A theranostic approach for risk stratification and intervention of deep vein thrombosis.

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Summary Data suggest that 60,000-100,000 Americans die of venous thromboembolism (VTE) each year, that 50% of the surviving patients will have long-term complications, and that about one third of the survivors have recurrence within 10 years. The US healthcare costs are staggering and carry a high burden for treatment of VTE patients; it is estimated that $10 billion US dollars are spent each year accounting for treatment and man- agement of VTE. There is a critical need for both, accurate clinical diagnosis of VTE, in particular deep vein thrombosis (DVT), and targeted therapies to reduce safety issues, specifically intracranial hemorrhage, asso- ciated with thrombolytic drugs. Current diagnostic methods are not accurate: blood test assessing D-dimer blood levels are only indicative of DVT. Imaging techniques such as X-ray venography and ultrasonography reflect changes in the venous anatomy, but these modalities do not provide information about the molecular composition of the thrombus. Only biopsy followed by histology gives the molecular information needed for ac- curate prognosis, but these methods are invasive and associated with significant risks. We propose a non- invasive, magnetic resonance imaging (MRI) approach using a targeted contrast agent to gain information of the thrombus molecular composition to aid prognosis. The probe will also be engineered to aid therapeutic in- tervention through disruption of disease-promoting pathways or drug delivery. The integrated imaging and therapeutic capabilities will also facilitate longitudinal follow-up to monitor disease progression and therapy success. We will target myeloid-related protein 14 (MRP-14,  also referred to as S100A9). MRP-14 is secreted from activated neutrophils, monocytes, and platelets and our data indicate a link between MRP-14 and DVT. MRP-14 is found at high levels in DVT and knockout of MRP-14 in mice attenuates DVT formation. Using a phage library combinatorial approach, we identified specific peptide ligands that target MRP-14 with high speci- ficity. We will integrate the MRP-14 binders with a macromolecular MRI contrast agent, and we will develop an MRI protocol for non-invasive detection of MRP-14 to aid diagnosis and prognosis of DVT. At the same time, we will develop a targeted therapeutic approach: first, we will test whether disruption of the MRP-14 function can attenuate DVT formation. Second, we will assess MRP-14 targeted delivery of the thrombolytic drug plas- minogen activator (tPA). The targeted therapeutic approach holds the potential to overcome bleeding risks as- sociated with the treatment. Disease progression and therapy success will be evaluated in a longitudinal MRI study.