title: Pre-clinical quantitative imaging and mouse-specific dosimetry for111In-labelled radiotracers.
abstract: BACKGROUND
  Accurate quantification in molecular imaging is essential to improve the assessment of novel drugs and compare the radiobiological effects of therapeutic agents prior to in-human studies. The aim of this study was to investigate the challenges and feasibility of pre-clinical quantitative imaging and mouse-specific dosimetry of111In-labelled radiotracers. Attenuation, scatter and partial volume effects were studied using phantom experiments, and an activity calibration curve was obtained for varying sphere sizes. Six SK-OV-3-tumour bearing mice were injected with111In-labelled HER2-targeting monoclonal antibodies (mAbs) (range 5.58-8.52 MBq). Sequential SPECT imaging up to 197 h post-injection was performed using the Albira SPECT/PET/CT pre-clinical scanner. Mice were culled for quantitative analysis of biodistribution studies. The tumour activity, mass and percentage of injected activity per gram of tissue (%IA/g) were calculated at the final scan time point and compared to the values determined from the biodistribution data. Delivered111In-labelled mAbs tumour absorbed doses were calculated using mouse-specific convolution dosimetry, and absorbed doses for90Y-labelled mAbs were extrapolated under the assumptions of equivalent injected activities, biological half-lives and uptake distributions as for111In.
  
  
  RESULTS
  For the sphere sizes investigated (volume 0.03-1.17 ml), the calibration factor varied by a factor of 3.7, whilst for the range of tumour masses in the mice (41-232 mg), the calibration factor changed by a factor of 2.5. Comparisons between the mice imaging and the biodistribution results showed a statistically significant correlation for the tumour activity (r = 0.999, P < 0.0001) and the tumour mass calculations (r = 0.977, P = 0.0008), whilst no correlation was found for the %IA/g (r = 0.521, P = 0.29). Median tumour-absorbed doses per injected activity of 52 cGy/MBq (range 36-69 cGy/MBq) and 649 cGy/MBq (range 441-950 cGy/MBq) were delivered by111In-labelled mAbs and extrapolated for90Y-labelled mAbs, respectively.
  
  
  CONCLUSIONS
  This study demonstrates the need for multidisciplinary efforts to standardise imaging and dosimetry protocols in pre-clinical imaging. Accurate image quantification can improve the calculation of the activity, %IA/g and absorbed dose. Diagnostic imaging could be used to estimate the injected activities required for therapeutic studies, potentially reducing the number of animals used.
authors.affiliation: Joint Department of Physics, The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust, London, SM2 5NG, United Kingdom. ana.denisbacelar@icr.ac.uk.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Denis-Bacelar
authors.affiliation: Joint Department of Physics, The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust, London, SM2 5NG, United Kingdom.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Cronin
authors.affiliation: Joint Department of Physics, The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust, London, SM2 5NG, United Kingdom.
authors.forename: Chiara
authors.initials: C
authors.lastname: Da Pieve
authors.affiliation: Joint Department of Physics, The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust, London, SM2 5NG, United Kingdom.
authors.forename: Rowena L
authors.initials: RL
authors.lastname: Paul
authors.affiliation: Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, United Kingdom.
authors.forename: Sue A
authors.initials: SA
authors.lastname: Eccles
authors.affiliation: Joint Department of Physics, The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust, London, SM2 5NG, United Kingdom.
authors.forename: Terence J
authors.initials: TJ
authors.lastname: Spinks
authors.affiliation: Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, United Kingdom.
authors.forename: Carol
authors.initials: C
authors.lastname: Box
authors.affiliation: Radiopharmacy Department, The Royal Marsden Hospital NHS Foundation Trust, London, SM2 5PT, United Kingdom.
authors.forename: Adrian
authors.initials: A
authors.lastname: Hall
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, United Kingdom.
authors.forename: Jane K
authors.initials: JK
authors.lastname: Sosabowski
authors.affiliation: Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, United Kingdom.|Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, SM2 5NG, United Kingdom.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kramer-Marek
authors.affiliation: Joint Department of Physics, The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust, London, SM2 5NG, United Kingdom.
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Flux
keywords: 111In; Dosimetry; HER2; Image quantification; Partial volume effect; Pre-clinical; Radiolabelled antibodies; SPECT