Our long-term goal is to revolutionize the effectiveness of vascular imaging by computed tomography (CT) for millions of Americans. Contrast-enhanced CT is the modality of choice for imaging many forms of vascular disease due to ease of use and wide availability. Unfortunately, currently available CT contrast agents are severely limited by poor vascular enhancement, particularly in large-to-obese patients because of beam hardening and loss of signal at the high kVp settings needed to image this patient population. Moreover, these so-called extravascular extracellular small-molecule agents equilibrate rapidly between the intravascular and interstitial fluid, and hence provide a washed out appearance of critical venous structures. Considering that obesity is a major risk factor for cardiovascular disease and is increasing in prevalence, a transformative contrast agent with improved imaging capabilities is urgently needed for this poorly served population. Patients with an allergy to iodine are without alternative CT contrast options. Furthermore, iodine contrast is poorly distinguished from vascular calcifications and metal-containing implants such as stents, despite the advent of dual energy CT. We propose to develop a safe blood pool tantalum nanoparticle contrast agent (TaCZ) to address these urgent unmet clinical needs. Our prior work showed excellent tolerance to TaCZ in four animal species, even up to 6X intended clinical dose and with repeat dosing. TaCZ shows superior X-ray signal in vivo and in vitro, even in simulated large body habitus. TaCZ shows the unique property of having both a blood pool distribution yet, surprisingly, rapid renal excretion and minimal biological retention on par with clinical iodinated contrast agents. With advanced metal artifact reduction algorithms for CT imaging, TaCZ is unlike iodinated agents in that it retains excellent signal, which makes it ideal for imaging post-surgical or trauma patients. The duration of intense vascular enhancement is over 5 minutes, unlike for iodinated agents 5 to 10 seconds, which minimizes risk for error and mis-timing at vascular imaging. Profoundly, TaCZ may be used simultaneously with iodine contrast agents as different colors at dual energy CT imaging to generate unprecedented information-rich co-registered color contrast CT images with a single 5 second pass of the scanner. In our project proposal, we will define processes and specifications for scaled-up TaCZ synthesis for tight size distribution. Preclinical toxicity data will be extended to include maximum feasible intraperitoneal and GLP maximum intravenous repeat dose testing to enable FDA-IND. Then first-in-human Clinical Phase 1 testing will assess safety and efficacy in normal and obese individuals. At the conclusion of this project, we will have validated data suitable for the Clinical Phase 2 and 3 human trials required for FDA-NDA approval and commercial use of this transformative CT contrast agent.
Public Health Relevance Statement: Project Narrative We will develop an urgently needed blood pool tantalum-based vascular CT contrast agent that dramatically improves CT imaging of vascular disease, particularly in patients with obesity, atherosclerotic disease, metallic implants, and inability to tolerate currently available iodinated contrast agents. To bring this agent to clinical use, we will define scale-up processes for contrast agent synthesis, perform required good laboratory practice preclinical toxicity tests, then obtain first-in-human Clinical Phase 1 tests.
Project Terms: absorption; acute toxicity; Address; Adipose tissue; Adverse event; Algorithms; American; Angiography; Animal Model; Animals; Appearance; Atherosclerosis; Award; base; Biological; biomaterial compatibility; Blood; Blood Vessels; Canis familiaris; Cardiovascular Diseases; cardiovascular risk factor; Characteristics; Clinical; clinical translation; Clinical Trials; Color; commercialization; contrast enhanced; contrast imaging; Contrast Media; Data; Development; Distant; Documentation; Dose; drug development; Drug Kinetics; Effectiveness; efficacy testing; Excretory function; experience; extracellular; Family suidae; first-in-human; Formulation; Frequencies; Goals; good laboratory practice; Human; Hypersensitivity; Image; imaging agent; imaging capabilities; Implant; improved; In Vitro; in vivo; Individual; Industry; Injections; Injury to Kidney; Intercellular Fluid; intraperitoneal; Intraperitoneal Injections; Intravenous; Iodine; Kidney; metallicity; Metals; Methods; Modality; Morphologic artifacts; nanoparticle; Obesity; Operative Surgical Procedures; Organ; Patient imaging; patient population; Patients; Phase; phase 1 testing; Phase II/III Trial; Plasma; Population; pre-clinical; preclinical safety; preclinical toxicity; Prevalence; Process; Property; prototype; Radiology Specialty; Rattus; Recovery; Reproducibility; Research; Research Personnel; Risk; risk minimization; Roentgen Rays; Route; Safety; safety testing; Sales; scale up; Scanning; Severities; Signal Transduction; Small Business Innovation Research Grant; small molecule; stability testing; Stents; Structure; Syncope; Tantalum; Testing; Time; Tissues; Toxic effect; Toxicity Tests; Trauma patient; Vascular calcification; Vascular Diseases; Venous; volunteer; Work; X-Ray Computed Tomography
