SBIR-STTR Award

This STTR phase 1 proposal investigates the safety and efficacy of a novel high-performance carbon nanostructure-based magnetic resonance imaging (MRI) contrast agent for the imaging and monitoring of patients with renal failure. Every year, in the US, approximately 20 million people are treated for mild to severe renal failure. A significant number of cases (greater than 50%) related to renal failure are at an advanced stage, and lead to incidences of morbidity, mortality and increase burden on health care resources and costs. Non-invasive imaging of renal injury or disease especially at advanced stages and /or other pathologies/ lesions in patients with renal failure is still a major challenge in clinic. X-ray computed tomography (CT) and MRI are routinely used in clinic to image the anatomy of kidneys and other organs. Exogenous chemicals called contrast agents (CAs) synthesized using the elements iodine and gadolinium has been widely employed to improve the diagnostic confidence of CT and MRI, respectively. However, in patients with advanced renal failure, these CAs have been linked to the onset of the disease nephrogenic systemic fibrosis (NSF). In these patients, NSF manifests as a severe debilitating condition that hardens and thickens the skin, causes contractures of the joints and restricts joint mobility triggering extreme pain. Furthermore, internal organs such as heart, lungs and liver can be affected, sometimes resulting in death. We have recently developed a novel carbon nanostructure-based MRI CA that comprises of high quality graphene (single sheet of graphite) nanoparticles (disk-shaped, diameter 25 nm, thickness 2-3 nm, 5-7 sheets of graphene, also called graphene nanoplatelets or GNPs) intercalated (chemical species inserted and trapped in the voids between two graphene sheets), and coordinated with graphene trace amounts of manganese (0.1 % w/w (w = weight)) The GNPs are water-solubilized via non-covalent functionalization with the natural biocompatible FDA-approved polymer dextran (hereafter called GNP-Dex). The overall objective of this proposal is to perform key proof-of-principle safety and efficacy studies with the GNP-Dex MRI CA, at potential therapeutic dosages, in a rodent model of renal failure. Successful completion of the studies will demonstrate that the GNP-Dex formulation substantially enhance the contrast (~10 times greater than current clinical MRI CA), and show no NSF like indicators or toxic effects on the various organs at potential therapeutic doses. The proof-of-principle studies detailed in this proposal represent a critical step in accelerating the translation of this technology into clinic, and we anticipate that it will allow us to initiate the safety and efficacy studies in a non- rodent animal model during STTR phase 2, and subsequently prepare for the first-in-human trials. The final commercial product(s) upon the complete development of this technology will be the first FDA-approved MRI CA for patients with renal failure. The GNP-Dex could also due to their high-efficacy be used in clinic for other applications as an alternative off-the-label MRI CA to currently existing gadolinium-basedT1 MRI CAs.

Public Health Relevance Statement:


Public Health Relevance:
Every year, in the US, approximately 20 million people are treated for mild to severe clinical cases of kidney disease or injury (also known as renal failure) A significant number of these clinical cases (greater than 50%) involve advanced stage renal failure, and lead to incidences of morbidity, mortality and increase burden on health care resources and costs. Non-invasive imaging and monitoring of the kidneys during renal failure especially at these advanced stages is still a major challenge in clinic. X-ray computed tomography (CT) and magnetic resonance imaging (MRI) are routinely used in clinic for this purpose. Exogenous chemicals called contrast agents (CAs), synthesized using the elements iodine and gadolinium, has been employed to improve the diagnostic confidence of CT and MRI, respectively. However, these CAs have been associated with the disease nephrogenic systemic fibrosis (NSF); a severely debilitating condition diagnosed in patients with advanced renal failure. This proposal describes the pre-clinical development of a novel high-performance carbon nanoparticle-based MRI CA that comprises of high quality graphene (single sheet of graphite) nanoparticles (disk-shaped, diameter 25 nm, thickness 2-3 nm, 5-7 sheets of graphene, also called graphene nanoplatelets or GNPs) intercalated (chemical species inserted and trapped in the voids between two graphene sheets), and coordinated with graphene trace amounts of manganese (0.1 % w/w (w = weight)) that can achieve ~10 times greater contrast enhancement at clinical dosages, compared to current clinical MRI CAs and does not cause NSF for the imaging and monitoring of patients with renal failure.

NIH Spending Category:
Bioengineering; Diagnostic Radiology; Kidney Disease; Nanotechnology

Project Terms:
Acute; Affect; Anatomy; Animal Model; base; Biocompatible; Biodistribution; Biological; Blood; Blood Circulation; Blood Circulation Time; Caliber; Carbon; Carbon nanoparticle; Cessation of life; Characteristics; Chemicals; Chronic; Chronic Kidney Failure; Clinic; Clinical; Clinical Trials; Contracture; Contrast Media; cost; Development; dextran; Dextrans; Diagnosis; Diagnostic; Disease; dosage; Dose; Drug Formulations; Elements; Evaluation; FDA approved; Fibrosis; Gadolinium; gadolinium oxide; Guidelines; Half-Life; Health; Healthcare; Heart; hemodynamics; Hour; Human; Image; improved; In Vitro; in vivo; Incidence; Injury; Iodine; Joints; Kidney; Kidney Diseases; Kidney Failure; Label; Lead; Lesion; Lethal Dose 50; Link; Liquid substance; Liver; Lung; Magnetic Resonance Imaging; Manganese; Measurable; Modeling; Monitor; Morbidity - disease rate; Mortality Vital Statistics; nanoparticle; Nanostructures; Natural graphite; Noise; novel; Onset of illness; Organ; Pain; Pathology; Pathway interactions; Patient Monitoring; Patients; Performance; Phase; Polymers; pre-clinical; preclinical efficacy; preclinical safety; Process; radiologist; Rattus; residence; Resources; Rodent; Rodent Model; Safety; Shapes; Signal Transduction; Skin; Small Business Technology Transfer Research; Staging; System; Technology; technology development; Testing; Therapeutic; Thick; Time; Tissues; Toxic effect; Translations; Water; Weight; X-Ray Computed Tomography

This SBIR phase 2 project focuses on preclinical investigational new drug (IND) enabling studies of a novel high performance carbon nanostructure-based magnetic resonance imaging (MRI) contrast agent (CA) to be used to diagnose and monitor patients with renal failure. Every year, in the US, approximately 20 million people are treated for mild to severe renal failure. A significant number of cases (greater than 30%) related to renal failure are at an advanced stage, and lead to incidences of morbidity, mortality and increase burden on health care resources and costs. Non-invasive imaging of renal injury or disease especially at advanced stages and /or other pathologies/ lesions in patients with renal failure is still a major challenge in clinic. X-ray computed tomography (CT) and MRI are routinely used in clinic to image the anatomy of kidneys and other organs. Exogenous chemicals called contrast agents (CAs) synthesized using the elements iodine and gadolinium has been widely employed to improve the diagnostic confidence of CT and MRI, respectively. However, in patients with advanced renal failure, these CAs have been linked to the onset of nephrotoxicity or the rare but potentially fatal disease nephrogenic systemic fibrosis (NSF). We have recently developed a novel carbon nanostructure-based MRI CA that comprises of high quality graphene (single sheet of graphite) nanoparticles (GNPs), intercalated (chemical species inserted and trapped in the voids between two graphene sheets), and coordinated with graphene trace amounts of manganese), and coated with natural biocompatible FDA-approved polymer dextran (hereafter called GNP-Dex). Our in vitro and in vivo (normal rats, and rat model of chronic kidney disease) safety and efficacy studies (pre-phase 1 and during phase 1) of this novel MRI CA showed good hemodynamic characteristics, increased in vivo circulation time (blood half-life of 1 hour), low acute toxicity (lethal dose LD5 value > 500 mg/kg), no chronic toxicity at therapeutic doses, no acute or chronic nephrotoxicity (including no NSF- like indicators), and greater contrast enhancement (~10 times greater) compared to clinical (Gd3+)-based MRI-CAs. These formed the basis of our recent request for an initial pre-IND meeting with the FDA (August 2013). Based on feedback from regulatory experts and FDA, the overall objective of SBIR phase 2 proposal is to scale up the manufacturing for GNP-Dex using GMPs practices for use in preclinical studies and to conduct of preclinical GLP safety and non- GLP efficacy studies in small and large animals. Successful completion of these aims will represent a critical step in accelerating the translation of this technology to the clinic; we anticipate that following completion of these aims, we will initiate te first-in-human trials. The final commercial product(s) will the first FDA-approved MRI CA for patients with renal failure. GNP-Dex will also prove useful as an alternative MRI CA to currently existing clinical first-pass and blood pool T1 MRI CAs.

Public Health Relevance Statement:


Public Health Relevance:
Every year, in the US, approximately 20 million people are treated for mild to severe clinical cases of kidney disease or injury (also known as renal failure) A significant number of these clinical cases (greater than 0.7 million) involve advanced stage renal failure, and lead to incidences of morbidity, mortality and increase burden on health care resources and costs. Non-invasive imaging and monitoring of the kidneys during renal failure especially at these advanced stages is still a major challenge in clinic. X-ray computed tomography (CT) and magnetic resonance imaging (MRI) are routinely used in clinic for this purpose. Exogenous chemicals called contrast agents (CAs), synthesized using the elements iodine and gadolinium, has been employed to improve the diagnostic confidence of CT and MRI, respectively. However, use of these CAs in patients with renal failure have been associated with nephrotoxicity and in some rare cases can lead to death. This proposal describes the pre-clinical development of a novel high-performance carbon nanoparticle-based MRI CA that comprises of high quality graphene (single sheet of graphite) nanoparticles (disk-shaped, diameter 25 nm, thickness 2-3 nm, 5-7 sheets of graphene, also called graphene nanoplatelets or GNPs) intercalated (chemical species inserted and trapped in the voids between two graphene sheets), and coordinated with graphene trace amounts of manganese (0.1 % w/w (w = weight)) that can achieve ~10 times greater contrast enhancement at clinical dosages, compared to current clinical MRI CAs and is not nephrotoxic for the imaging and monitoring of patients with renal failure.

NIH Spending Category:
Bioengineering; Diagnostic Radiology; Kidney Disease; Nanotechnology

Project Terms:
Acute; Address; Anatomy; Animal Model; Animals; base; Biocompatible; Biological; Blood; Blood Circulation Time; Caliber; Carbon; Carbon nanoparticle; Cessation of life; Characteristics; Chemicals; Chemistry; Chronic; Chronic Kidney Failure; Clinic; Clinical; Contracture; Contrast Media; cost; Development; Dextrans; Diagnosis; Diagnostic; Disease; dosage; Dose; Drug Formulations; Elements; Evaluation; FDA approved; Feedback; Fibrosis; Gadolinium; gadolinium oxide; good laboratory practice; Half-Life; Health; Healthcare; Heart; hemodynamics; Hour; Human; Image; improved; In Vitro; in vivo; Incidence; Injection of therapeutic agent; Injury; Investigational Drugs; Investigational New Drug Application; Iodine; Joints; Kidney; Kidney Diseases; Kidney Failure; Lead; Lesion; Lethal Dose 50; Link; Liquid substance; liver injury; Lung; Magnetic Resonance Imaging; Manganese; manufacturing process; manufacturing scale-up; meetings; Modeling; Monitor; Morbidity - disease rate; Mortality Vital Statistics; nanoparticle; Nanostructures; Natural graphite; Nephrotoxic; nephrotoxicity; non-invasive imaging; novel; Organ; Pain; Pathology; Pathway interactions; Patient Monitoring; Patients; Performance; Phase; Polymers; pre-clinical; preclinical efficacy; preclinical safety; preclinical study; Procedures; Rattus; Research; Resources; Safety; safety study; scale up; Shapes; Skin; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Staging; Technology; Therapeutic; Thick; Time; Toxic effect; Translations; Ultrasonography; Water; Weight; X-Ray Computed Tomography