In Vivo Quantification of Tumor Receptor Binding Potential with Dual-Reporter Molecular Imaging

PurposeReceptor availability represents a key component of current cancer management. However, no approaches have been adopted to do this clinically, and the current standard of care is invasive tissue biopsy. A dual-reporter methodology capable of quantifying available receptor binding potential of tumors in vivo within a clinically relevant time scale is presented.ProceduresTo test the methodology, a fluorescence imaging-based adaptation was validated against ex vivo and in vitro measures of epidermal growth factor receptor (EGFR) binding potential in four tumor lines in mice, each line expected to express a different level of EGFR.ResultsA strong correlation was observed between in vivo and ex vivo measures of binding potential for all tumor lines (r = 0.99, p < 0.01, slope = 1.80 ± 0.48, and intercept = −0.58 ± 0.84) and between in vivo and in vitro for the three lines expressing the least amount of EGFR (r = 0.99, p < 0.01, slope = 0.64 ± 0.32, and intercept = 0.47 ± 0.51).ConclusionsBy providing a fast and robust measure of receptor density in tumors, the presented methodology has powerful implications for improving choices in cancer intervention, evaluation, and monitoring, and can be scaled to the clinic with an imaging modality like SPECT.

[1]  Tayyaba Hasan,et al.  Detecting epidermal growth factor receptor tumor activity in vivo during cetuximab therapy of murine gliomas. , 2010, Academic radiology.

[2]  P. Carmeliet,et al.  Angiogenesis in cancer and other diseases , 2000, Nature.

[3]  P. Lambin,et al.  Disparity Between In Vivo EGFR Expression and 89Zr-Labeled Cetuximab Uptake Assessed with PET , 2008, Journal of Nuclear Medicine.

[4]  M. Mintun,et al.  A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography , 1984, Annals of neurology.

[5]  N. Volkow,et al.  Distribution Volume Ratios without Blood Sampling from Graphical Analysis of PET Data , 1996, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[6]  M. Korc,et al.  Production of transforming growth factor alpha in human pancreatic cancer cells: evidence for a superagonist autocrine cycle. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[7]  R. P. Maguire,et al.  Consensus Nomenclature for in vivo Imaging of Reversibly Binding Radioligands , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[8]  L. Norton,et al.  Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  Bart Cornelissen,et al.  Associations between the uptake of 111In-DTPA-trastuzumab, HER2 density and response to trastuzumab (Herceptin) in athymic mice bearing subcutaneous human tumour xenografts , 2008, European Journal of Nuclear Medicine and Molecular Imaging.

[10]  Sergio Fantini,et al.  Near-infrared absorption and scattering spectra of tissues in vivo , 1999, Photonics West - Biomedical Optics.

[11]  R. McLendon,et al.  Cell surface localization and density of the tumor-associated variant of the epidermal growth factor receptor, EGFRvIII. , 1997, Cancer research.

[12]  Vincent J. Cunningham,et al.  Parametric Imaging of Ligand-Receptor Binding in PET Using a Simplified Reference Region Model , 1997, NeuroImage.

[13]  R. Weissleder,et al.  Fluorescence molecular tomography resolves protease activity in vivo , 2002, Nature Medicine.

[14]  R K Jain,et al.  Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure. , 1988, Cancer research.

[15]  J N Weinstein,et al.  A modeling analysis of monoclonal antibody percolation through tumors: a binding-site barrier. , 1990, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[16]  A. Lammertsma,et al.  Simplified Reference Tissue Model for PET Receptor Studies , 1996, NeuroImage.

[17]  Tayyaba Hasan,et al.  Imaging tumor variation in response to photodynamic therapy in pancreatic cancer xenograft models. , 2010, International journal of radiation oncology, biology, physics.

[18]  Brian W. Pogue,et al.  High Vascular Delivery of EGF, but Low Receptor Binding Rate Is Observed in AsPC-1 Tumors as Compared to Normal Pancreas , 2011, Molecular Imaging and Biology.

[19]  Christopher H Contag,et al.  Quantifying cell-surface biomarker expression in thick tissues with ratiometric three-dimensional microscopy. , 2009, Biophysical journal.

[20]  Tayyaba Hasan,et al.  Imaging targeted-agent binding in vivo with two probes. , 2010, Journal of biomedical optics.

[21]  E. Kim,et al.  Radioimmunodetection of cancer with radioactive antibodies to carcinoembryonic antigen. , 1980, Cancer research.

[22]  Vladimir Tolmachev,et al.  Imaging of EGFR expression in murine xenografts using site-specifically labelled anti-EGFR 111In-DOTA-ZEGFR:2377 Affibody molecule: aspect of the injected tracer amount , 2010, European Journal of Nuclear Medicine and Molecular Imaging.

[23]  R. Weissleder,et al.  Imaging in the era of molecular oncology , 2008, Nature.

[24]  H. Maeda,et al.  Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[25]  S. Wise Nanocarriers as an emerging platform for cancer therapy , 2007 .

[26]  V. Chernomordik,et al.  Quantitative analysis of Her2 receptor expression in vivo by near-infrared optical imaging. , 2009, Molecular imaging.

[27]  R. Weissleder,et al.  In vivo imaging of tumors with protease-activated near-infrared fluorescent probes , 1999, Nature Biotechnology.

[28]  A. Bradwell,et al.  Radioimmunodetection of gastrointestinal neoplasms with antibodies to carcinoembryonic antigen. , 1980, Cancer research.