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Home , Radiation therapy, Radionuclide therapy, Radiopharmaceutical

Radiopharmaceuticals for

F. F. (Russ) Knapp • Ashutosh Dash

Radiopharmaceuticals f o r T h e r a p y F. F. (Russ) Knapp Ashutosh Dash Nuclear Security and Division Isotope Production and Oak Ridge National Laboratory Applications Division OAK RIDGE Bhabha Atomic Research Centre USA Mumbai India

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.

Printed on acid-free paper

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

F o r ew o r d

The use of radioactivity for treatment of disease is more than a century old and began with the use of naturally occurring -226 in the early part of the twentieth century. However, the fi eld of 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 -131 for the treatment of which began in 1946. The uptake of radioactive iodide anions is governed by a well-defi ned mechanism involving the symporter protein and is the most basic and fi nest example of molecular nuclear . 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 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 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 . In this regard, introduction of peptide receptor (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 surface receptors which are very often upregulated on cancer cells. Although several radioisotopes have been identifi ed that are used for PRRNT, -177 and yttrium-90 are two key examples as radionu- clides used for both PRRNT and radioactive antibody targeting. Currently, PRRNT using 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

vii viii Foreword

routine clinical introduction of the Xofi go® (radium-223 chloride) for the treatment of castration-resistant 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 . Adenocarcinoma of the prostate gland overexpresses prostate-specifi c membrane (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 . 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 . 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, , 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

Acknowledgments

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.

xi

Contents

Part I Radiopharmaceuticals

1 Introduction: Radiopharmaceuticals Play an Important Role in Both Diagnostic and Therapeutic Nuclear Medicine ...... 3 1.1 Introduction: Use of Radioisotopes in Nuclear Medicine . . . 3 1.2 Key Examples of Nuclear Medicine ...... 4 1.2.1 Nuclear Medicine Imaging ...... 4 1.2.2 Molecular Imaging ...... 4 1.2.3 In Vivo Function Tests ...... 6 1.2.4 Nuclear Medicine Therapy ...... 6 1.3 Radiopharmaceuticals ...... 6 1.3.1 Diagnostic Radiopharmaceuticals ...... 8 1.3.2 Nuclear Medicine Imaging ...... 9 1.4 Therapeutic Radiopharmaceuticals ...... 13 1.4.1 Traditional Applications of Therapeutic Radiopharmaceuticals ...... 14 1.4.2 Current and New Therapeutic Applications ...... 15 1.5 Historical Timeline of Nuclear Medicine ...... 17 1.6 Summary ...... 20 References ...... 21 2 Therapeutic Decay with Particle Emission for Therapeutic Applications ...... 25 2.1 Introduction ...... 25 2.2 Criteria for Selection of Therapeutic Radionuclides ...... 27 2.2.1 Particle Emission ...... 27 2.2.2 Tissue Treatment Morphology ...... 28 2.2.3 Radionuclide Half-Life ...... 28 2.2.4 Radionuclide Decay Products ...... 28 2.2.5 Radionuclide Purity ...... 28 2.2.6 Gamma Emissions ...... 28 2.2.7 Radiolabeling Chemistry ...... 29 2.2.8 Economic Factors ...... 29 2.3 Beta-Particle-Emitting Radionuclides ...... 29 2.4 Alpha-Particle-Emitting Radionuclides ...... 29 2.5 Low-Energy Emitters ...... 30 2.6 Radionuclide Production ...... 30

xiii xiv Contents

2.6.1 Targets for ...... 32 2.6.2 Production of Therapeutic Radionuclides ...... 33 2.6.3 Auger Electron-Emitting Radionuclides ...... 33 2.6.4 Alpha-Particle-Emitting Radionuclides ...... 33 References ...... 34 3 Alpha Radionuclide Therapy ...... 37 3.1 Introduction ...... 37 3.2 Alpha Particles ...... 38 3.2.1 Energy Dissipation of Alpha Particles in a Medium . . 38 3.2.2 (LET) ...... 38 3.2.3 Relative Biological Effectiveness (RBE) ...... 39 3.2.4 Interaction of Alpha Particles in a Biological System ...... 40 3.2.5 Basis of Alpha Radionuclide Therapy ...... 40 3.2.6 ...... 41 3.3 Alpha-Particle-Emitting Radionuclides for Radiotherapy . . . 42 3.3.1 -211 ...... 42 3.3.2 Terbium-149 ...... 47 3.3.3 -225 ...... 47 3.3.4 -213 ...... 50 3.3.5 Bismuth-212 ...... 51 3.3.6 Radium-223 ...... 51 3.3.7 Radium-224 ...... 52 3.3.8 -227 ...... 52 3.4 Summary: Future Prospects of Alpha Radionuclide Therapy ...... 53 References ...... 53 4 Auger Electron-Based Radionuclide Therapy ...... 57 4.1 Introduction: Cancer Treatment with Radioisotopes ...... 57 4.2 Particle Emission ...... 57 4.3 The Auger Process ...... 58 4.4 Cell Killing with Auger Electron Emitters ...... 58 4.5 The Importance of Auger Electron-Emitting Radionuclides for Cancer Therapy ...... 60 4.6 Key Auger Emitters ...... 61 4.6.1 Iodine-125 ...... 61 4.6.2 Platinum-195m ...... 61 4.6.3 Rhodium-103m ...... 62 4.6.4 Holmium-161 ...... 63 4.7 Dosimetry ...... 63 4.7.1 Electron Transport Evaluation and Dosimetry Assessment ...... 64 4.7.2 Auger Electron Spectra ...... 64 4.7.3 Energy Loss by Auger ...... 64 4.7.4 Dosimetry Issues ...... 65 4.8 Summary ...... 65 References ...... 65 Contents xv

Part II Production, Processing and Availability of Therapeutic Radioisotopes 5 Reactor-Produced Therapeutic Radionuclides ...... 71 5.1 Introduction ...... 71 5.2 Reactor Production of Radionuclides ...... 71 5.3 Calculation of Production Yield ...... 71 5.4 Direct (n, γ) Activation (Radiative Route) ...... 73 5.5 Activation Followed by β− Decay (n, γ → β−) ...... 73 5.6 The (n, p) Production Reaction ...... 74 5.7 Beta-Particle-Emitting Radionuclides ...... 74 5.7.1 Arsenic-77 ...... 74 5.7.2 Copper-67 ...... 76 5.7.3 Erbium-169 ...... 76 5.7.4 Gold-198 ...... 77 5.7.5 Gold-199 ...... 77 5.7.6 Holmium-166 ...... 77 5.7.7 Iodine-131 ...... 79 5.7.8 Lutetium-177 ...... 81 5.7.9 Phosphorous-32 ...... 84 5.7.10 Praseodymium-143 ...... 87 5.7.11 Promethium-149 ...... 87 5.7.12 Rhenium-186 ...... 88 5.7.13 Rhenium-188 ...... 89 5.7.14 Rhodium-105 ...... 90 5.7.15 -153 ...... 91 5.7.16 Scandium-47 ...... 92 5.7.17 Silver-111 ...... 93 5.7.18 -89 ...... 93 5.7.19 Terbium-161 ...... 96 5.7.20 Thulium-170 ...... 98 5.7.21 Tin-117 m ...... 99 5.7.22 Ytterbium-175 ...... 99 5.7.23 Yttrium-90 ...... 100 5.8 Auger Electron-Emitting Radioisotopes ...... 101 5.8.1 Iodine-125 ...... 102 5.9 Summary ...... 103 References ...... 103 6 Accelerator-Produced Therapeutic Radionuclides ...... 115 6.1 Introduction ...... 115 6.2 Accelerators for Radionuclide Production ...... 115 6.2.1 Calculation of Production Yield ...... 116 6.2.2 Saturation Factor ...... 117 6.3 Key Accelerator-Produced Therapeutic Radionuclides . . . . . 118 6.3.1 Actinum-225 and Radium-223 ...... 118 6.3.2 Astatine-211 ...... 119 xvi Contents

6.3.3 Copper-67 ...... 121 6.3.4 -67 ...... 124 6.3.5 Indium-111 ...... 125 6.3.6 Rhenium-186 ...... 125 6.4 Tin-117 m ...... 126 6.5 Summary ...... 126 References ...... 126 7 Radionuclide Generator Systems Represent Convenient Production Systems to Provide Therapeutic Radionuclides . . . 131 7.1 Introduction ...... 131 7.2 Production of Parent Radionuclides ...... 132 7.3 Decay and In-Growth Principles ...... 133 7.4 Radiochemical Separation of Therapeutic Radionuclides . . . 136 7.5 Methods for Parent–Daughter Separation ...... 137 7.5.1 Exchange Column Chromatography ...... 137 7.5.2 Solvent Extraction ...... 138 7.5.3 Distillation ...... 139 7.5.4 Precipitation ...... 140 7.5.5 Extraction Chromatography ...... 140 7.5.6 Solid-Phase Column Extraction ...... 140 7.5.7 Electrochemical Separation ...... 141 7.6 Key Examples of Therapeutic Radioisotopes Available from Radionuclide Generator Systems ...... 141 7.6.1 Radionuclide Generator Systems Which Provide Beta-Emitting Radioisotopes ...... 142 7.6.2 Radionuclide Generator Systems Which Provide Alpha-Emitting Radioisotopes ...... 146 7.6.3 Radionuclide Generator Systems Which Provide Auger Electron-Emitting Radioisotopes ...... 149 7.6.4 Ruthenium-103/Rhodium- 103m Generator ...... 150 7.7 Summary ...... 151 References ...... 152 8 Availability of Alpha-Emitting Radioisotopes by Reactor and Accelerator Production and via Decay of Naturally Occurring Parents ...... 159 8.1 Introduction ...... 159 8.2 Production and Processing of Alpha Emitters in the Thorium Series ...... 159 8.2.1 Actinium-225 ...... 159 8.2.2 Actinium-227 ...... 161 8.2.3 Bismuth-212 ...... 161 8.2.4 Radium-223 ...... 163 8.2.5 Radium-224 ...... 164 8.2.6 Radium-226 ...... 165 8.2.7 Thorium-226 ...... 165 8.2.8 Thorium-227 ...... 165 8.3 Summary ...... 165 References ...... 165 Contents xvii

Part III Therapeutic Radiopharmaceuticals for Cancer Therapy

9 (RIT) ...... 169 9.1 Introduction ...... 169 9.2 Identifi cation of Cell Surface Markers ...... 169 9.3 Antibodies ...... 170 9.3.1 B Cells and T Cells ...... 170 9.3.2 Polyclonal and Monoclonal Antibodies ...... 171 9.3.3 Monoclonal Antibodies (mAbs) ...... 171 9.4 ...... 173 9.4.1 Affi nity ...... 175 9.4.2 Avidity ...... 175 9.4.3 Specifi city ...... 175 9.4.4 Cross-Reactivity ...... 175 9.5 ...... 175 9.6 Radioimmunotherapy (RIT) ...... 176 9.6.1 Advantages of RIT ...... 177 9.6.2 Selection of Target Antigen ...... 177 9.6.3 Antibody Selection ...... 178 9.6.4 Selection of a Radionuclide for RIT ...... 179 9.7 Treatment of Non-Hodgkin’s B-Cell ...... 179 9.8 Summary ...... 181 References ...... 183 10 Peptide Receptor Radionuclide Therapy (PRRT) ...... 185 10.1 Introduction ...... 185 10.2 Amino Acids, Peptides, and Proteins ...... 185 10.2.1 Amino Acids ...... 185 10.2.2 Peptides and Proteins ...... 186 10.2.3 Regulatory Peptides ...... 187 10.2.4 Peptides as Therapeutic Vectors ...... 188 10.2.5 Advantages of Peptides for Therapy ...... 189 10.2.6 Limitations of Peptides for Therapy ...... 189 10.2.7 Development of Peptide- Based Radiopharmaceuticals ...... 190 10.2.8 Preparation of Radiolabeled Peptides ...... 190 10.2.9 Radionuclides for Receptor- Mediated Peptide Therapy ...... 191 10.3 Peptide Receptor Radionuclide Therapy (PRRT) for Neuroendocrine Tumors ...... 193 10.3.1 PRRT Studies with [111In-DTPA]octreotide ...... 194 10.3.2 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 xviii Contents

10.4 Bombesin Peptide Analogs ...... 197 10.5 Vasoactive Intestinal Peptide (VIP) Analogs ...... 198 10.6 Cholecystokinin (CCK)/Gastrin Peptide Analogs ...... 199 10.7 Neurotensin Peptide Analogs ...... 199 10.8 Glucagon-Like Peptide (GLP) Analogs ...... 199

10.9 RGD Peptides for Targeting Integrin αvβ3 Expression ...... 200 10.9.1 Angiogenesis ...... 200 10.9.2 RGD Peptide-Based

Radiotherapeutics Targeting Integrin αvβ3 ...... 202 10.10 Summary ...... 202 References ...... 203 11 Therapeutic Radiopharmaceuticals for Treatment of Primary and Metastatic Hepatic Cancer ...... 209 11.1 Introduction ...... 209 11.2 Direct Intratumor Implantation ...... 210 11.3 Radioimmunotherapy ...... 211 11.4 Trans-arterial Radioisotope Therapy (TART) ...... 211 11.5 Selection of Radionuclide for TART ...... 212 11.6 Selection of Microspheres ...... 212 11.7 Common Microsphere Materials ...... 212 11.8 Radionuclide Used for Treatment of HCC ...... 213 11.9 Radioisotopes for TART ...... 213 11.9.1 Iodine-131-Lipiodol ...... 213 11.9.2 90Y-Labeled Agents ...... 214 11.9.3 Rhenium-188 Lipiodol/Microspheres ...... 215 11.9.4 Holmium-166 ...... 217 11.10 Comparison of Properties of Radioisotopes Used for TART ...... 217 11.11 Summary ...... 218 References ...... 219 Part IV Therapeutic Radiopharmaceuticals for Treatment of Chronic Disease

12 Therapeutic Radiopharmaceuticals for Palliation ...... 225 12.1 Introduction ...... 225 12.2 Treatment of Metastatic Bone Pain with Therapeutic Radioisotopes ...... 225 12.3 Commercially Available Beta-Particle-Emitting Approved Agents for Bone Pain Palliation ...... 228 12.3.1 Rhenium-186 HEDP ...... 228 12.3.2 Samarium-153 EDTMP (“Quadramet®”) ...... 229 12.3.3 Stronium-89 Chloride ...... 229 12.4 Examples of Bone Pain Palliation Agents under Development and in Clinical Trials ...... 229 12.4.1 Iodine-131 ...... 230 12.4.2 Phosphorus-32 ...... 230 Contents xix

12.4.3 Yttrium-90-Labeled Citrate and EDTMP ...... 231 12.5 New Radiolabeled Agents Being Developed for Bone Pain Palliation ...... 231 12.5.1 Rhenium-188 ...... 231 12.5.2 Lutetium-177 Diphosphonates ...... 236 12.5.3 Samarium-153 and Holmium-166 ...... 237 12.5.4 Thulium-170 ...... 237 12.5.5 Ytterbium-175 ...... 238 12.6 Bone Pain Palliation Agents Using Radioisotopes Which Have Minimal Soft Tissue Penetration ...... 239 12.6.1 Tin-117m (117mSn) DTPA ...... 240 12.6.2 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 12.9 Summary ...... 246 References ...... 246 13 Locoregional Radionuclide Therapy for Nonmelanoma (NMSC) ...... 253 13.1 Introduction ...... 253 13.2 Radioisotopes for Treatment of Skin Cancer ...... 253 13.3 Strategies for Treatment on NMSC ...... 253 13.4 Topical Use of Radioisotopes for NMSC Therapy ...... 254 13.4.1 Holmium-166 ...... 255 13.4.2 Phosphorus-32 ...... 256 13.4.3 Rhenium-188 ...... 258 13.4.4 Yttirum-90 ...... 260 13.5 Summary ...... 263 References ...... 264 14 Radionuclide Synovectomy: Treatment of of the Synovial Joints ...... 265 14.1 Introduction ...... 265 14.1.1 Advantages of Radiosynovectomy ...... 265 14.1.2 Selection of Radionuclides ...... 266 14.2 Dosimetry and Dose Rate ...... 269 14.3 Key Therapeutic Radioisotopes Used for Synovectomy . . . . 270 14.3.1 Dysprosium-165 ...... 270 14.3.2 Erbium-169 ...... 270 14.3.3 Gold-198 ...... 270 14.3.4 Holmium-166 ...... 270 14.3.5 Lutetium-177 ...... 271 14.3.6 Phosphorus-32 ...... 271 14.3.7 Rhenium-186 ...... 272 14.3.8 Rhenium-188 ...... 272 14.3.9 Samarium-153 ...... 272 xx Contents

14.3.10 Yttrium-90 ...... 273 14.4 Summary ...... 273 References ...... 274 15 Inhibition of Arterial Following Balloon Angioplasty ...... 279 15.1 Introduction ...... 279 15.2 Radioisotopes for Intravascular Irradiation (IVRT) of Coronary Vessels ...... 280 15.2.1 Solid Radioactive Sources for Vessel Irradiation . . . . 280 15.2.2 Dosimetry of Vessel Wall Irradiation Is an Important Issue ...... 280 15.2.3 Radioactive Liquid-Filled Balloons for Vessel Wall Irradiation ...... 283 15.3 Examples of Clinical Trials with 188Re-Filled Balloon Sources ...... 285 15.3.1 The SPARE Trial ...... 286 15.3.2 The DRAIN Study ...... 286 15.4 Radioisotopes for IVRT of the Peripheral Vessels ...... 287 15.5 Use of 188Re Balloons for IVRT of the Peripheral Vessels . . . 288 15.6 Other Therapeutic Applications of 188Re-Liquid- Filled Balloons ...... 288 15.7 Summary ...... 288 References ...... 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 ...... 295 16.1 Introduction ...... 295 16.2 Therapeutic Strategies Based on Nanotargeting ...... 296 16.3 Selection of Radionuclides for NP Therapy ...... 297 16.3.1 Passive NP Targeting ...... 298 16.3.2 Active NP Targeting ...... 299 16.4 Ligand Conjugation Strategies ...... 300 16.4.1 Pre-conjugation ...... 301 16.4.2 Post-formulation ...... 301 16.4.3 Bioconjugation Based on Covalent Approaches . . . . . 301 16.4.4 Bioconjugation Based on Non-covalent Approaches . . . 302 16.4.5 Infl uence of the Architecture of Actively Targeted NPs ...... 302 16.5 NP Targeting Groups ...... 302 16.5.1 Monoclonal Antibodies ...... 303 16.5.2 Antibody Fragments ...... 304 16.5.3 Other Proteins ...... 305 16.5.4 Peptides ...... 305 Contents xxi

16.5.5 Aptamers ...... 306 16.5.6 Vitamins ...... 306 16.5.7 Specifi c Ligands ...... 307 16.6 Radiolabeling ...... 307 16.7 Nanoparticles for Therapy ...... 308 16.7.1 Particle Size ...... 308 16.7.2 Composition ...... 308 16.7.3 Surface and Ligand Charge ...... 308 16.7.4 Surface Hydrophobicity ...... 308 16.7.5 Mechanical Properties ...... 309 16.7.6 NP Surface Coating ...... 309 16.8 Biomedically Important NPs ...... 310 16.8.1 Organic NPs ...... 310 16.8.2 Liposomes ...... 310 16.8.3 Dendrimers ...... 311 16.8.4 Micelles ...... 312 16.9 Inorganic NPs ...... 312 16.9.1 Gold Nanoparticles...... 312 16.10 Quantum Dots (QDs) ...... 313 16.11 Iron Oxide Nanoparticles ...... 314 16.12 Silica Nanoparticles ...... 315 16.13 Summary, Challenges, and Future Directions ...... 316 References ...... 317 17 Translation of Radiopharmaceuticals from Bench to Bedside: Regulatory and Manufacturing Issues ...... 323 17.1 Introduction ...... 323 17.2 The Radiopharmaceutical Manufacturing Process Elements...... 323 17.2.1 Quality Assurance (QA) ...... 323 17.2.2 Good Manufacturing Practices (GMP) for Radiopharmaceuticals ...... 324 17.2.3 Quality Control (QC) ...... 325 17.3 Personnel ...... 326 17.4 Active Pharmaceutical Ingredient (API) ...... 326 17.5 Radionuclide Production ...... 327 17.6 Radiopharmaceutical Manufacture ...... 327 17.6.1 Sterile Production ...... 327 17.6.2 Terminal Sterilization ...... 328 17.6.3 Aseptic Sterilization ...... 328 17.6.4 Sanitation and Hygiene ...... 329 17.7 Documentation ...... 330 17.7.1 Site Master File ...... 330 17.7.2 Drug Master Files (DMF) for Individual Batches ...... 331 17.7.3 Validation Master File ...... 331 17.7.4 Specifi cations for Materials ...... 331 xxii Contents

17.8 Container Labeling ...... 332 17.9 Centralized Radiopharmacy (CRPh) Concept ...... 332 17.10 Infusion of Automation in Radiopharmaceutical Production ...... 333 17.11 Constraints in the Transition of Radiopharmaceuticals from Bench to Bedside ...... 334 17.12 Barriers to Success ...... 337 17.13 Summary ...... 342 References ...... 342

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

ADME Adsorption, distribution, metabolism, and excretion AE Auger electron BFCA Bifunctional chelating agent CD Cluster of differentiation Ci 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 HDR High-dose HEHA 1, 4, 7, 10, 13, 16-hexaazacyclohexane-N, N′, N″, Nು, Nಿಿಿಿ, Nಿಿಿಿಿ-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 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

xxiii xxiv Abbreviations

PET emission tomography PLA Polylactic acid PPRT Peptide receptor radionuclide therapy 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, , cm24 SIRC Surgically created resection cavity SIRT Selective internal radiation therapy SKID Severe combined immunodefi ciency SPECT Single- 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, DOTA0 –Phe1 –Tyr3 US Ultrasound