This SBIR phase 2 project focuses on preclinical investigational new drug (IND) enabling studies of a novel high performance carbon nanostructure-based X-ray computer tomography (CT) contrast agent (CA) to be used to diagnose and monitor patients with renal failure or at risk of contrast induced nephropathy (CIN). Routine contrast-enhanced CT provides crucial information about diseases and injuries. However, contrast induced nephropathy (CIN) which may result from this procedure, remains a leading cause of hospital-acquired Acute Kidney Injury (AKI). About 0.6 million US residents suffer from acute kidney disease, and approximately 20 million people are treated for mild to severe chronic kidney disease each year. Many diseases or conditions can lead to acute kidney injury and/or chronic kidney disease. Additionally, non-invasive imaging of kidney or other disease/pathologies (e.g. cancer) for patients with renal failure, especially at advanced stages, still remains significant major challenge in clinical settings. We have developed a novel nanoparticle-based X-ray CT CA called GNP-I for imaging and monitoring in patients with renal failure or at risk of CIN. GNP-I is comprised of graphene (single sheet of graphite) nanoparticles called graphene oxide nanoplatelets (GNP) functionalized with iodine (~105 iodine per GNP nanoparticle). Our synthesis procedure leads to entrapment and covalently functionalization of iodine to the inner graphene sheet layers. Subsequent functionalization with dextran imparts water dispersibility to the hydrophobic graphene particles. Our in vitro and in vivo studies indicate that equivalent CT performance can be achieved at substantially lower (three orders lower) dosages than currently CAs. These results, taken together with our in vivo small animal safety study in a contrast induced acute kidney injury (CI-AKI) rat model (i.e., no nephrotoxicity at diagnostic doses), and increased in vivo circulation time suggest exciting possibilities for its use as an organ (kidney)-specific CA and extended-residence-intravascular blood pool agent. During phase 2, the overall objective will conduct key preclinical safety and efficacy studies towards investigational new drug (IND) approval. Additionally, the GNP-I test article used in these studies will be synthesized and scaled up using a protocol that will eventually be used for the final clinical material; therefore, will be representative of the drug substance to be used in the clinical setting.
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.
