(683d) Non-Invasive Screening of Diseases Using an Orally Available Near-Infrared Imaging Agent

Early detection of diseases is crucial to improving the chances of successful treatment, such as curative surgery of cancer or early intervention with disease-modifying treatments to prevent irreversible damage in rheumatoid arthritis. Current methods of detection involve either minimally invasive blood tests or medical imaging modalities. Blood tests can provide large amounts of molecular information but lack spatial information about the site of the disease, and imaging modalities can provide spatial information but only offer anatomical data. Molecular imaging modalities can bridge the gap between the aforementioned techniques, but the drawbacks include safety concerns with ionizing radiation and the associated high cost.

We aimed at developing a near-infrared orally available imaging agent to detect diseases non-invasively. This technique employs near-infrared fluorescence as a method of detection that makes the process safe (non-ionizing radiation) but limits the detection of diseases within 1 to 2 cm from the surface of the skin. This method of detection is easily portable, cheap and the use of an orally available imaging agent makes it completely non-invasive. Importantly, oral delivery avoids associated risks with parenteral delivery and could improve compliance in a screening setting.

As proof of concept, we chose a single-digit nanomolar integrin binding peptidomimetic as a model system. The small molecule ligand has the highest affinity for α_vβ₃ integrin, which is highly expressed on certain forms on cancer and on macrophages present at sites of inflammation such as arthritic joints. The binder was conjugated to several near-infrared dyes in order to make a series of agents with varying physicochemical and optical properties to ascertain what properties are important for orally available imaging agents. In vitro and preliminary in vivo experiments were conducted to find the agent that had the best mix of oral bioavailability, in vivo optical properties and specificity. Based on these results the IRDye 800CW conjugate was used in an orthotopic breast cancer model to show that this method of detection is effective following oral delivery. We were able to produce target-to-background ratios (TBR) of 4.7 and tumor-to-muscle ratios over 20 using our method of delivery and detection. A mechanistic model based on partial differential equations was also made to correlate the properties of the agents to TBR, in order to highlight the most important properties from a quantitative pharmacokinetic and transport perspective.