Generalized paired-agent kinetic model for in vivo quantification of cancer cell-surface receptors under receptor saturation conditions

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Physics in Medicine and Biology


New precision medicine drugs oftentimes act through binding to specific cellsurface cancer receptors, and thus their efficacy is highly dependent on the availability of those receptors and the receptor concentration per cell. Pairedagent molecular imaging can provide quantitative information on receptor status in vivo, especially in tumor tissue; however, to date, published approaches to paired-agent quantitative imaging require that only ‘trace’ levels of imaging agent exist compared to receptor concentration. This strict requirement may limit applicability, particularly in drug binding studies, which seek to report on a biological effect in response to saturating receptors with a drug moiety. To extend the regime over which paired-agent imaging may be used, this work presents a generalized simplified reference tissue model (GSRTM) for pairedagent imaging developed to approximate receptor concentration in both nonreceptor-saturated and receptor-saturated conditions. Extensive simulation studies show that tumor receptor concentration estimates recovered using the GSRTM are more accurate in receptor-saturation conditions than the standard simple reference tissue model (SRTM) (% error (mean ± sd): GSRTM 0 ± 1 and SRTM 50 ± 1) and match the SRTM accuracy in non-saturated conditions (% error (mean ± sd): GSRTM 5 ± 5 and SRTM 0 ± 5). To further test the approach, GSRTM-estimated receptor concentration was compared to SRTMestimated values extracted from tumor xenograft in vivo mouse model data. The GSRTM estimates were observed to deviate from the SRTM in tumors with low receptor saturation (which are likely in a saturated regime). Finally, a general ‘rule-of-thumb’ algorithm is presented to estimate the expected level of receptor saturation that would be achieved in a given tissue provided dose N Sadeghipour et al Printed in the UK 394 PHMBA7 © 2016 Institute of Physics and Engineering in Medicine 62 Phys. Med. Biol. PMB 10.1088/1361-6560/62/2/394 Paper 2 394 414 Physics in Medicine & Biology Institute of Physics and Engineering in Medicine IOP 2017 1361-6560 1361-6560/17/020394+21$33.00 © 2016 Institute of Physics and Engineering in Medicine Printed in the UK Phys. Med. Biol. 62 (2017) 394–414 doi:10.1088/1361-6560/62/2/394 395 and pharmacokinetic information about the drug or imaging agent being used, and physiological information about the tissue. These studies suggest that the GSRTM is necessary when receptor saturation exceeds 20% and highlight the potential for GSRTM to accurately measure receptor concentrations under saturation conditions, such as might be required during high dose drug studies, or for imaging applications where high concentrations of imaging agent are required to optimize signal-to-noise conditions. This model can also be applied to PET and SPECT imaging studies that tend to suffer from noisier data, but require one less parameter to fit if images are converted to imaging agent concentration (quantitative PET/SPECT).