Identifying optimal kinetic parameters in quantitative paired-agent molecular imaging by applying computational biology techniques

Accurate and sensitive discrimination of cancerous tissue from the healthy tissue has been a difficult problem to deal with, resulting in the incomplete resection of cancerous tissue and giving rise to 'call-back' surgery. Fluorescence guided surgery, which employs a fluorescent imaging agent to highlight key molecular differences between cancerous and healthy tissue is a promising approach for improving cancer discrimination during tumor resection surgery. However, conventional fluorescence guided surgery methods have not been optimized in terms of maximizing the contrast of cancer to healthy tissue and nonspecific sources of contrast in images can potentially obfuscate the reliability of such approaches, typically owing to variable vascular permeability and retention kinetics of fluorescent imaging agents in cancerous tissues. Paired-agent approaches have been proposed to account for these nonspecific factors. The approaches employ co-administration of a control (untargeted) imaging agent with a cancer targeted imaging agents, the measured signal of which is used to "normalize" out nonspecific components of targeted agent distribution so that the highest possible contrast between cancer and healthy tissue can be realized. This thesis explores how tumor contrast can be optimized by a ratiometric application of paired-agent imaging approach depending on pharmacokinetic characteristics of the targeted and control imaging-agents used. Overall, two parameters were found to be of upmost importance: 1) the plasma elimination half-life of the imaging agents should be long or large compared to the tissue efflux rate, k2, ideally > 10 h for typical k2 levels; 2) the efflux rate of the imaging agents from the extracellular space to the intravascular space needs to be relatively high in the range of 0.05-0.13 min-1. This thesis also highlights the importance of the appropriate imaging time while quantifying the cell surface receptors. With the use of simulations and animal models this thesis identifies the use of kinetic parameters playing a role in the paired-agent imaging approach. By making use of the paired-agent imaging approach in the fluorescence guided surgery it would be possible to accurately quantify the cancer cell surface receptors to optimize identification of the cancerous tissue from the healthy tissue.