Spatiotemporal Targeting of a Dual-Ligand K-Edge Nanoprobe for Photon Counting TBI Imaging

Mild to moderate traumatic brain injuries (mTBIs), including those from explosive blast from improvised explosive devices, are the most common traumatic brain injury (TBI), affecting a significant segment of our military population; however, they are the least understood in terms of its long-term sequelae and are the most difficult to diagnose. Noninvasive neuroimaging techniques have become an indispensable part for the diagnosis of TBI patients, especially within 24 hours of injury, because an early diagnosis can significantly alter the clinical course. New technology has emerged that enhances the way current CT systems are used. The new system, called photon counting CT (PCCT), allows for distinguishing different materials and can provide images depicting each of those materials (as a 'color' map) and provide quantitative information. To take advantage of this, one can design imaging probes (sometimes called K-edge probes) based on metals with high atomic number and combine with molecularly targeted 'multicolor' agents to provide spatially specific and quantifiable information facilitating better diagnosis and therapeutic management. Here, we propose to investigate a novel dual-ligand nanoprobe to effectively image TBI with a novel stepwise targeting approach. By using two different chemical specificities, the dual-ligand strategy will first consider the spatiotemporal targeting of cortical region of interest and sequentially probe towards a highly specific TBI tissue biomarker. If successful, the outcome will generate quantitative and spatially selective data that may transform the early TBI diagnosis for the military professionals without increasing the complexity of clinical workflow.

We believe that the development of dual-targeted imaging probe will provide quantitative information by sequentially directing the nanoprobes to two tissue biomarkers of interest, i.e., CNS-specific delivery of the nanoprobe and in vivo detection of PDE4B2. The outcome will generate quantitative and spatially selective data that may transform the early TBI diagnosis without increasing the complexity of clinical workflow.

The proposed innovative dual ligand K-edge nanoprobes for spatiotemporal targeting of TBI and imaging with PCCT to obtain spatially specific and quantifiable information would allow physicians to directly visualize the location of injury and the inflammatory processes at the acute presentation stage, which will have the potential to revolutionize how TBI patients are triaged in an emergency setting. If successful, this proposal has the potential to not only revolutionize the way diagnostic imaging contributes to the early detection of TBI but may have a significant impact on the diagnosis of other neurological disorders. The novel use of PCCT to report on early neuronal damage through detection of overexpressed PDE4B2 marker during early stages of injury, along with standard CT, is one of the key innovation aspects of this proposal. This technology can lead to revolutionary improvement in the spatial recognition of biomarkers, quantification, and stratification of TBI biomarkers and guide medical decisions for early intervention and promote targeted therapy.

The agents developed here will be based on metallic agent hafnium. Hafnium has well documented biocompatibility. Hafnium oxide-based agents were investigated for radiation therapy in human. Therefore, the probes that are selected in this proposal are readily translatable for human use.