Advantages of a dual-tracer model over reference tissue models for binding potential measurement in tumors

Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, USA.
Physics in Medicine and Biology (Impact Factor: 2.76). 10/2012; 57(20):6647-59. DOI: 10.1088/0031-9155/57/20/6647
Source: PubMed


The quantification of tumor molecular expression in vivo could have a significant impact for informing and monitoring emerging targeted therapies in oncology. Molecular imaging of targeted tracers can be used to quantify receptor expression in the form of a binding potential (BP) if the arterial input curve or a surrogate of it is also measured. However, the assumptions of the most common approaches (reference tissue models) may not be valid for use in tumors. In this study, the validity of reference tissue models is investigated for use in tumors experimentally and in simulations. Three different tumor lines were grown subcutaneously in athymic mice and the mice were injected with a mixture of an epidermal growth factor receptor-targeted fluorescent tracer and an untargeted fluorescent tracer. A one-compartment plasma input model demonstrated that the transport kinetics of both tracers was significantly different between tumors and all potential reference tissues, and using the reference tissue model resulted in a theoretical underestimation in BP of 50% ± 37%. On the other hand, the targeted and untargeted tracers demonstrated similar transport kinetics, allowing a dual-tracer approach to be employed to accurately estimate BP (with a theoretical error of 0.23% ± 9.07%). These findings highlight the potential for using a dual-tracer approach to quantify receptor expression in tumors with abnormal hemodynamics, possibly to inform the choice or progress of molecular cancer therapies.

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    • "Finally, C b , representing the tracer concentration in the blood, is named Input Function (IF) and plays the role of trigger for the process of tracer kinetics in the system. This corresponds to considering a Single Input Model, which is more feasible than the Dual Input Model [27] [26] for application of micro-PET analysis to mice. "
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    • "The uptake of the untargeted tracer can then essentially be used as a surrogate of the nonspecific component of targeted tracer uptake to better identify binding related uptake and retention (Wang et al 2012). By using reference tissue mathematical models (Lammertsma and Hume 1996, Logan et al 1996) from the neurotransmitter positron emission tomography community, the uptake of the targeted and untargeted tracers can be used to quantify binding potential—a parameter proportional to the concentration of the biomolecule targeted by the tracer (Innis et al 2007)—for tissues of interest having no suitable reference tissue, such as in cancer imaging (Tichauer et al 2012a). One major limitation of the DT-RCI method is that it requires the arterial input functions (i.e., the time-varying concentration of tracer in blood) and the ratio of tissue delivery and retention rates (i.e., K 1 /k 2 ) to be the same for the targeted and untargeted tracers. "
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