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Stability evaluation of Gd chelates for macromolecular MRI contrast agents

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Abstract

Objective

We try to establish designs for the macromolecular agents possessing high Gd3+-chelating stability, because free Gd3+ ion released from Gd chelates is known as a risk factor to cause toxic side effects and a safety concern.

Materials and methods

We prepared three types of Gd-based macromolecular MRI contrast agents from a synthetic polymer (poly(glutamic acid) homopolymer or poly(ethylene glycol)-b-poly(lysine) block copolymer) and a chelating moiety (DO3A or DOTA) having two strategic designs for high chelate stability. Then, we examine the in vitro Gd3+-chelate stability of these macromolecular MRI contrast agents.

Results

The prepared macromolecular agents exhibited the same or higher Gd3+-chelate stability as/than did Gd-DOTA that possesses the highest Gd3+-chelate stability among the approved small-MW Gd-chelate MRI contrast agent.

Discussion

Our macromolecular design was considered to work well for high Gd3+-chelate stability.

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References

  1. Caravan P, Ellison JJ, McMurry TJ, Lauffer RB (1999) Gadolinium(III) chelates as MRI contrast agents: structure, dynamics, and applications. Chem Rev 99:2293–2352. https://doi.org/10.1021/cr980440x

    Article  CAS  PubMed  Google Scholar 

  2. Kubíček V, Tóth É (2009) Design and function of metal complexes as contrast agents in MRI. Adv Inorg Chem 61:63–129. https://doi.org/10.1016/S0898-8838(09)00202-5

    Article  CAS  Google Scholar 

  3. Aime S, Caravan PJ (2009) Biodistribution of gadolinium-based contrast agents, including gadolinium deposition. Magn Reson Imaging 30:1259–1267. https://doi.org/10.1002/jmri.21969

    Article  Google Scholar 

  4. Tóth É, Helm L, Merbach AE (2009) Metal complexes as MRI contrast enhancement agents. In: McCleverty JA, Meyer J (eds) Comprehensive coordination chemistry II, vol 9. Elsevier Science, Amsterdam, pp 841–881. https://doi.org/10.1016/B0-08-043748-6/09007-1

  5. Pesaresi I, Cosottini M (2010) MR angiography contrast agents. In: Neri R, Cosottini M, Caramella D (eds) MR angiography of the body technique and clinical application. Springer, New York, pp 7–16. https://doi.org/10.1007/978-3-540-79717-3

  6. Tóth É, Helm L, Merbach AE (2015) Metal complexes as MRI contrast enhancement agents. In: Reference module in chemistry, molecular sciences and chemical engineering. Elsevier, Amsterdam. https://doi.org/10.1016/B978-0-12-409547-2.11263-6

  7. Tweedle MF (1992) Physicochemical properties of gadoteridol and other magnetic resonance contrast agents. Investig Radiol 27(Suppl 1):S7

    Article  Google Scholar 

  8. Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG, Thomsen HS (2006) Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 17:2359–2362. https://doi.org/10.1681/ASN.2006060601

    Article  PubMed  Google Scholar 

  9. Do C, Barnes JL, Tan C, Wagner B (2014) Type of MRI contrast, tissue gadolinium, and fibrosis. Am J Physiol Renal Physiol 307:F844–855. https://doi.org/10.1152/ajprenal.00379.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Thomsen HS, Morcos SK, Dawson P (2006) Is there a causal relation between the administration of gadolinium based contrast media and the development of nephrogenic systemic fibrosis (NSF)? Clin Radiol 61:905–906. https://doi.org/10.1016/j.crad.2006.09.003

    Article  CAS  PubMed  Google Scholar 

  11. Thomsen HS (2006) Nephrogenic systemic fibrosis: a serious late adverse reaction to gadodiamide. Eur Radiol 16:2619–2621. https://doi.org/10.1007/s00330-006-0495-8

    Article  PubMed  PubMed Central  Google Scholar 

  12. Morcos SK (2007) Nephrogenic systemic fibrosis following the administration of extracellular gadolinium based contrast agents: is the stability of the contrast agent molecule an important factor in the pathogenesis of this condition? Br J Radiol 80:73–76. https://doi.org/10.1259/bjr/17111243

    Article  CAS  PubMed  Google Scholar 

  13. Braveman IM, Cowper S (2010) Nephrogenic systemic fibrosis. F1000 Med Rep 2:84. https://doi.org/10.3410/M2-84

    Article  Google Scholar 

  14. Ramalho J, Ramalho M, Jay M, Burke LM, Semelka RC (2016) Gadolinium toxicity and treatment. Magn Reson Imaging 34:1394–1398. https://doi.org/10.1016/j.mri.2016.09.005

    Article  CAS  PubMed  Google Scholar 

  15. Semelka RC, Ramalho M, AlObaidy M, Ramalho J (2016) Gadolinium in humans: a family of disorders. Am J Roentgenol 207:229–233. https://doi.org/10.2214/AJR.15.15842

    Article  Google Scholar 

  16. Hao D, Ai T, Goerner F, Hu X, Runge VM, Tweedle M (2012) MRI contrast agents: basic chemistry and safety. J Magn Reson Imaging 36:1060–1071. https://doi.org/10.1002/jmri.23725

    Article  PubMed  Google Scholar 

  17. Kanda T, Ishii K, Kawaguchi H, Kitajima K, Takenaka D (2014) High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material. Radiology 270:834–841. https://doi.org/10.1148/radiol.13131669

    Article  PubMed  Google Scholar 

  18. Kanda T, Osawa M, Oba H, Toyoda K, Kotoku J, Haruyama T, Takeshita K, Furui S (2015) High signal intensity in dentate nucleus on unenhanced T1-weighted MR images: association with linear versus macrocyclic gadolinium chelate administration. Radiology 275:803–809. https://doi.org/10.1148/radiol.14140364

    Article  PubMed  Google Scholar 

  19. Kanda T, Fukusato T, Matsuda M, Toyoda K, Oba H, Kotoku J, Haruyama T, Kitajima K, Furui S (2015) Gadolinium-based contrast agent accumulates in the brain even in subjects without severe renal dysfunction: evaluation of autopsy brain specimens with inductively coupled plasma mass spectroscopy. Radiology 276:228–232. https://doi.org/10.1148/radiol.2015142690

    Article  PubMed  Google Scholar 

  20. Kanda T, Nakai Y, Oba H, Toyoda K, Kitajima K, Furui S (2016) Gadolinium deposition in the brain. Magn Reson Imaging 34:1346–1350. https://doi.org/10.1016/j.mri.2016.08.024

    Article  CAS  PubMed  Google Scholar 

  21. Tweedle MF, Hagan JJ, Kumar K, Mantha S, Chang CA (1991) Reaction of gadolinium chelates with endogenously available ions. Magn Reson Imaging 9:409–415

    Article  CAS  PubMed  Google Scholar 

  22. Wedeking P, Kumar K, Tweedle MF (1992) Dissociation of gadolinium chelates in mice: relationship to chemical characteristics. Magn Reson Imaging 10:641–648

    Article  CAS  PubMed  Google Scholar 

  23. Tweedle MF (2016) Gadolinium deposition: is it chelated or dissociated gadolinium? How can we tell? Magn Reson Imaging 34:1377–1382. https://doi.org/10.1016/j.mri.2016.09.003

    Article  CAS  PubMed  Google Scholar 

  24. Idée JM, Port M, Raynal I, Schaefer M, Le Greneur S, Corot C (2006) Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: a review. Fundam Clin Pharmacol 20:563–576. https://doi.org/10.1111/j.1472-8206.2006.00447.x

    Article  CAS  PubMed  Google Scholar 

  25. White GW, Gibby WA, Tweedle MF (2006) Comparison of Gd(DTPA-BMA) (Omniscan) versus Gd(HP-DO3A) (ProHance) relative to gadolinium retention in human bone tissue by inductively coupled plasma mass spectroscopy. Investig Radiol 41:272–278. https://doi.org/10.1097/01.rli.0000186569.32408.95

    Article  Google Scholar 

  26. Gibby WA, Gibby KA, Gibby WA (2004) Comparison of Gd DTPA-BMA (Omniscan) versus Gd HP-DO3A (ProHance) retention in human bone tissue by inductively coupled plasma atomic emission spectroscopy. Investig Radiol 39:138–142

    Article  Google Scholar 

  27. Ostrowitzki S, Fick J, Roberts TP, Wendland MF, Aldape KD, Mann JS, Israel MA, Brasch RC (1998) Comparison of gadopentetate dimeglumine and albumin-(Gd-DTPA)30 for microvessel characterization in an intracranial glioma model. J Magn Reson Imaging 8:799–806. https://doi.org/10.1002/jmri.1880080408

    Article  CAS  PubMed  Google Scholar 

  28. Helbich TH, Gossman A, Mareski PA, Radüchel B, Roberts TP, Shames DM, Mühler M, Turetschek K, Brasch RC (2000) A new polysaccharide macromolecular contrast agent for MR imaging: biodistribution and imaging characteristics. J Magn Reson Imaging 11:694–701. https://doi.org/10.1002/1522-2586(200006)11:6%3c694:AID-JMRI17%3e3.0.CO;2-1

    Article  CAS  PubMed  Google Scholar 

  29. Granato L, Vander Elst L, Henoumont C, Muller RN, Laurent S (2018) Optimizing water exchange rates and rotational mobility for high-relaxivity of a novel Gd-DO3A derivative complex conjugated to inulin as macromolecular contrast agents for MRI. Chem Biodivers 15:e1700487. https://doi.org/10.1002/cbdv.201700487

    Article  CAS  Google Scholar 

  30. Lu ZR, Wang X, Parker DL, Goodrich KC, Buswell HR (2003) Poly(l-glutamic acid) Gd(III)-DOTA conjugate with a degradable spacer for magnetic resonance imaging. Bioconj Chem 14:715–719. https://doi.org/10.1021/bc0340464

    Article  CAS  Google Scholar 

  31. Ye F, Ke T, Jeong EK, Wang X, Sun Y, Johnson M, Lu ZR (2003) Noninvasive visualization of in vivo drug delivery of poly(l-glutamic acid) using contrast-enhanced MRI. Mol Pharm 3:507–515. https://doi.org/10.1021/mp060052g

    Article  CAS  Google Scholar 

  32. Schuhmann-Giampieri G, Schmitt-Willich H, Frenzel T, Press WR, Weinmann HJ (1991) In vivo and in vitro evaluation of Gd-DTPA-polylysine as a macromolecular contrast agent for magnetic resonance imaging. Investig Radiol 26:969–974

    Article  CAS  Google Scholar 

  33. Grandin C, Van Beers BE, Demeure R, Goudemant JF, Mottet I, Pringot J (1995) Comparison of gadolinium-DTPA and polylysine-gadolinium-DTPA-enhanced magnetic resonance imaging of hepatocarcinoma in the rat. Investig Radiol 30:572–581

    Article  CAS  Google Scholar 

  34. Bogdanov A Jr, Wright SC, Marecos EM, Bogdanova A, Martin C, Petherick P, Weissleder R (1997) A long-circulating co-polymer in “passive targeting” to solid tumors. Drug Target 4:321–330. https://doi.org/10.3109/10611869708995848

    Article  CAS  Google Scholar 

  35. Bogdanov AA Jr, Weissleder R, Frank W, Bogdanova AV, Nossif N, Schaffer BK, Tsai E, Papisov MI, Brady TJ (1993) A new macromolecule as a contrast agent for MR angiography: preparation, properties, and animal studies. Radiology 187:701–706. https://doi.org/10.1148/radiology.187.3.8497616

    Article  CAS  PubMed  Google Scholar 

  36. Tombach B, Schneider J, Reimer P, Mahler M, Ebert W, Shams K, Heindel W (2006) CMR 2005: 6.05; Phase I clinical trial of gadomer. Contrast Media Mol Imaging 1:69. https://doi.org/10.1002/cmmi.38

    Article  Google Scholar 

  37. Kobayashi H, Kawamoto S, Choyke PL, Sato N, Knopp MV, Star RA, Waldmann TA, Tagaya Y, Brechbiel MW (2003) Comparison of dendrimer-based macromolecular contrast agents for dynamic micro-magnetic resonance lymphangiography. Magn Reson Med 50:758–766. https://doi.org/10.1002/mrm.10583

    Article  CAS  PubMed  Google Scholar 

  38. Venditto VJ, Regino CA, Brechbiel MW (2005) PAMAM dendrimer based macromolecules as improved contrast agents. Mol Pharm 2:302–311. https://doi.org/10.1021/mp050019e

    Article  CAS  PubMed  Google Scholar 

  39. Ndiaye M, Malytskyi V, Vangijzegem T, Sauvage F, Wels M, Cadiou C, Moreau J, Henoumont C, Boutry S, Muller RN, Harakat D, Smedt S, Laurent S, Chuburu F (2019) Comparison of MRI properties between multimeric DOTAGA and DO3A Gadolinium-Dendron conjugates. Inorg Chem 58:12798–12808. https://doi.org/10.1021/acs.inorgchem.9b01747

    Article  CAS  PubMed  Google Scholar 

  40. Ladd DL, Hollister R, Peng X, Wei D, Wu G, Delecki D, Snow RA, Toner JL, Kellar K, Eck J, Desai VC, Raymond G, Kinter LB, Desser TS, Rubin DL (1999) Polymeric gadolinium chelate magnetic resonance imaging contrast agents: design, synthesis, and properties. Bioconj Chem 10:361–370. https://doi.org/10.1021/bc980086+

    Article  CAS  Google Scholar 

  41. Ye Z, Zhou Z, Ayat N, Wu X, Jin E, Shi X, Lu ZR (2016) A neutral polydisulfide containing Gd(III) DOTA monoamide as a redox-sensitive biodegradable macromolecular MRI contrast agent. Contrast Media Mol Imaging 11:32–40. https://doi.org/10.1002/cmmi.1655

    Article  CAS  PubMed  Google Scholar 

  42. Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46:6387–6392

    CAS  PubMed  Google Scholar 

  43. Maeda H (2012) Macromolecular therapeutics in cancer treatment: the EPR effect and beyond. J Control Release 164:138–144. https://doi.org/10.1016/j.jconrel.2012.04.038

    Article  CAS  PubMed  Google Scholar 

  44. Thonon D, Jacques V, Desreux JF (2007) A gadolinium triacetic monoamide DOTA derivative with a methanethiosulfonate anchor group. Relaxivity properties and conjugation with albumin and thiolated particles. Contrast Media Mol Imaging 2:24–34. https://doi.org/10.1002/cmmi.121

    Article  CAS  PubMed  Google Scholar 

  45. Shiraishi K, Kawano K, Minowa T, Maitani Y, Yokoyama M (2009) Preparation and in vivo imaging of PEG-poly(l-lysine)-based polymeric micelle MRI contrast agents. J Control Release 136:14–20. https://doi.org/10.1016/j.jconrel.2009.01.010

    Article  CAS  PubMed  Google Scholar 

  46. Frenzel T, Lengsfeld P, Schirmer H, Hütter J, Weinmann HJ (2008) Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37 degrees C. Investig Radiol 4:817–828. https://doi.org/10.1097/RLI.0b013e3181852171

    Article  CAS  Google Scholar 

  47. Ma H, Shiraishi K, Minowa T, Kawano K, Yokoyama M, Hattori Y, Maitani Y (2010) Accelerated blood clearance was not induced for a gadolinium-containing PEG-poly(l-lysine)-based polymeric micelle in mice. Pharm Res 27:296–302. https://doi.org/10.1007/s11095-009-0018-9

    Article  CAS  PubMed  Google Scholar 

  48. Yokoyama M, Kwon GS, Okano T, Sakurai Y, Seto T, Kataoka K (1992) Preparation of micelle-forming polymer-drug conjugates. Bioconj Chem 3:295–301

    Article  CAS  Google Scholar 

  49. Duncan R, Kopecková-Rejmanová P, Strohalm J, Hume I, Cable HC, Pohl J, Lloyd JB, Kopecek J (1987) Anticancer agents coupled to N-(2-hydroxypropyl)methacrylamide copolymers. I. Evaluation of daunomycin and puromycin conjugates in vitro. Br J Cancer 55:165–174. https://doi.org/10.1038/bjc.1987.33

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Funding

This research was supported by the Ministry of Education, Science, Sports and Culture, Grant-in-Aid for Scientific Research (B) (No. 26282139).

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Authors and Affiliations

  1. Division of Medical Engineering, Research Center for Medical Sciences, The Jikei University School of Medicine, 163-1, Kashiwashita, Kashiwa-shi, Chiba, 277-8567, Japan

    Masayuki Yokoyama & Kouichi Shiraishi

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  1. Masayuki Yokoyama
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  2. Kouichi Shiraishi
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Contributions

Both the authors designed and planned the study. Both the authors synthesized macromolecular agents. MY performed Gd-chelate stability analysis and wrote the first draft of the manuscript, and both the authors contributed to the revision of the manuscript. Both the authors approved the final manuscript.

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Correspondence to Masayuki Yokoyama.

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Yokoyama, M., Shiraishi, K. Stability evaluation of Gd chelates for macromolecular MRI contrast agents. Magn Reson Mater Phy 33, 527–536 (2020). https://doi.org/10.1007/s10334-019-00805-8

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