SBIR-STTR Award

This SBIR phase 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 T iso osmolar iso viscous Magnetic Resonance Imaging MRI CA This comprises of manganese Mn 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 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 Nephrex rat Successful completion of the aims outlined in this proposal will lead to submission of a SBIR phase 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 Project Narrative 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

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.

Thesaurus Terms:
Acute; Acute Renal Failure With Renal Papillary Necrosis; Address; Adult; Animal Model; Animals; Base; Blood; Blood Circulation; Cancer Patient; Carbon; Chemistry; Child; Chronic Kidney Failure; Clinical; Clinical Diagnostics; Clinical Material; Cohort; Computers; Contrast Enhanced; Contrast Media; Creatinine; Deterioration; Development; Dextrans; Diabetes Mellitus; Diagnosis; Diagnostic; Dialysis Procedure; Disease; Dosage; Dose; Efficacy Study; Exposure To; Fda Approved; First-In-Human; Formulation; Functional Disorder; Functional Group; Graphene; Heart Failure; High Risk; Hospitals; Hour; Hydrophobicity; Hydroxyl Radical; Image; Imaging Agent; Impairment; In Vitro; In Vivo; Injury; Investigational Drugs; Investigational New Drug Application; Iodine; Kidney; Kidney Diseases; Kidney Failure; Kidney Imaging; Kidney Transplantation; Label; Laboratories; Lead; Manufacturing Scale-Up; Measures; Modeling; Molecular Computers; Monitor; Nanoparticle; Nanostructures; Natural Graphite; Nephrotoxicity; New Drug Approvals; Non-Invasive Imaging; Novel; Organ; Oxides; Particle; Pathology; Pathway Interactions; Patient Monitoring; Patient Risk; Patients; Performance; Pharmaceutical Preparations; Pharmacology Study; Phase; Pre-Clinical; Preclinical Safety; Preventive Screening; Procedures; Protocols Documentation; Rattus; Renal Artery; Renal Function; Research; Residence; Risk; Roentgen Rays; Safety; Safety Practice; Safety Study; Scale Up; Scanning; Serum; Small Business Innovation Research Grant; Technology; Testing; Thyroid Gland; Time; Tomography; Tool; Water; X-Ray Computed Tomography;