New Technologies for 211At Targeted Α-Therapy Research Using 211Rn and 209At
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New technologies for 211At targeted α-therapy research using 211Rn and 209At Jason Raymond Crawford BSc, University of British Columbia, 2007 MSc, University of Victoria, 2010 A dissertation submitted in partial fulfilment of the requirements for the degree of Doctorate of Philosophy in the Department of Physics and Astronomy c Jason Raymond Crawford, 2016 University of Victoria All rights reserved. This dissertation may not be reproduced in whole or in part by photocopy or other means, without the permission of the author. ii New technologies for 211At targeted α-therapy research using 211Rn and 209At by Jason Raymond Crawford BSc, University of British Columbia, 2007 MSc, University of Victoria, 2010 Supervisory Committee Dr. Thomas J Ruth, Co-Supervisor Department of Physics and Astronomy Dr. Andrew Jirasek, Co-Supervisor Department of Physics and Astronomy Dr. Wayne Beckham, Committee Member Department of Physics and Astronomy Dr. Dean Karlen, Committee Member Department of Physics and Astronomy Dr. Julian Lum, Outside Member Department of Biochemistry & Microbiology iii Abstract The most promising applications for targeted α-therapy with astatine-211 (211At) in- clude treatments of disseminated microscopic disease, the major medical problem for cancer treatment. The primary advantages of targeted α-therapy with 211At are that the α-particle radiation is densely ionizing, translating to high relative biological effectiveness (RBE), and short-range, minimizing damage to surrounding healthy tissues. In addition, theranostic imaging with 123I surrogates has shown promise for developing new therapies with 211At and translating them to the clinic. Currently, Canada does not have a way of producing 211At by conventional methods because it lacks α-particle accelerators with necessary beam energy and intensity. The work presented here was aimed at studying the 211Rn/211At generator system as an alternative production strategy by leveraging TRI- UMF's ability to produce rare isotopes. Recognizing that TRIUMF provided production opportunities for a variety of astatine isotopes, this work also originally hypothesized and evaluated the use of 209At as a novel isotope for preclinical Single Photon Emission Computed Tomography (SPECT) with applications to 211At therapy research. At TRIUMF's Isotope Separator and Accelerator (ISAC) facility, mass separated ion beams of short-lived francium isotopes were implanted into NaCl targets where 211Rn or 209At were produced by radioactive decay, in situ. This effort required methodological developments for safely relocating the implanted radioactivity to the radiochemistry lab- oratory for recovery in solution. For multiple production runs, 211Rn was quantitatively transferred from solid NaCl to solution (dodecane) from which 211At was efficiently ex- tracted and evaluated for clinical applicability. This validated the use of dodecane for capturing 211Rn as an elegant approach to storing and shipping 211Rn/211At in the future. 207Po contamination (also produced by 211Rn decay) was removed using a granular tel- lurium (Te) column before proceeding with biomolecule labelling. Although the produced quantities were small, the pure 211At samples demonstrated these efforts to have a clear path of translation to animal studies. For the first time in history, SPECT/CT was evaluated for measuring 209At radioac- tivity distributions using high energy collimation. The spectrum detected for 209At by the SPECT camera presented several photopeaks (energy windows) for reconstruction. The 77-90 Po X-ray photopeak reconstructions were found to provide the best images overall, in terms of resolution/contrast and uniformity. Collectively, these experiments helped es- tablish guidelines for determining the optimal injected radioactivity, depending on scan parameters. Moreover, 209At-based SPECT demonstrated potential for pursuing image- based dosimetry in mouse tumour models, in the future. Simultaneous SPECT imaging with 209At and 123I was demonstrated to be feasible, supporting the future evaluation of 209At for studying/validating 123I surrogates for clinical image-based 211At dosimetry. This work also pursued a novel strategy for labelling cancer targeting peptides with 211At, iv using octreotate (TATE, a somatostatin analogue for targeting tumour cells, mostly neu- roendocrine tumours) prepared with or without N-terminus PEGylation (PEG2), followed by conjugation with a closo-decaborate linking moiety (B10) for attaching 211At. Bind- ing affinity and in vivo biodistributions for the modified peptides were determined using iodine surrogates. The results indicated that B10-PEG2-TATE retained target binding affinity but that the labelling reaction with iodine degraded this binding affinity sig- 123 nificantly, and although having high in vivo stability, no I-B10-PEG2-TATE tumour uptake was observed by SPECT in a mouse tumour model positive for the somatostatin receptor (sstr2a). This suggested that further improvements are required for labelling. A new method for producing 211At at TRIUMF is established, and 209At-based SPECT imaging is now demonstrated as a new preclinical technology to measure astatine biodis- tributions in vivo for developing new radiopharmaceuticals with 211At. Combined with the theranostic peptide labelling efforts with iodine, these efforts provide a foundation for future endeavours with 211At-based α-therapy at TRIUMF. All procedures were per- formed safely and rapidly, suitable for preclinical evaluations. All animal studies received institutional ethics approval from the University of British Columbia (UBC). v Table of Contents Supervisory Committee ii Abstract iii Table of Contentsv List of Tables viii List of Figures ix Nomenclature xii Acknowledgements xv Dedication xvii 1 Introduction1 1.1 Destroying cancer with radiation......................1 1.2 Targeted Alpha Therapy (TAT).......................5 1.3 Advancing targeted α-therapy at TRIUMF.................8 1.4 Thesis scope..................................9 2 Targeted α-therapy with Astatine-211 11 2.1 The therapeutic advantage of 211At..................... 11 2.2 Considerations of 211At biodistributions................... 12 2.3 Biomolecular targeting with 211At...................... 13 2.4 Clinical trials with 211At........................... 15 2.5 Dosimetry and imaging with 211At...................... 16 2.6 Chapter summary............................... 20 3 211At Production and the ISAC Facility 22 3.1 211At production via the 209Bi(α,2n)211At reaction............. 22 3.2 The 211Rn/211At generator system...................... 25 3.3 The ISAC facility for RIB production.................... 28 vi 3.4 Chapter summary............................... 34 4 Methods for 211Rn/211At and 209At Recovery at ISAC 35 4.1 Production by mass separated beams of francium and radium...... 36 4.2 RIB production and delivery......................... 47 4.3 Instrumentation for RIB implantation.................... 50 4.4 Target processing............................... 57 4.5 Antibody labelling with 211At and 209At.................. 59 4.6 Activity measurements............................ 60 4.7 Chapter summary............................... 63 5 Methods for SPECT Imaging with 209At 64 5.1 Image acquisition............................... 66 5.2 Image reconstruction............................. 67 5.3 Phantom imaging............................... 68 5.4 Mouse imaging................................ 71 5.5 Chapter summary............................... 73 6 Results of 211Rn/211At and 209At Recovery at ISAC 74 6.1 Summary of RIB implantations....................... 74 6.2 Recovery yields following target processing................. 77 6.3 211At isolation................................. 84 6.4 Antibody labelling results.......................... 88 6.5 Further observations............................. 92 6.6 Discussion................................... 95 7 Results of SPECT Imaging with 209At 99 7.1 Description of detected energy spectra for 209At SPECT measurements. 99 7.2 Phantom imaging studies with 209At.................... 101 7.3 Mouse imaging studies with 209At...................... 111 7.4 Further discussion............................... 122 8 Peptide Labelling with I/123I Surrogates for 211At 125 8.1 Background.................................. 125 8.2 Peptide modifications for labelling...................... 126 8.3 Competitive binding assays......................... 130 123 8.4 Preparation of radiopeptides ( I-B10-PEG2-TATE)........... 133 8.5 Small animal SPECT imaging study.................... 134 8.6 Discussion................................... 136 vii 9 Conclusion 137 9.1 Thesis summary................................ 137 9.2 Future work.................................. 138 9.3 Final thoughts................................. 139 Bibliography 141 viii List of Tables 1.1 α-particle emitting isotopes with potential for therapeutic applications. .......7 3.1 RIB production rates at ISAC relevant to the production of 211Rn/211At and 211At. 34 4.1 Radiations from the 211Ra decay chain leading to 211Rn/211At ........... 39 4.2 Radiations from the 213Ra decay chain leading to 209At .............. 45 5.1 Energy and intensity of photon emissions from 211At and 209At (relevant to SPECT imaging). .................................... 65 5.2 Description of phantom imaging experiments. ................... 68 5.3 Description of mouse imaging experiments with 209At. ............... 72 6.1 RIB production run parameters and calculated ion yield from IYS measurements.