Safety and efficacy of a high-performance graphene-based magnetic resonance imaging contrast agent for renal abnormalities
The etiology of renal insufficiency includes primary (e.g., polycystic kidney disease) or secondary (e.g., contrast media, diabetes) causes. The regulatory restrictions placed on the use of contrast agents (CAs) for noninvasive imaging modalities such as X-ray computed tomography (CT) and magnetic resonance imaging (MRI) affect the clinical management of these patients. With the goal to develop a next-generation CA for unfettered use for renal MRI, here we report, in a rodent model of chronic kidney disease, the preclinical safety and efficacy of a novel nanoparticle CA comprised of manganese (Mn2+) ions-intercalated graphene coated with dextran (hereafter called Mangradex). Nephrectomized rats received single or 5 times/week repeat (2 or 4 weeks) intravenous (IV) injections of Mangradex at two potential (low = 5 mg/kg, and high = 50 mg/kg) therapeutic doses. Histopathology results indicate that Mangradex does not elicit nephrogenic systemic fibrosis (NSF)-like indicators or questionable effects on vital organs of rodents. MRI at 7 Tesla magnetic field was performed on these rats immediately after IV injections of Mangradex at one potential therapeutic dose (25 mg/kg, [Mn2+] = 60 nmoles/kg) for 90 min. The results indicated significant (>100 %) and sustained contrast enhancement in the kidney and renal artery at these low paramagnetic ion (Mn2+) concentration; 2 orders of magnitude lower than the paramagnetic ion concentration in a typical clinical dose of long-circulating Gd3+-based MRI CA gadofosveset trisodium. The results open avenues for further development of Mangradex as an MRI CA to diagnose and monitor abnormalities in renal anatomy and vasculature.
KeywordsNephrogenic systemic fibrosis Gadolinium Mangradex Chronic kidney disease Contrast agent Magnetic resonance imaging
This work was supported by the Wallace H Coulter Foundation Translational Research Award, Fusion Award from the Stony Brook School of Medicine and the Office of the Vice President for Research, Technology Accelerator Fund from the Research Foundation for SUNY, and the National Institute of Health (1R41DK100205-01A1 and 2R44DK100205-02).
Compliance with ethical standards
Conflict of interest
Stony Brook University, along with its researchers, has filed patents related to the technology reported in this article. If licensing or commercialization occurs, the researchers are entitled to standard royalties. Balaji Sitharaman has financial interest in Theragnostic Technologies Inc., which, however, did not directly support this work.
- 14.Bolskar RD, Benedetto AF, Husebo LO, Price RE, Jackson EF, Wallace S, Wilson LJ, Alford JM (2003) First soluble M@ C60 derivatives provide enhanced access to metallofullerenes and permit in vivo evaluation of Gd@ C60 [C (COOH) 2] 10 as a MRI contrast agent. J Am Chem Soc 125:5471–5478CrossRefGoogle Scholar
- 19.Braverman IM, Cowper S (2010) Nephrogenic systemic fibrosis. F1000 Medicine Reports 2:84Google Scholar
- 20.Gibson SE, Farver CF, Prayson RA (2006) Multiorgan involvement in nephrogenic fibrosing dermopathy: an autopsy case and review of the literature. Arch Pathol Lab Med 130:209–212Google Scholar
- 22.FDA Drug Safety Communication (2010) New warnings for using gadolinium-based contrast agents in patients with kidney dysfunction. U.S. Food and Drug Administration, MarylandGoogle Scholar
- 23.Manual on contrast media. American College of Radiology, version 9, 2010Google Scholar
- 28.Milne DB, Sims RL, Ralston NV (1990) Manganese content of the cellular components of blood. Clin Chem 36:450–452Google Scholar
- 29.Sullivan JF, Blotcky AJ, Jetton MM, Hahn HK, Burch RE (1979) Serum levels of selenium, calcium, copper magnesium, manganese and zinc in various human diseases. J Nutr 109:1432–1437Google Scholar
- 30.Kanakia S, Toussaint J, Chowdhury SM, Lalwani G, Tem-bulkar T, Button T et al (2013) Physicochemical characterization of a novel graphene-based magnetic resonance imaging contrast agent. Int J Nanomed 8:2821–2833Google Scholar
- 39.Guidance for industry (1987) Food and Drug Administration, MarylandGoogle Scholar
- 40.Sieber MA, Lengsfeld P, Frenzel T, Golfier S, Schmitt-Willich H, Siegmund F et al (2008) Preclinical investigation to compare different gadolinium-based contrast agents regarding their propensity to release gadolinium in vivo and to trigger nephrogenic systemic fibrosis-like lesions. Eur Radiol 18:2164–2173CrossRefGoogle Scholar
- 53.The National Academies (2001) Dietary reference intakes for vitamin A, vitamin K, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Institute of Medicine of the National Academies, Washington, DC, pp 394–419Google Scholar