Abstract
BackgroundAccurate 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 of 111In-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 with 111In-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. Delivered 111In-labelled mAbs tumour absorbed doses were calculated using mouse-specific convolution dosimetry, and absorbed doses for 90Y-labelled mAbs were extrapolated under the assumptions of equivalent injected activities, biological half-lives and uptake distributions as for 111In.ResultsFor 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 by 111In-labelled mAbs and extrapolated for 90Y-labelled mAbs, respectively.ConclusionsThis 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.
Highlights
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
For mice 5 and 6, imaged at 197 h pi, 83 and 79% of the activity was taken up by the tumours, highlighting the importance of acquiring scans at later time points to improve the Immunoconjugate preparation and radiolabelling The radiolabelling of ICR12 with 99mTc, 124I and 131I has previously been reported [30,31,32], and this study demonstrates that it can be efficiently labelled with 111In
This study investigated the challenges associated with pre-clinical imaging and mouse-specific dosimetry and compared the mass, activity and %IA/g in the tumour obtained from the imaging and the ex vivo biodistribution data
Summary
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. Molecular imaging enables minimally-invasive visualisation of molecular and cellular biological processes in living organisms It plays an important role in cancer drug development and in monitoring disease progression and tumour response to therapeutic interventions [1,2,3]. Ex vivo biodistribution and/or autoradiography studies are traditionally used to investigate the uptake characteristics of novel radiolabelled tracers prior to translation to inhuman clinical trials. These methods are limited, as they require animals to be culled at various time points and the pharmacokinetics are based on data from different animals at different times. SPECT and PET pre-clinical imaging enables the prospect of longitudinal studies and has the potential to provide quantitative measurements of radiotracer biodistribution and to reduce the number of animals required per study, which is both more cost effective and more ethical than traditional methods [4]
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