Pre-clinical quantitative imaging and mouse-specific dosimetry for 111In-labelled radiotracers

Denis-Bacelar, Ana M.; Cronin, Sarah; Pieve, Chiara Da; Paul, Rowena L.; Eccles, Sue; Spinks, T.; Box, Carol; Hall, A.; Sosabowski, Jane; Kramer‐Marek, Gabriela; Flux, Glenn

doi:10.1186/s13550-016-0238-z

Cited by 4 publications

(6 citation statements)

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“…Denis-Bacelar et al compared microSPECT imaging and organ harvesting for the calculation of %IA/g in subcutaneous tumors after the injection of 111 In-labeled monoclonal antibodies [23]. They obtained a median %IA/g difference of about 30% between the two methods, resulting from discrepancies in the calculation of both tumor masses and activity concentrations.…”

Section: Discussionmentioning

confidence: 99%

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Internal radiation dosimetry of a 152Tb-labeled antibody in tumor-bearing mice

et al. 2019

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Background Biodistribution studies based on organ harvesting represent the gold standard pre-clinical technique for dose extrapolations. However, sequential imaging is becoming increasingly popular as it allows the extraction of longitudinal data from single animals, and a direct correlation with deterministic radiation effects. We assessed the feasibility of mouse-specific, microPET-based dosimetry of an antibody fragment labeled with the positron emitter 152 Tb [( T 1/2 = 17.5 h, Eβ + mean = 1140 keV (20.3%)]. Image-based absorbed dose estimates were compared with those obtained from the extrapolation to 152 Tb of a classical biodistribution experiment using the same antibody fragment labeled with 111 In. 152 Tb was produced by proton-induced spallation in a tantalum target, followed by mass separation and cation exchange chromatography. The endosialin-targeting scFv78-Fc fusion protein was conjugated with the chelator p -SCN-Bn-CHX-A”-DTPA, followed by labeling with either 152 Tb or 111 In. Micro-PET images of four immunodeficient female mice bearing RD-ES tumor xenografts were acquired 4, 24, and 48 h after the i.v. injection of 152 Tb-CHX-DTPA-scFv78-Fc. After count/activity camera calibration, time-integrated activity coefficients (TIACs) were obtained for the following compartments: heart, lungs, liver, kidneys, intestines, tumor, and whole body, manually segmented on CT. For comparison, radiation dose estimates of 152 Tb-CHX-DTPA-scFv78-Fc were extrapolated from mice dissected 4, 24, 48, and 96 h after the injection of 111 In-CHX-DTPA-scFv78-Fc (3–5 mice per group). Imaging-derived and biodistribution-derived organ TIACs were used as input in the 25 g mouse model of OLINDA/EXM® 2.0, after appropriate mass rescaling. Tumor absorbed doses were obtained using the OLINDA2 sphere model. Finally, the relative percent difference (RD%) between absorbed doses obtained from imaging and biodistribution were calculated. Results RD% between microPET-based dosimetry and biodistribution-based dose extrapolations were + 12, − 14, and + 17 for the liver, the kidneys, and the tumors, respectively. Compared to biodistribution, the imaging method significantly overestimates the absorbed doses to the heart and the lungs (+ 89 and + 117% dose difference, respectively). Conclusions MicroPET-based dosimetry of 152 Tb is feasible, and the comparison with organ harvesting resulted in acceptable dose discrepancies for body districts that can be segmented on CT. These encouraging results warrant additional validation using radiolabeled biomolecules with a different biodistribution pattern.

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Section: Discussionmentioning

confidence: 99%

“…They obtained a median %IA/g difference of about 30% between the two methods, resulting from discrepancies in the calculation of both tumor masses and activity concentrations. However, %IA/g was calculated from single time-points only, rather than from longitudinal imaging and biodistribution data [23].…”

Section: Discussionmentioning

confidence: 99%

Internal radiation dosimetry of a 152Tb-labeled antibody in tumor-bearing mice

et al. 2019

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“…In addition to SPECT image-related factors, the accuracy of SPECT-based activity quantification can also be affected by other factors such as delineation of the volume of interest (VOI), activity calibration and post-reconstruction filtration. These aspects should also be considered carefully in the design and reporting of small-animal quantitative SPECT studies [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Assessment of mouse-specific pharmacokinetics in kidneys based on 131I activity measurements using micro-SPECT

et al. 2022

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Background In order to acquire accurate drug pharmacokinetic information, which is required for tissue dosimetry, micro-SPECT must be quantitative to allow for an accurate assessment of radioligand activity in the relevant tissue. This study investigates the feasibility of deriving accurate mouse-specific time-integrated drug pharmacokinetic data in mouse kidneys from activity measurements using micro-SPECT. Methods An animal experiment was carried out to evaluate the accuracy of 131I activity quantification in mouse kidneys (mean tissue volume of 0.140 mL) using a micro-SPECT system against conventional ex vivo gamma counting (GC) in a NaI(Tl) detector. The imaging setting investigated was that of the mouse biodistribution of a 131I-labelled single-domain antibody fragment (sdAb), currently being investigated for targeted radionuclide therapy of HER2-expressing cancer. SPECT imaging of 131I 365-keV photons was done with a VECTor/CT system (MILabs, Netherlands) using a high-energy mouse collimator with 1.6-mm-diameter pinholes. For both activity quantification techniques, the pharmacokinetic profile of the radioligand from approximately 1–73 h p.i. was derived and the time-integrated activity coefficient per gram of tissue (ã/M) was estimated. Additionally, SPECT activity recovery coefficients were determined in a phantom setting. Results SPECT activities underestimate the reference activities by an amount that is dependent on the 131I activity concentration in the kidney, and thus on the time point of the pharmacokinetic profile. This underestimation is around − 12% at 1.5 h (2.89 MBq mL−1 mean reference activity concentration), − 13% at 6.6 h (149 kBq mL−1), − 40% at 24 h (17.6 kBq mL−1) and − 46% at 73 h (5.2 kBq mL−1) p.i. The ã/M value estimated from SPECT activities is, nevertheless, within − 14% from the reference (GC) ã/M value. Furthermore, better quantitative accuracy (within 2% from GC) in the SPECT ã/M value is achieved when SPECT activities are compensated for partial recovery with a phantom-based recovery coefficient of 0.85. Conclusion The SPECT imaging system used, together with a robust activity quantification methodology, allows an accurate estimation of time-integrated pharmacokinetic information of the 131I-labelled sdAb in mouse kidneys. This opens the possibility to perform mouse-specific kidney-tissue dosimetry based on pharmacokinetic data acquired in vivo on the same mice used in nephrotoxicity studies.

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“…use of image denoising lters), etc. ; so these aspects should also be considered carefully in the design and reporting of small-animal quantitative SPECT studies [12,13].…”

Section: Introductionmentioning

confidence: 99%

Assessment of Mouse-Specific Pharmacokinetics in Kidneys Based on 131I Activity Measurements Using Micro-SPECT

Vargas¹,

Struelens²,

D’Huyvetter³

et al. 2021

Preprint

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Background In order to acquire accurate drug pharmacokinetic information, such as that required for tissue dosimetry, micro-SPECT must be quantitative and allow an accurate assessment of radioligand activity in the relevant tissue. This study investigates the feasibility of deriving accurate mouse-specific time-integrated drug pharmacokinetic data in mouse kidneys from activity measurements using micro-SPECT. Methods An animal experiment was done to evaluate the accuracy of 131I activity quantification in mouse kidneys using a micro-SPECT system against conventional ex vivo gamma counting (GC) in a NaI(Tl) detector. The imaging setting investigated was that of the mouse biodistribution of a 131I-labelled single-domain antibody fragment (sdAb) currently being investigated for targeted radionuclide therapy of HER2-expressing cancer. SPECT imaging of 131I 365-keV photons was done with a VECTor/CT system (MILabs, Netherlands) using a high-energy mouse collimator with 1.6-mm-diameter pinholes. For each activity quantification technique, the pharmacokinetic profile from approximately 1 to 73 h p.i. of the radioligand was derived and the time-integrated activity coefficient per gram of tissue (ã/M) was estimated. Additionally, SPECT activity recovery coefficients were determined in a phantom setting. Results SPECT activities underestimate the reference activities by an amount that is dependent on the 131I activity concentration in the kidney, and thus on the time point of the pharmacokinetic profile. This underestimation is around − 12% at 1.5 h (2.78 MBq.mL− 1 mean reference activity concentration), -13% at 6.6 h (143 kBq.mL− 1), -40% at 24 h (15 kBq.mL− 1) and − 46% at 73 h (5 kBq.mL− 1) p.i. The ã/M value estimated from SPECT activities is, nevertheless, within − 15% from the reference (GC) ã/M value. Furthermore, better quantitative accuracy (within 2% from GC) in the SPECT ã/M value is achieved when SPECT activities are compensated for partial recovery with a phantom-based correction factor. Conclusion The SPECT imaging system used, together with a robust activity quantification methodology, allows an accurate estimation of time-integrated pharmacokinetic information of the 131I-labelled sdAb in mouse kidneys. This opens the possibility to perform mouse-specific kidney-tissue dosimetry based on pharmacokinetic data acquired in vivo on the same mice used in nephrotoxicity studies.

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Pre-clinical quantitative imaging and mouse-specific dosimetry for 111In-labelled radiotracers

Cited by 4 publications

References 32 publications

Internal radiation dosimetry of a 152Tb-labeled antibody in tumor-bearing mice

Internal radiation dosimetry of a 152Tb-labeled antibody in tumor-bearing mice

Assessment of mouse-specific pharmacokinetics in kidneys based on 131I activity measurements using micro-SPECT

Assessment of Mouse-Specific Pharmacokinetics in Kidneys Based on 131I Activity Measurements Using Micro-SPECT

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