Currently used X-ray imaging contrast agents are primarily iodinated small molecules. These iodinated small molecule agents are used in the diagnosis and treatment of cardiovascular disease, among other conditions. However, they frequently cause a condition known as contrast-induced nephropathy in patients with poor kidney function. This condition results in higher morbidity, mortality and costs. More than 10% of American adults have poor kidney function, and that proportion is rapidly increasing, due to the rise in prevalence of diabetes, a complication of which is reduced kidney function. In addition, the risk of cardiovascular disease for diabetics is trebled and it is predicted that 30% of the US population will be diabetic by 2050. Therefore there is an increasing number of patients who will suffer from cardiovascular disease, will need to receive current agents for diagnosis and treatment, but will suffer increased morbidity and mortality as a result. Gold nanoparticles are biocompatible, more strongly attenuating, long-circulating alternatives to iodinated agents. However, these nanoparticles suffer from poor excretion and are expensive. To address these issues, we propose to develop novel, small (<5 nm) metal nanoparticles that can be easily excreted, made from lanthanum, tantalum and gold. We have found that combining several elements further increases contrast in CT, compared with gold alone, as the k-edges of the elements are spread over the diagnostic X-ray spectrum. As lanthanum and tantalum are more than tenfold cheaper than gold, this reduces the cost of the agent. In addition, the risk of toxiciy is decreased as the dose of the nanoparticles formed from each element is lowered by a factor of three. We will then encapsulate these small nanoparticles into hydrophilic polyphosphazene nanospheres to create polymetal nanoparticles. These nanospheres are a novel contrast agent delivery platform, are biodegradable and coated with polyethylene glycol to promote long circulation. These larger nanostructures are designed to break down into harmless byproducts and release the small nanoparticles for swift excretion when applied in vivo. We hypothesize that nanoparticles, having a much lower surface to volume to ratio than small molecules, will prove less toxic than iodinated small molecules. Furthermore, encapsulation in a slow-releasing polymer matrix should result in a low dose of agent reaching the kidneys at any time, additionally reducing the potential for toxicity. Both smaller and larger nanoparticles will be characterized, tested for biocompatibility in vitro and selected formulations will be probed for their excretion and effectiveness as contrast agents in blood vessel imaging with CT. We will use a model of kidney disease and compare the novel agents to clinically approved agents. Thorough toxicological assessments will be performed, with the goal of identifying highly biocompatible agents to be moved towards the clinic.
The currently used contrast agents for X-ray based imaging are necessary to detect and treat cardiovascular disease, yet they can cause a condition known as contrast-induced nephropathy (CIN) in patients with reduced kidney function. CIN results in increased morbidity and mortality and since the number of patients with kidney disease is rapidly increasing, CIN is a growing health risk. In this application, we seek to address this issu by developing degradable, highly attenuating, nanoparticle X-ray contrast agents suitable for patients with kidney disease, thereby enabling their safe diagnosis and treatment.
Showing the most recent 10 out of 12 publications
