Preclinical Efficacy And Safety Evaluation Of Graphene Nanoparticle-based Magneti

Abstract 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 areroutinely 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 STTRphase 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 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 increaseburden 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 CAshave 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.