are not used to the most effective extent for the benefi t of mankind. Nevertheless, the scientists working in this area put forth extensive efforts to develop new therapeutic radiopharmaceuticals.

There are many young colleagues who wish to work in the fascinating multidisciplinary fi eld of therapeutic radiopharmaceuticals, which, by nature, requires broad knowledge in many fi elds, which includes radioisotope pro-duction, chemistry, radiochemistry, and biology and physiology. There is extensive literature available on therapeutic radiopharmaceuticals; however, a primary source which will provide basic knowledge is highly useful, not only for new investigators in this area but also for those scientists, physicians, and

Foreword

ix

other professionals already working in the fi eld of nuclear medicine. For these reasons this book on “radiopharmaceuticals for therapy” authored by Prof. F. F. (Russ) Knapp and Dr. A. Dash is expected to fi ll an important niche in the literature. The 17 chapters span all key aspects describing the develop-ment and use of therapeutic radiopharmaceuticals. The expertise and exten-sive experience of these authors are refl ected in the appropriate selection of chapters and their contents. This book will be highly useful to scientists and nuclear medicine physicians working in this fascinating fi eld, and I am honored to have been given the opportunity to provide the Foreword to Therapeutic Radiopharmaceuticals .

Cochin, India M.R.A. Pillai, PhD, DSc

Foreword

xi

The authors extend their sincere appreciation to Dr. M. R. A. Pillai, Ph.D., D.Sc., for his vision in conceiving the important need for a book on therapeu-tic radiopharmaceuticals and for providing the Foreword . He had initially recommended this book to Springer Verlag and had encouraged the authors to move forward. The authors also thank their families for their patience and their colleagues who have helped in many different ways and who had pro-vided information and insights which encouraged the authors. Special thanks are also extended to Mr. Mark Dickey, a senior member of the ORNL techni-cal library staff, for his enthusiastic assistance in identifying and obtaining reference and reprint materials.

Acknowledgments

xiii

Contents

Part I Radiopharmaceuticals

1 Introduction: Radiopharmaceuticals Play an Important Role in Both Diagnostic and Therapeutic Nuclear Medicine . . . . . . 31.1 Introduction: Use of Radioisotopes in Nuclear Medicine . . . 31.2 Key Examples of Nuclear Medicine . . . . . . . . . . . . . . . . . . . . 4

1.2.1 Nuclear Medicine Imaging . . . . . . . . . . . . . . . . . . . . . 41.2.2 Molecular Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.2.3 In Vivo Function Tests . . . . . . . . . . . . . . . . . . . . . . . . . 61.2.4 Nuclear Medicine Therapy . . . . . . . . . . . . . . . . . . . . . 6

1.3 Radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61.3.1 Diagnostic Radiopharmaceuticals . . . . . . . . . . . . . . . . 81.3.2 Nuclear Medicine Imaging . . . . . . . . . . . . . . . . . . . . . 9

1.4 Therapeutic Radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . 131.4.1 Traditional Applications of Therapeutic

Radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . 141.4.2 Current and New Therapeutic Applications . . . . . . . . 15

1.5 Historical Timeline of Nuclear Medicine . . . . . . . . . . . . . . . . 171.6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

2 Therapeutic Radionuclides Decay with Particle Emission for Therapeutic Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252.2 Criteria for Selection of Therapeutic Radionuclides . . . . . . . 27

2.2.1 Particle Emission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272.2.2 Tissue Treatment Morphology . . . . . . . . . . . . . . . . . . 282.2.3 Radionuclide Half-Life . . . . . . . . . . . . . . . . . . . . . . . . 282.2.4 Radionuclide Decay Products . . . . . . . . . . . . . . . . . . . 282.2.5 Radionuclide Purity . . . . . . . . . . . . . . . . . . . . . . . . . . . 282.2.6 Gamma Emissions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282.2.7 Radiolabeling Chemistry . . . . . . . . . . . . . . . . . . . . . . . 292.2.8 Economic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

2.3 Beta-Particle-Emitting Radionuclides . . . . . . . . . . . . . . . . . . 292.4 Alpha-Particle-Emitting Radionuclides . . . . . . . . . . . . . . . . . 292.5 Low-Energy Electron Emitters . . . . . . . . . . . . . . . . . . . . . . . . 302.6 Radionuclide Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

xiv

2.6.1 Targets for Irradiation . . . . . . . . . . . . . . . . . . . . . . . . . 322.6.2 Production of Therapeutic Radionuclides . . . . . . . . . . 332.6.3 Auger Electron-Emitting Radionuclides . . . . . . . . . . . 332.6.4 Alpha-Particle-Emitting Radionuclides . . . . . . . . . . . 33

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

3 Alpha Radionuclide Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373.2 Alpha Particles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

3.2.1 Energy Dissipation of Alpha Particles in a Medium . . 383.2.2 Linear Energy Transfer (LET) . . . . . . . . . . . . . . . . . . . 383.2.3 Relative Biological Effectiveness (RBE) . . . . . . . . . . 393.2.4 Interaction of Alpha Particles in a Biological

System . . . . . . . . . . . . . . . . . . . . . . . . 403.2.5 Basis of Alpha Radionuclide Therapy . . . . . . . . . . . . . 403.2.6 Dosimetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

3.3 Alpha-Particle-Emitting Radionuclides for Radiotherapy . . . 423.3.1 Astatine-211 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423.3.2 Terbium-149 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473.3.3 Actinium-225 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473.3.4 Bismuth-213 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503.3.5 Bismuth-212 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513.3.6 Radium-223 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513.3.7 Radium-224 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523.3.8 Thorium-227 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

3.4 Summary: Future Prospects of Alpha Radionuclide Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

4 Auger Electron-Based Radionuclide Therapy . . . . . . . . . . . . . . 574.1 Introduction: Cancer Treatment with Radioisotopes . . . . . . . 574.2 Particle Emission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574.3 The Auger Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584.4 Cell Killing with Auger Electron Emitters . . . . . . . . . . . . . . . 584.5 The Importance of Auger Electron-Emitting

Radionuclides for Cancer Therapy . . . . . . . . . . . . . . . . . . . . . 604.6 Key Auger Emitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

4.6.1 Iodine-125 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614.6.2 Platinum-195m . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614.6.3 Rhodium-103m . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624.6.4 Holmium-161 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

4.7 Dosimetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634.7.1 Electron Transport Evaluation and Dosimetry

Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 644.7.2 Auger Electron Spectra . . . . . . . . . . . . . . . . . . . . . . . . 644.7.3 Energy Loss by Auger Electrons . . . . . . . . . . . . . . . . . 644.7.4 Dosimetry Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

4.8 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

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xv

Part II Production, Processing and Availability of Therapeutic Radioisotopes

5 Reactor-Produced Therapeutic Radionuclides . . . . . . . . . . . . . 715.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715.2 Reactor Production of Radionuclides . . . . . . . . . . . . . . . . . . . 715.3 Calculation of Production Yield . . . . . . . . . . . . . . . . . . . . . . . 715.4 Direct (n, γ) Activation (Radiative Route) . . . . . . . . . . . . . . . 735.5 Neutron Activation Followed by β− Decay (n, γ → β−) . . . . . . 735.6 The (n, p) Production Reaction . . . . . . . . . . . . . . . . . . . . . . . 745.7 Beta-Particle-Emitting Radionuclides . . . . . . . . . . . . . . . . . . 74

5.7.1 Arsenic-77 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 745.7.2 Copper-67 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 765.7.3 Erbium-169 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 765.7.4 Gold-198 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 775.7.5 Gold-199 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 775.7.6 Holmium-166 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 775.7.7 Iodine-131 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795.7.8 Lutetium-177 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 815.7.9 Phosphorous-32 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845.7.10 Praseodymium-143 . . . . . . . . . . . . . . . . . . . . . . . . . . . 875.7.11 Promethium-149 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 875.7.12 Rhenium-186 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 885.7.13 Rhenium-188 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 895.7.14 Rhodium-105 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 905.7.15 Samarium-153 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 915.7.16 Scandium-47 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 925.7.17 Silver-111 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 935.7.18 Strontium-89 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 935.7.19 Terbium-161 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 965.7.20 Thulium-170 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985.7.21 Tin-117 m . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 995.7.22 Ytterbium-175 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 995.7.23 Yttrium-90 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

5.8 Auger Electron-Emitting Radioisotopes . . . . . . . . . . . . . . . . . 1015.8.1 Iodine-125 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102


6 Accelerator-Produced Therapeutic Radionuclides . . . . . . . . . . 1156.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1156.2 Accelerators for Radionuclide Production . . . . . . . . . . . . . . . 115

6.2.1 Calculation of Production Yield . . . . . . . . . . . . . . . . . 1166.2.2 Saturation Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

6.3 Key Accelerator-Produced Therapeutic Radionuclides . . . . . 1186.3.1 Actinum-225 and Radium-223 . . . . . . . . . . . . . . . . . . 1186.3.2 Astatine-211 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

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6.3.3 Copper-67 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1216.3.4 Gallium-67 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1246.3.5 Indium-111 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1256.3.6 Rhenium-186 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

6.4 Tin-117 m . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1266.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

7 Radionuclide Generator Systems Represent Convenient Production Systems to Provide Therapeutic Radionuclides . . . 1317.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1317.2 Production of Parent Radionuclides . . . . . . . . . . . . . . . . . . . . 1327.3 Decay and In-Growth Principles . . . . . . . . . . . . . . . . . . . . . . 1337.4 Radiochemical Separation of Therapeutic Radionuclides . . . 1367.5 Methods for Parent–Daughter Separation . . . . . . . . . . . . . . . 137

7.5.1 Ion Exchange Column Chromatography . . . . . . . . . . . 1377.5.2 Solvent Extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1387.5.3 Distillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1397.5.4 Precipitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1407.5.5 Extraction Chromatography . . . . . . . . . . . . . . . . . . . . 1407.5.6 Solid-Phase Column Extraction . . . . . . . . . . . . . . . . . 1407.5.7 Electrochemical Separation . . . . . . . . . . . . . . . . . . . . . 141

7.6 Key Examples of Therapeutic Radioisotopes Available from Radionuclide Generator Systems . . . . . . . . . . . . . . . . . 1417.6.1 Radionuclide Generator Systems

Which Provide Beta-Emitting Radioisotopes . . . . . . . 1427.6.2 Radionuclide Generator Systems Which

Provide Alpha-Emitting Radioisotopes . . . . . . . . . . . 1467.6.3 Radionuclide Generator Systems Which Provide

Auger Electron-Emitting Radioisotopes . . . . . . . . . . . 1497.6.4 Ruthenium-103/Rhodium- 103m Generator . . . . . . . . 150


8 Availability of Alpha-Emitting Radioisotopes by Reactor and Accelerator Production and via Decay of Naturally Occurring Parents . . . . . . . . . . . . . . . . . . . . 1598.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1598.2 Production and Processing of Alpha Emitters

in the Thorium Series . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1598.2.1 Actinium-225 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1598.2.2 Actinium-227 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1618.2.3 Bismuth-212 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1618.2.4 Radium-223 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1638.2.5 Radium-224 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1648.2.6 Radium-226 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1658.2.7 Thorium-226 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1658.2.8 Thorium-227 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165


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Part III Therapeutic Radiopharmaceuticals for Cancer Therapy

9 Radioimmunotherapy (RIT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1699.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1699.2 Identifi cation of Cell Surface Markers . . . . . . . . . . . . . . . . . . 1699.3 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170

9.3.1 B Cells and T Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . 1709.3.2 Polyclonal and Monoclonal Antibodies . . . . . . . . . . . 1719.3.3 Monoclonal Antibodies (mAbs) . . . . . . . . . . . . . . . . . 171

9.4 Antigens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1739.4.1 Affi nity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1759.4.2 Avidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1759.4.3 Specifi city . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1759.4.4 Cross-Reactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

9.5 Lymphomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1759.6 Radioimmunotherapy (RIT) . . . . . . . . . . . . . . . . . . . . . . . . . . 176

9.6.1 Advantages of RIT . . . . . . . . . . . . . . . . . . . . . . . . . . . 1779.6.2 Selection of Target Antigen . . . . . . . . . . . . . . . . . . . . . 1779.6.3 Antibody Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . 1789.6.4 Selection of a Radionuclide for RIT . . . . . . . . . . . . . . 179

9.7 Treatment of Non-Hodgkin’s B-Cell Lymphoma . . . . . . . . . . 1799.8 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183

10 Peptide Receptor Radionuclide Therapy (PRRT) . . . . . . . . . . . 18510.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18510.2 Amino Acids, Peptides, and Proteins . . . . . . . . . . . . . . . . . . . 185

10.2.1 Amino Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18510.2.2 Peptides and Proteins . . . . . . . . . . . . . . . . . . . . . . . . . 18610.2.3 Regulatory Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . 18710.2.4 Peptides as Therapeutic Vectors . . . . . . . . . . . . . . . . . 18810.2.5 Advantages of Peptides for Therapy . . . . . . . . . . . . . . 18910.2.6 Limitations of Peptides for Therapy . . . . . . . . . . . . . . 18910.2.7 Development of Peptide- Based

Radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . 19010.2.8 Preparation of Radiolabeled Peptides . . . . . . . . . . . . . 19010.2.9 Radionuclides for Receptor- Mediated

Peptide Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19110.3 Peptide Receptor Radionuclide Therapy (PRRT)

for Neuroendocrine Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . 19310.3.1 PRRT Studies with [111In-DTPA]octreotide . . . . . . . . 19410.3.2 Somatostatin Receptor Radiotherapy

with [90Y-DOTA0,Tyr3]octreotide (90Y-DOTATOC) and [90Y-DOTA0,Tyr3]octreotate (DOTATATE). . . . . . 196

10.3.3 Somatostatin Receptor Radiotherapy with [177Lu-DOTA0,Tyr3]octreotate (DOTATATE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

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10.4 Bombesin Peptide Analogs . . . . . . . . . . . . . . . . . . . . . . . . . . . 19710.5 Vasoactive Intestinal Peptide (VIP) Analogs . . . . . . . . . . . . . 19810.6 Cholecystokinin (CCK)/Gastrin Peptide Analogs . . . . . . . . . 19910.7 Neurotensin Peptide Analogs . . . . . . . . . . . . . . . . . . . . . . . . . 19910.8 Glucagon-Like Peptide (GLP) Analogs . . . . . . . . . . . . . . . . . 19910.9 RGD Peptides for Targeting Integrin αvβ3 Expression . . . . . . 200

10.9.1 Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20010.9.2 RGD Peptide-Based

Radiotherapeutics Targeting Integrin αvβ3 . . . . . . . . . 20210.10 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

11 Therapeutic Radiopharmaceuticals for Treatmentof Primary and Metastatic Hepatic Cancer . . . . . . . . . . . . . . . . 20911.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20911.2 Direct Intratumor Implantation . . . . . . . . . . . . . . . . . . . . . . . . 21011.3 Radioimmunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21111.4 Trans-arterial Radioisotope Therapy (TART) . . . . . . . . . . . . . 21111.5 Selection of Radionuclide for TART . . . . . . . . . . . . . . . . . . . 21211.6 Selection of Microspheres . . . . . . . . . . . . . . . . . . . . . . . . . . . 21211.7 Common Microsphere Materials . . . . . . . . . . . . . . . . . . . . . . 21211.8 Radionuclide Used for Treatment of HCC . . . . . . . . . . . . . . . 21311.9 Radioisotopes for TART . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

11.9.1 Iodine-131-Lipiodol . . . . . . . . . . . . . . . . . . . . . . . . . . 21311.9.2 90Y-Labeled Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . 21411.9.3 Rhenium-188 Lipiodol/Microspheres . . . . . . . . . . . . . 21511.9.4 Holmium-166 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

11.10 Comparison of Properties of Radioisotopes Used for TART . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

11.11 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

Part IV Therapeutic Radiopharmaceuticals for Treatment of Chronic Disease

12 Therapeutic Radiopharmaceuticals for Bone Pain Palliation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22512.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22512.2 Treatment of Metastatic Bone Pain with

Therapeutic Radioisotopes . . . . . . . . . . . . . . . . . . . . . . . . . . . 22512.3 Commercially Available Beta-Particle-Emitting

Approved Agents for Bone Pain Palliation . . . . . . . . . . . . . . 22812.3.1 Rhenium-186 HEDP . . . . . . . . . . . . . . . . . . . . . . . . . . 22812.3.2 Samarium-153 EDTMP (“Quadramet®”) . . . . . . . . . . 22912.3.3 Stronium-89 Chloride . . . . . . . . . . . . . . . . . . . . . . . . . 229

12.4 Examples of Bone Pain Palliation Agents under Development and in Clinical Trials . . . . . . . . . . . . . . . . . . . . 22912.4.1 Iodine-131 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23012.4.2 Phosphorus-32 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230

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12.4.3 Yttrium-90-Labeled Citrate and EDTMP . . . . . . . . . . 23112.5 New Radiolabeled Agents Being

Developed for Bone Pain Palliation . . . . . . . . . . . . . . . . . . . . 23112.5.1 Rhenium-188 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23112.5.2 Lutetium-177 Diphosphonates . . . . . . . . . . . . . . . . . . 23612.5.3 Samarium-153 and Holmium-166 . . . . . . . . . . . . . . . . 23712.5.4 Thulium-170 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23712.5.5 Ytterbium-175 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238

12.6 Bone Pain Palliation Agents Using Radioisotopes Which Have Minimal Soft Tissue Penetration . . . . . . . . . . . . 23912.6.1 Tin-117m (117mSn) DTPA . . . . . . . . . . . . . . . . . . . . . . . 24012.6.2 Radium-223 Chloride . . . . . . . . . . . . . . . . . . . . . . . . . 242

12.7 Soft Tissue Penetration and Effi cacy of Radioisotopes for Bone Pain Palliation . . . . . . . . 244

12.8 The Possibility of Therapeutic Effects on Bone Metastases with High Activity Doses of Agents Used for Bone Pain Palliation . . . . . . . . . . . . . . . . . . . . . . . . 245


13 Locoregional Radionuclide Therapy for Nonmelanoma Skin Cancer (NMSC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25313.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25313.2 Radioisotopes for Treatment of Skin Cancer . . . . . . . . . . . . . 25313.3 Strategies for Treatment on NMSC . . . . . . . . . . . . . . . . . . . . 25313.4 Topical Use of Radioisotopes for NMSC Therapy . . . . . . . . . 254

13.4.1 Holmium-166 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25513.4.2 Phosphorus-32 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25613.4.3 Rhenium-188 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25813.4.4 Yttirum-90 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260


14 Radionuclide Synovectomy: Treatment of Inflammation of the Synovial Joints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26514.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265

14.1.1 Advantages of Radiosynovectomy . . . . . . . . . . . . . . . 26514.1.2 Selection of Radionuclides . . . . . . . . . . . . . . . . . . . . . 266

14.2 Dosimetry and Dose Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26914.3 Key Therapeutic Radioisotopes Used for Synovectomy . . . . 270

14.3.1 Dysprosium-165 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27014.3.2 Erbium-169 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27014.3.3 Gold-198 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27014.3.4 Holmium-166 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27014.3.5 Lutetium-177 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27114.3.6 Phosphorus-32 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27114.3.7 Rhenium-186 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27214.3.8 Rhenium-188 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27214.3.9 Samarium-153 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272

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14.3.10 Yttrium-90 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27314.4 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274

15 Inhibition of Arterial Restenosis Following Balloon Angioplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27915.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27915.2 Radioisotopes for Intravascular Irradiation (IVRT)

of Coronary Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28015.2.1 Solid Radioactive Sources for Vessel Irradiation . . . . 28015.2.2 Dosimetry of Vessel Wall Irradiation

Is an Important Issue . . . . . . . . . . . . . . . . . . . . . . . . . . 28015.2.3 Radioactive Liquid-Filled Balloons for Vessel Wall

Irradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28315.3 Examples of Clinical Trials with 188Re-Filled

Balloon Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28515.3.1 The SPARE Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28615.3.2 The DRAIN Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286

15.4 Radioisotopes for IVRT of the Peripheral Vessels . . . . . . . . . 28715.5 Use of 188Re Balloons for IVRT of the Peripheral Vessels . . . 28815.6 Other Therapeutic Applications

of 188Re-Liquid- Filled Balloons . . . . . . . . . . . . . . . . . . . . . . . 28815.7 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289

Part V Looking Ahead: New Radiopharmaceutical Strategies for Therapeutic Applications

16 Moving Forward: Expected Opportunities for the Development of New Therapeutic Agents Based on Nanotechnologies . . . . . . 29516.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29516.2 Therapeutic Strategies Based on Nanotargeting . . . . . . . . . . . 29616.3 Selection of Radionuclides for NP Therapy . . . . . . . . . . . . . . 297

16.3.1 Passive NP Targeting . . . . . . . . . . . . . . . . . . . . . . . . . . 29816.3.2 Active NP Targeting . . . . . . . . . . . . . . . . . . . . . . . . . . 299

16.4 Ligand Conjugation Strategies . . . . . . . . . . . . . . . . . . . . . . . . 30016.4.1 Pre-conjugation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30116.4.2 Post-formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30116.4.3 Bioconjugation Based on Covalent Approaches . . . . . 30116.4.4 Bioconjugation Based on Non- covalent Approaches . . . 30216.4.5 Infl uence of the Architecture of

Actively Targeted NPs . . . . . . . . . . . . . . . . . . . . . . . . 30216.5 NP Targeting Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

16.5.1 Monoclonal Antibodies . . . . . . . . . . . . . . . . . . . . . . . . 30316.5.2 Antibody Fragments . . . . . . . . . . . . . . . . . . . . . . . . . . 30416.5.3 Other Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30516.5.4 Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305

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16.5.5 Aptamers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30616.5.6 Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30616.5.7 Specifi c Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

16.6 Radiolabeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30716.7 Nanoparticles for Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 308

16.7.1 Particle Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30816.7.2 Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30816.7.3 Surface and Ligand Charge . . . . . . . . . . . . . . . . . . 30816.7.4 Surface Hydrophobicity . . . . . . . . . . . . . . . . . . . . . 30816.7.5 Mechanical Properties . . . . . . . . . . . . . . . . . . . . . . 30916.7.6 NP Surface Coating . . . . . . . . . . . . . . . . . . . . . . . . 309

16.8 Biomedically Important NPs . . . . . . . . . . . . . . . . . . . . . . . . 31016.8.1 Organic NPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31016.8.2 Liposomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31016.8.3 Dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31116.8.4 Micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312

16.9 Inorganic NPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31216.9.1 Gold Nanoparticles. . . . . . . . . . . . . . . . . . . . . . . . . 312

16.10 Quantum Dots (QDs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31316.11 Iron Oxide Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . 31416.12 Silica Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31516.13 Summary, Challenges, and Future Directions . . . . . . . . . . . 316References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317

17 Translation of Radiopharmaceuticals from Bench to Bedside: Regulatory and Manufacturing Issues . . . . . . . . . . 32317.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32317.2 The Radiopharmaceutical

Manufacturing Process Elements. . . . . . . . . . . . . . . . . . . . . 32317.2.1 Quality Assurance (QA) . . . . . . . . . . . . . . . . . . . . . 32317.2.2 Good Manufacturing Practices (GMP) for

Radiopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . 32417.2.3 Quality Control (QC) . . . . . . . . . . . . . . . . . . . . . . . 325

17.3 Personnel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32617.4 Active Pharmaceutical Ingredient (API) . . . . . . . . . . . . . . . 32617.5 Radionuclide Production . . . . . . . . . . . . . . . . . . . . . . . . . . . 32717.6 Radiopharmaceutical Manufacture . . . . . . . . . . . . . . . . . . . 327

17.6.1 Sterile Production . . . . . . . . . . . . . . . . . . . . . . . . . . 32717.6.2 Terminal Sterilization . . . . . . . . . . . . . . . . . . . . . . . 32817.6.3 Aseptic Sterilization . . . . . . . . . . . . . . . . . . . . . . . . 32817.6.4 Sanitation and Hygiene . . . . . . . . . . . . . . . . . . . . . 329

17.7 Documentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33017.7.1 Site Master File . . . . . . . . . . . . . . . . . . . . . . . . . . . 33017.7.2 Drug Master Files (DMF) for

Individual Batches . . . . . . . . . . . . . . . . . . . . . . . . . 33117.7.3 Validation Master File . . . . . . . . . . . . . . . . . . . . . . 33117.7.4 Specifi cations for Materials . . . . . . . . . . . . . . . . . . 331

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17.8 Container Labeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33217.9 Centralized Radiopharmacy (CRPh) Concept . . . . . . . . . . . 33217.10 Infusion of Automation in

Radiopharmaceutical Production . . . . . . . . . . . . . . . . . . . . . 33317.11 Constraints in the Transition of Radiopharmaceuticals

from Bench to Bedside . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33417.12 Barriers to Success . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33717.13 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342

Glossary: Definitions and Terminology . . . . . . . . . . . . . . . . . . . . . . 345

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ADME Adsorption, distribution, metabolism, and excretion AE Auger electron BFCA Bifunctional chelating agent CD Cluster of differentiation Ci Curie C-K Coster–Kroenig CT Computed tomography DES Drug eluting stent DNA Deoxyribonucleic acid DOTA 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid DTPA Diethylenetriamine pentaacetic acid EC Electron capture HAMA Human automouse antibody HCC Hepatocellular carcinoma HDR High-dose radiation HEHA 1, 4, 7, 10, 13, 16-hexaazacyclohexane-N, N′, N″, N , N ,

N -hexanoic acid HER-2 Receptor tyrosine-protein kinase erbB-2 (CD340) HSA High specifi c activity HSA Human serum albumin IC Internal conversion IT Isomeric transition IVRT Intravascular radiation therapy LATO Late acute thrombotic occlusion LER Lower extremity revascularization LET Linear energy transfer LSA Low specifi c activity MABG Meta-astatobenzyl guanidine mCi Millicurie MDP Methylene diphosphonate MeV Mega (million) electron volts MIBG Metaiodobenzylguanidine MIBI Methoxy isobutyl nitrile (ligand) MRI Magnetic resonance imaging MTB Maximal tolerated dose NIS Sodium iodide transporter NMSC Nonmelanoma skin cancer

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PET Positron emission tomography PLA Polylactic acid PPRT Peptide receptor radionuclide therapy RAD Radiation adsorbed dose RAIT Radioimmunotherapy RBE Relative biological effectiveness RDG Arginine–glycine–aspartate acid (tripeptide sequence) RNT Radionuclide therapy SA Specifi c activity σ Sigma, neutron cross section, cm 24 SIRC Surgically created resection cavity SIRT Selective internal radiation therapy SKID Severe combined immunodefi ciency SPECT Single-photon emission computerized tomography Super-C–K Super Coster–Kroenig TACE Trans-arterial chemoembolization TARE Trans-arterial radioembolization TART Trans-arterial radionuclide therapy TATE Peptide sequence TOC Peptide sequence, DOTA 0 –Phe 1 –Tyr 3 US Ultrasound

Abbreviations

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