New class of collagen-targeted contrast agents for Magnetic Resonance Imaging

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Project Summary Chronic liver disease is one of the leading and most rapidly rising causes of mortality worldwide. Chronic liver disease is multifactorial and can be brought upon from damages ranging from viral hepatitis infection to alcohol abuse to poor diet. Leading these is the epidemic of nonalcoholic steatohepatitis (NASH), but all chronic liver diseases progress to liver fibrosis if unchecked. Fibrosis may resolve following effective treatment, but when left untreated liver fibrosis can progress to liver failure or liver cancer. Accurate diagnosis, staging, and surveillance of liver fibrosis is key to chronic liver disease patient management. The present standard of care for diagnosis and staging of liver fibrosis is biopsy, which runs the risk of internal bleeding, samples only a small portion of liver, and suffers from interobserver variability. Fibrosis stage, and not steatosis nor inflammation, is the only feature of disease associated with worse outcomes in NASH. Besides biopsy we lack good tools to noninvasively detect liver fibrosis, stage fibrosis, or monitor response to treatment. Elastography methods are not sensitive to early changes in disease. Serum biomarkers and biomarker panels to identify NASH and/or liver fibrosis, are also limited and lack accuracy for staging. None of these techniques has the accuracy to monitor treatment. An accurate, safe method to diagnose and monitor NASH and associated fibrosis is of utmost importance in both clinical practice and clinical research. Collagen Medical has developed type I collagen-binding peptides (CBP) conjugated to gadolinium chelates for noninvasive MRI staging of liver fibrosis. These probes (EP-3533 and CM-101) are injected intravenously, binding to fibrotic liver in proportion to the degree of fibrosis, while the unbound probe is rapidly renally eliminated. Despite efficacy in multiple animal models at low doses of probe (5 – 10 µmol/kg), the anticipated cost of goods at this dose is expected to be too high to be commercially viable. This Phase I SBIR proposal seeks to reduce the cost of goods of a collagen-targeted MR imaging probe by combining Collagen Medical’s CBP technology with exceedingly small iron-oxide nanoparticle (ESPION) technology developed at MIT. ESPIONs provide strong positive contrast in T1-weighted MRI scans, are small enough to extravasate from blood vessels, and are eliminated via renal filtration. The relaxivity of ESPIONs is 5 – 20 times higher than CM-101. A higher relaxivity should equate to a lower dose and we hypothesize that an ESPION-CBP conjugate would be as effective at a 5 – 20 fold lower dose than CM-101, and thus a significantly lower cost of goods. Furthermore, ESPIONs can are prepared from cheap raw materials whereas synthesis of the bifunctional Gd-chelates that have been previously conjugated to the CBP require multiple synthetic steps and costly chromatographic purification. Our approach is to synthesize a small library of ESPION-CBP conjugates and screen for relaxivity, collagen-binding affinity, collagen specificity, and metabolic stability in vitro. We will then demonstrate that our lead ESPION-CBP conjugate is capable of visualizing liver fibrosis with superior detection sensitivity to the previously studied Gd-based collagen-targeting probe CM-101 in a murine model of liver fibrosis.