Nanoparticle CT Contrast Agent for New Capabilities in Tumor Detection, Staging, and Therapy Planning and Response

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PROJECT SUMMARY/ABSTRACT Our long-term goal is to revolutionize the effectiveness of oncologic imaging for millions of Americans. Accurate and early detection of liver tumors and their associated vascular anatomy is critical for tumor staging, pre-surgical planning, and treatment monitoring. Unfortunately, with currently available contrast agents, computed tomography (CT) only shows a sensitivity of 60% for liver tumors <1 cm in diameter, even in modern studies with PET/CT. Available CT contrast agents are severely limited by poor liver and vascular enhancement, particularly for larger patients, and renal and allergic-type contraindications. Obesity is associated with higher risk of cancer mortality, yet current CT agents perform particularly poorly at the high-kVp CT settings needed to image such patients. All current CT agents use iodine, which loses up to 50% of its signal at high kVp. These so-called “extravascular extracellular” agents equilibrate rapidly between the intravascular and interstitial fluid, and hence provide a “washed out” appearance of critical structures. These small-molecule contrast agents are unable to quantify angiogenesis, which is a universal characteristic of tumors that correlates with aggressiveness. Unfortunately, prior experimental CT blood-pool contrast agents that can quantify angiogenesis have not been translated to clinical use in part due to slow bioelimination, complex synthetic processes, or toxicity. We developed a scalable process to produce a tantalum oxide nanoparticle contrast agent (TaCZ1) of prototype size (3.1 nm) that provides outstanding blood pool contrast, superior liver enhancement, and rapid renal clearance with no observable kidney pathology. However, reduction in the viscosity and osmolality of TaCZ is desirable to broaden its potential clinical value. Our Specific Aims are to 1) Increase TaCZ particle size to reduce osmolality and viscosity and improve imaging benefits; 2) Demonstrate TaCZ safety in preparation for clinical translation as a contrast agent; and 3) Show the agent's superior detection, characterization, and treatment monitoring of liver tumors. At project conclusion, we will have completed a major step toward clinical translation of a transformative tantalum-based blood-pool CT contrast agent, defined the ideal nanoparticle size for excellent safety, rapid renal clearance, and outstanding CT liver tumor imaging, and assessed this agent for primary and metastatic liver tumor detection, characterization, and treatment response.