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Graphene Technology

, Volume 1, Issue 1–4, pp 17–28 | Cite as

Safety and efficacy of a high-performance graphene-based magnetic resonance imaging contrast agent for renal abnormalities

  • Shruti Kanakia
  • Jimmy Toussaint
  • Praveen Kukarni
  • Stephen Lee
  • Sayan Mullick Chowdhury
  • Slah Khan
  • Sandeep K. Mallipattu
  • Kenneth R. Shroyer
  • William Moore
  • Balaji Sitharaman
Original Article

Abstract

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.

Keywords

Nephrogenic systemic fibrosis Gadolinium Mangradex Chronic kidney disease Contrast agent Magnetic resonance imaging 

Notes

Acknowledgments

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.

Supplementary material

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References

  1. 1.
    Hoste EAJ, Schurgers M (2008) Epidemiology of acute kidney injury: how big is the problem? Crit Care Med 36:S146–S151CrossRefGoogle Scholar
  2. 2.
    Coresh JSESLA et al (2007) Prevalence of chronic kidney disease in the United States. J Am Med Assoc 298:2038–2047CrossRefGoogle Scholar
  3. 3.
    Robinson BE (2006) Epidemiology of chronic kidney disease and anemia. J Am Med Dir Assoc 7:S3–S6CrossRefGoogle Scholar
  4. 4.
    Roggeri DP, Roggeri A, Salomone M (2014) Chronic kidney disease: evolution of healthcare costs and resource consumption from predialysis to dialysis in piedmont region, Italy. Adv Nephrol 2014:6CrossRefGoogle Scholar
  5. 5.
    Murphree DD, Thelen SM (2010) Chronic kidney disease in primary care. J Am Board Family Med 23:542–550CrossRefGoogle Scholar
  6. 6.
    Katzberg RW (1997) Urography into the 21st century: new contrast media, renal handling, imaging characteristics, and nephrotoxicity. Radiology 204:297–312CrossRefGoogle Scholar
  7. 7.
    Thomsen HS, Morcos SK (2003) Contrast media and the kidney: European Society of Urogenital Radiology (ESUR) Guidelines. Br J Radiol 76:513–518CrossRefGoogle Scholar
  8. 8.
    Runge VM (2001) Safety of magnetic resonance contrast media. Top Magn Reson Imaging 12:309–314CrossRefGoogle Scholar
  9. 9.
    Grenier N, Basseau F, Ries M, Tyndal B, Jones R, Moonen C (2003) Functional MRI of the kidney. Abdom Imaging 28:164–175CrossRefGoogle Scholar
  10. 10.
    Grenier N, Pedersen M, Hauger O (2006) Contrast agents for functional and cellular MRI of the kidney. Eur J Radiol 60:341–352CrossRefGoogle Scholar
  11. 11.
    Nikken JJ, Krestin GP (2007) MRI of the kidney—state of the art. Eur Radiol 17:2780–2793CrossRefGoogle Scholar
  12. 12.
    Pooley RA (2005) Fundamental physics of MR imaging. Radiographics. 25:1087–1099CrossRefGoogle Scholar
  13. 13.
    Ananta JS, Godin B, Sethi R, Moriggi L, Liu X, Serda RE et al (2010) Geometrical confinement of gadolinium-based contrast agents in nanoporous particles enhances T1 contrast. Nat Nanotechnol 5:815–821CrossRefGoogle Scholar
  14. 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
  15. 15.
    Bae KT, Tao C, Zhu F, Bost JE, Chapman AB, Grantham JJ et al (2009) MRI-based kidney volume measurements in ADPKD: reliability and effect of gadolinium enhancement. Clin J Am Soc Nephrol 4:719–725CrossRefGoogle Scholar
  16. 16.
    Broome DR (2008) Nephrogenic systemic fibrosis associated with gadolinium based contrast agents: a summary of the medical literature reporting. Eur J Radiol 66:230–234CrossRefGoogle Scholar
  17. 17.
    Grobner T (2006) Gadolinium–a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 21:1104–1108CrossRefGoogle Scholar
  18. 18.
    Cowper SE, Kuo PH, Bucala R (2007) Nephrogenic systemic fibrosis and gadolinium exposure: association and lessons for idiopathic fibrosing disorders. Arthritis Rheum 56:3173–3175CrossRefGoogle Scholar
  19. 19.
    Braverman IM, Cowper S (2010) Nephrogenic systemic fibrosis. F1000 Medicine Reports 2:84Google Scholar
  20. 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
  21. 21.
    Ting WW, Stone MS, Madison KC, Kurtz K (2003) Nephrogenic fibrosing dermopathy with systemic involvement. Arch Dermatol 139:903–906CrossRefGoogle Scholar
  22. 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. 23.
    Manual on contrast media. American College of Radiology, version 9, 2010Google Scholar
  24. 24.
    Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG et al (2006) Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 17:2359–2362CrossRefGoogle Scholar
  25. 25.
    Rydahl C, Thomsen HS, Marckmann P (2008) High prevalence of nephrogenic systemic fibrosis in chronic renal failure patients exposed to gadodiamide, a gadolinium-containing magnetic resonance contrast agent. Invest Radiol 43:141–144CrossRefGoogle Scholar
  26. 26.
    Kanal E, Tweedle MF (2015) Residual or retained gadolinium: practical implications for radiologists and our patients. Radiology 275:630–634CrossRefGoogle Scholar
  27. 27.
    Pan D, Caruthers SD, Senpan A, Schmieder AH, Wickline SA, Lanza GM (2010) Revisiting an old friend: manganese-based MRI contrast agents. Wiley Interdiscip Rev Nanomed Nanobiotechnol 3:162–173CrossRefGoogle Scholar
  28. 28.
    Milne DB, Sims RL, Ralston NV (1990) Manganese content of the cellular components of blood. Clin Chem 36:450–452Google Scholar
  29. 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. 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
  31. 31.
    Paratala BS, Jacobson BD, Kanakia S, Francis LD, Sitharaman B (2012) Physicochemical characterization, and relaxometry studies of micro-graphite oxide, graphene nanoplatelets, and nanoribbons. PLoS ONE 7:e38185CrossRefGoogle Scholar
  32. 32.
    Chowdhury SM, Kanakia S, Toussaint JD, Frame MD, Dewar AM, Shroyer KR et al (2013) In vitro hematological and in vivo vasoactivity assessment of dextran functionalized graphene. Sci Rep 3:2584CrossRefGoogle Scholar
  33. 33.
    Kanakia S, Toussaint JD, Mullick Chowdhury S, Tembulkar T, Lee S, Jiang Y-P et al (2014) Dose ranging, expanded acute toxicity and safety pharmacology studies for intravenously administered functionalized graphene nanoparticle formulations. Biomaterials 35:7022–7031CrossRefGoogle Scholar
  34. 34.
    Kanakia S, Toussaint J, Hoang DM, Chowdhury SM, Lee S, Shroyer KR et al (2015) Towards an advanced graphene-based magnetic resonance imaging contrast agent: sub-acute toxicity and efficacy studies in small animals. Sci Rep 5:17182 CrossRefGoogle Scholar
  35. 35.
    Grant D, Johnsen H, Juelsrud A, Lovhaug D (2009) Effects of gadolinium contrast agents in naive and nephrectomized rats: relevance to nephrogenic systemic fibrosis. Acta Radiol 50:156–169CrossRefGoogle Scholar
  36. 36.
    Pietsch H, Lengsfeld P, Steger-Hartmann T, Lowe A, Frenzel T, Hutter J et al (2009) Impact of renal impairment on long-term retention of gadolinium in the rodent skin following the administration of gadolinium-based contrast agents. Invest Radiol 44:226–233CrossRefGoogle Scholar
  37. 37.
    Fretellier N, Idee JM, Guerret S, Hollenbeck C, Hartmann D, Gonzalez W et al (2011) Clinical, biological, and skin histopathologic effects of ionic macrocyclic and nonionic linear gadolinium chelates in a rat model of nephrogenic systemic fibrosis. Invest Radiol 46:85–93CrossRefGoogle Scholar
  38. 38.
    Haylor J, Dencausse A, Vickers M, Nutter F, Jestin G, Slater D et al (2010) Nephrogenic gadolinium biodistribution and skin cellularity following a single injection of Omniscan in the rat. Invest Radiol 45:507–512CrossRefGoogle Scholar
  39. 39.
    Guidance for industry (1987) Food and Drug Administration, MarylandGoogle Scholar
  40. 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
  41. 41.
    Sadowski EA, Bennett LK, Chan MR, Wentland AL, Garrett AL, Garrett RW et al (2007) Nephrogenic systemic fibrosis: risk factors and incidence estimation. Radiology 243:148–157CrossRefGoogle Scholar
  42. 42.
    Morris MF, Zhang Y, Zhang H, Prowda JC, Silvers DN, Fawwaz RA et al (2009) Features of nephrogenic systemic fibrosis on radiology examinations. Am J Roentgenol 193:61–69CrossRefGoogle Scholar
  43. 43.
    Wagner B, Tan C, Barnes JL, Ahuja S, Davis TL, Gorin Y et al (2012) Nephrogenic systemic fibrosis: evidence for oxidative stress and bone marrow-derived fibrocytes in skin, liver, and heart lesions using a 5/6 nephrectomy rodent model. Am J Pathol 181:1941–1952CrossRefGoogle Scholar
  44. 44.
    Pereira LV, Shimizu MH, Rodrigues LP, Leite CC, Andrade L, Seguro AC (2012) N-acetylcysteine protects rats with chronic renal failure from gadolinium-chelate nephrotoxicity. PLoS ONE 7:e39528CrossRefGoogle Scholar
  45. 45.
    Penfield JG, Reilly RF (2007) What nephrologists need to know about gadolinium. Nature Clin Pract Nephrol 3:654–668CrossRefGoogle Scholar
  46. 46.
    Noebauer-Huhmann IM, Szomolanyi P, Juras V, Kraff O, Ladd ME, Trattnig S (2010) Gadolinium-based magnetic resonance contrast agents at 7 tesla: in vitro T1 relaxivities in human blood plasma. Invest Radiol 45:554–558CrossRefGoogle Scholar
  47. 47.
    Caravan P, Farrar CT, Frullano L, Uppal R (2009) Influence of molecular parameters and increasing magnetic field strength on relaxivity of gadolinium- and manganese-based T1 contrast agents. Contrast Media Mol Imaging 4:89–100CrossRefGoogle Scholar
  48. 48.
    Rohrer M, Bauer H, Mintorovitch J, Requardt M, Weinmann H-J (2005) Comparison of magnetic properties of MRI contrast media solutions at different magnetic field strengths. Invest Radiol 40:715–724CrossRefGoogle Scholar
  49. 49.
    Lewis M, Yanny S, Malcolm PN (2012) Advantages of blood pool contrast agents in MR angiography: a pictorial review. J Med Imaging Radiat Oncol 56:187–191CrossRefGoogle Scholar
  50. 50.
    Aime S, Caravan P (2009) Biodistribution of gadolinium-based contrast agents, including gadolinium deposition. J Magn Reson Imaging 30:1259–1267CrossRefGoogle Scholar
  51. 51.
    Sabach AS, Bruno M, Kim D, Mulholland T, Lee L, Kaura S et al (2013) Gadofosveset trisodium: abdominal and peripheral vascular applications. Am J Roentgenol 200:1378–1386CrossRefGoogle Scholar
  52. 52.
    Maki JH, Prince MR, Londy FJ, Chenevert TL (1996) The effects of time varying intravascular signal intensity and k-space acquisition order on three-dimensional MR angiography image quality. J Magn Reson Imaging 6:642–651CrossRefGoogle Scholar
  53. 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
  54. 54.
    Yang K, Zhang S, Zhang G, Sun X, Lee S-T, Liu Z (2010) Graphene in mice: ultrahigh in vivo tumor uptake and efficient photothermal therapy. Nano Lett 10:3318–3323CrossRefGoogle Scholar
  55. 55.
    Nurunnabi M, Khatun Z, Huh KM, Park SY, Lee DY, Cho KJ et al (2013) In vivo biodistribution and toxicology of carboxylated graphene quantum dots. ACS Nano 7:6858–6867CrossRefGoogle Scholar
  56. 56.
    Sitharaman B, Wilson LJ (2007) Gadofullerenes and gadonanotubes: a new paradigm for high-performance magnetic resonance imaging contrast agent probes. J Biomed Nanotechnol 3:342–352CrossRefGoogle Scholar
  57. 57.
    Lalwani G, Sitharaman B (2013) Multifunctional fullerene-and metallofullerene-based nanobiomaterials. Nano Life 3:1342003CrossRefGoogle Scholar
  58. 58.
    Gizzatov A, Keshishian V, Guven A, Dimiev AM, Qu F, Muthupillai R et al (2014) Enhanced MRI relaxivity of aquated Gd3+ ions by carboxyphenylated water-dispersed graphene nanoribbons. Nanoscale 6:3059–3063CrossRefGoogle Scholar
  59. 59.
    Hung AH, Duch MC, Parigi G, Rotz MW, Manus LM, Mastarone DJ et al (2013) Mechanisms of gadographene-mediated proton spin relaxation. J Phys Chem C 117(31):16263–16273CrossRefGoogle Scholar
  60. 60.
    Fatouros PP, Corwin FD, Chen Z-J, Broaddus WC, Tatum JL, Kettenmann B et al (2006) In vitro and in vivo imaging studies of a new endohedral metallofullerene nanoparticle. Radiology 240:756–764CrossRefGoogle Scholar
  61. 61.
    Berns AS (1989) Nephrotoxicity of contrast media. Kidney Int 36:730–740CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Biomedical EngineeringNortheastern UniversityBostonUSA
  2. 2.Center for Translational NeuroimagingNortheastern UniversityBostonUSA
  3. 3.Division of Nephrology, Department of MedicineStony Brook UniversityStony BrookUSA
  4. 4.Department of PathologyStony Brook UniversityStony BrookUSA
  5. 5.Department of RadiologyStony Brook UniversityStony BrookUSA

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