This SBIR phase 1 proposal is to demonstrate the pre-clinical safety and efficacy of a novel carbon-nanostructure-based X-ray computer tomography (CT) contrast agent (CA) for imaging and monitoring in patients with renal failure or at risk of contrast induced nephropathy (CIN). Routine contrast enhanced CT scans relays crucial information about diseases and injuries, thus aiding the clinician in improving diagnosis and management of patients. The present day CT CAs available on the market are all based on covalently bonded tri-iodinated benzene rings. However, they are all contraindicated for patients with renal insufficiency, diabetes, heart failure and thyroid dysfunction. Use of these CT CAs in these patient cohorts has been linked to CIN which deteriorates normal or further exacerbate pre-existing kidney functions. These adverse effects have been associated with high osmolality and viscosity CT CAs and the inability of these and even low or iso-osmolar and/or iso-viscous CT CA formulations to be completely eliminated of cytotoxic free iodine ions in solution. The technology detailed in this proposal builds on our previously reported novel carbon- nanoparticle based T1 iso-osmolar, iso-viscous Magnetic Resonance Imaging (MRI) CA. This comprises of manganese (Mn2+) intercalated graphene oxide nanoplatelets (GNP) covalently functionalized with dextran, and named GNP-Dex. This formulation shows low acute toxicity, high blood stability and high renal clearance through the urine. For expanded multimodal use, we intercalated and covalently functionalized iodine ions to the inner graphene sheet layers. This method of sequestration of iodine prevents its dissociation as free ions into solution. This formulation we termed GNP-I. In vitro studies done on kidney epithelial cell culture demonstrated favorable GNP-I cyto-compatibility. Furthermore, at equimolar concentration of iodine, GNP-I showed very high CT (~10 times greater) radio-opacity signals in phantoms compared to the control?Iohexol (Omnipaque?) ? a commonly used CT CA. Thus these lower detection limits will allow the same clinical imaging performance at substantially lower dosages, thus lowering healthcare costs. Based on GNP-I characteristics, inclusive of its apparent higher safety and efficacy profiles than that of currently available CT CAs, the thrust in this proposal is to develop it specifically for monitoring and diagnosis of kidney and other vital organs for patients at risk of CIN. Thus, thereby overcoming the limitations of present day CT CAs. For this, we will conduct pre-clinical safety and efficacy feasibility studies in a well validated rodent model of acute kidney injury, that is, the 5/6 Nephrex rat. Successful completion of the aims outlined in this proposal will lead to submission of a SBIR phase 2 proposal to perform safety and efficacy pre-clinical studies in a suitable large animal model under good laboratory practice (GLP) followed by Investigational New Drug (IND) application to the FDA. Furthermore, successful development will lead to the first FDA- approved CT CA specifically for use in these high risks, distinctly disadvantaged patient groups.
Routine X-ray contrast enhanced Computer Tomography (CT) scan is essential for preventative screening and detecting diseased pathologies, however presently available contrast agents are contraindicated in patients with renal insufficiency, diabetes, heart failure and thyroid dysfunction; these subjects being at risk for contrast induced nephropathy. There is an urgent requirement for safe and efficacious CT contrast agents to address this unmet clinical need. Our proposed technology is a novel nanoparticle- based CT contrast agent for imaging and monitoring of vital organs in this high risk patient group.
