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19 February 2020 Noninvasive in vivo mapping of intracellular signaling proteins using a pairing of targeted and untargeted fluorescently labeled small molecule kinase inhibitors
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Abstract
Small molecule kinase inhibitors (SMKIs) drugs have the potential to offer exquisite specificity in controlling aberrant intracellular signaling pathways in cancer and other disease states. However, while nearly 50 SMKIs have been FDA-approved, patient responses have been variable, and sensitive populations not easy to identify. For instance, in non-small-cell lung cancer, only 30% of patients respond to the epidermal growth factor receptor (EGFR) targeted SMKI, erlotinib, yet the level of erlotinib uptake is a poor indicator of treatment efficacy. The development of fluorescently-labeled SMKIs that maintain their viability as drugs has facilitated the use of paired-agent molecular imaging protocols that are able to discriminate, in vivo, between imaging agent uptake and binding. Here we present a mathematical framework of SMKI transport and binding, in vivo, and derive a kinetic model for extracting SMKI binding potential (BP) from kinetic fluorescent-SMKI imaging data-proposed as a more effective indicator of potential therapeutic response than SMKI uptake alone. The accuracy and precision of the SMKI BP kinetic model was demonstrated in simulation studies and in an in ovo xenograft experiment. In simulation, the SMKI BP estimates were within 20 􀀀 5% of expected values over a large range of physiologically relevant blood flow, vascular permeability and cell permeability; and over a range of SMKI affinity, cell membrane permeability, and blood plasma pharmacokinetics. The in ovo experiment bolstered the simulation findings, demonstrating a statistically significant spatial correlation (r > 0.9, p < 0.01) between EGFR concentration measured by a validated extracellular approach and the SMKI BP approach.
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Kenneth M. Tichauer, Lei Wang, Allison Solanki, Jesse R. Korber, Summer L. Gibbs, and Kimberley S. Samkoe "Noninvasive in vivo mapping of intracellular signaling proteins using a pairing of targeted and untargeted fluorescently labeled small molecule kinase inhibitors", Proc. SPIE 11219, Visualizing and Quantifying Drug Distribution in Tissue IV, 112190K (19 February 2020); https://doi.org/10.1117/12.2545926
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