Quantitativein vivocell-surface receptor imaging in oncology: kinetic modeling and paired-agent principles from nuclear medicine and optical imaging

Abstract

The development of methods to accurately quantify cell-surface receptors in living tissues would have a seminal impact in oncology. For example, accurate measures of receptor density in vivo could enhance early detection or surgical resection of tumors via protein-based contrast, allowing removal of cancer with high phenotype specificity. Alternatively, accurate receptor expression estimation could be used as a biomarker to guide patient-specific clinical oncology targeting of the same molecular pathway. Unfortunately, conventional molecular contrast-based imaging approaches are not well adapted to accurately estimating the nanomolar-level cell-surface receptor concentrations in tumors, as most images are dominated by nonspecific sources of contrast such as high vascular permeability and lymphatic inhibition. This article reviews approaches for overcoming these limitations based upon tracer kinetic modeling and the use of emerging protocols to estimate binding potential and the related receptor concentration. Methods such as using single time point imaging or a reference-tissue approach tend to have low accuracy in tumors, whereas paired-agent methods or advanced kinetic analyses are more promising to eliminate the dominance of interstitial space in the signals. Nuclear medicine and optical molecular imaging are the primary modalities used, as they have the nanomolar level sensitivity needed to quantify cell-surface receptor concentrations present in tissue, although each likely has a different clinical niche.

Surgical Guidance via Multiplexed Molecular Imaging of Fresh Tissues Labeled With SERS-Coded Nanoparticles

“…6 and 8), the measured ratio is not necessarily proportional to the receptor density. Kinetic modeling has been demonstrated as an effective approach to estimate the receptor density by analyzing the retention and washout of exogenous contrast agents over time [95]. Most recently, a kinetic model has been developed to quantify the binding potential (BP: proportional to receptor densities) of cell-surface receptors in fresh tissues based on SERS NP retention kinetics [62].…”

Rinsing paired-agent model (RPAM) to quantify cell-surface receptor concentrations in topical staining applications of thick tissues

“…3b and 3c)—both the ratiometric and DPM-NS methods displayed improved separation of the different tissue types ( p < 0.05, Fig. 4) by accounting for nonspecific signal retention through paired-agent imaging principles (Tichauer et al , 2015). Thick ex vivo tissue rinsing did show a promising outcome with larger SERS nanoparticles (Figs.…”

“…To date, most paired-agent kinetic models have been applied to in vivo studies employing systemic administration of imaging agents (Tichauer et al , 2015). Only one model has been applied to thick tissue imaging, a paired-agent model accounting for nonspecific binding (DPM-NS) (Sinha et al , 2015).…”

Multiplexed imaging for diagnosis and therapy

“…The successful application of these advances in multiplexing was elegantly illustrated by the profiling of two orthotopic breast-cancer xenografts based on their distinct receptor expression of EGFR or HER2, using a cocktail of probes injected simultaneously 109 . However, achieving accurate quantification, delivery and scatter need also to be considered 112 , and the utility of this technique remains to be shown in clinical settings. In nuclear-medical imaging, most experience in multi-tracer imaging has been gained using differences in photon emission energy (in the case of SPECT) but also in half-life and tracer kinetics (in PET), and thus has focused on compound metabolism 113 , bone metastasis 114 and tissue vasculature 115 .…”