Journal of Materials Science

, Volume 52, Issue 13, pp 7625–7636 | Cite as

Preparation of MRI-visible gadolinium methacrylate nanoparticles with low cytotoxicity and high magnetic relaxivity

  • Xu Dong
  • Yuxue Ding
  • Pan Wu
  • Changchun Wang
  • Christian G. Schäfer


A new convenient and easy-scalable one-step synthetic strategy to achieve metal-containing polymer nanoparticles for applications as magnetic resonance imaging contrast agent is reported. In this study, a novel contrast agent based on poly(gadolinium methacrylate) (poly(Gd(MAA)3)) nanoparticles was prepared by one-step aqueous dispersion polymerization of gadolinium methacrylate monomer (Gd(MAA)3), whereby stable particles were obtained due to the association of GdIII with the polymer carboxylate anions, which provided latent crosslinking of the polymer nanoparticles without the addition of further crosslinking reagents. The morphology and final composition of the corresponding nanoparticles was thoroughly characterized and their cytotoxicity as well as their potential use in MRI was evaluated in vitro on HEK 293T cells by using the CCK-8 assay. The presented results demonstrated, that the poly(Gd(MAA)3) nanoparticles had a spherical morphology with mesoporous substructure, a sufficiently low cytotoxicity and an exceptionally high longitudinal relaxivity of r1 = 12.613 mM−1 s−1, making these nanoparticles excellent candidates for in vivo imaging systems. Herein described poly(Gd(MAA)3) nanoparticles can be valuable in a wide range of biomedical applications with simultaneous bioconjugation, drug delivery as well as imaging capabilities for the early detection of lesions of the brain and the central nervous system, for assessing cardiac function, and for detecting tumors.

Supplementary material

10853_2017_1070_MOESM1_ESM.docx (148 kb)
Supplementary material 1 (DOCX 148 kb)


  1. 1.
    Dickerson BC (2007) Advances in functional magnetic resonance imaging: technology and clinical applications. Neurotherapeutics 4:360–370CrossRefGoogle Scholar
  2. 2.
    Fox MD, Raichle ME (2007) Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci 8:700–711CrossRefGoogle Scholar
  3. 3.
    Bulte JWM, Kraitchman DL (2004) Iron oxide MR contrast agents for molecular and cellular imaging. NMR Biomed 17:484–499CrossRefGoogle Scholar
  4. 4.
    Bao Y, Wen T, Samia ACS, Khandhar A, Krishnan KM (2016) Magnetic nanoparticles: material engineering and emerging applications in lithography and biomedicine. J Mater Sci 51:513–553. doi:10.1007/s10853-015-9324-2 CrossRefGoogle Scholar
  5. 5.
    Rodriguez SM, Garcia MED, Manzorro AG, Saez MS (2008) A review of gadolinium based contrast media by a hospital pharmacy service. Int J Clin Pharm-Net 30:1021–1022Google Scholar
  6. 6.
    de Sousa PL, Livramento JB, Helm L, Merbach AE, Même W, Doan BT, Beloeil JC, Prata MIM, Santos AC, Geraldes CFGC (2008) In vivo MRI assessment of a novel GdIII-based contrast agent designed for high magnetic field applications. Contrast Media Mol Imaging 3:78–85CrossRefGoogle Scholar
  7. 7.
    Zheng-Rong Lu AMMYZYF (2006) Polydisulfide Gd(III) chelates as biodegradable macromolecular magnetic resonance imaging contrast agents. Int J Nanomed 1:31–40Google Scholar
  8. 8.
    Kircher MF, de la Zerda A, Jokerst JV, Zavaleta CL, Kempen PJ, Mittra E, Pitter K, Huang R, Campos C, Habte F, Sinclair R, Brennan CW, Mellinghoff IK, Holland EC, Gambhir SS (2012) A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle. Nat Med 18:829–834CrossRefGoogle Scholar
  9. 9.
    Rogosnitzky M, Branch S (2016) Gadolinium-based contrast agent toxicity: a review of known and proposed mechanisms. Biometals 29:1–12CrossRefGoogle Scholar
  10. 10.
    Ersoy H, Rybicki FJ (2007) Biochemical safety profiles of gadolinium-based extracellular contrast agents and nephrogenic systemic fibrosis. J Magn Reson Imaging 26:1190–1197CrossRefGoogle Scholar
  11. 11.
    Hermann P, Kotek J, Kubicek V, Lukes I (2008) Gadolinium(III) complexes as MRI contrast agents: ligand design and properties of the complexes. Dalton Trans 37:3027–3047CrossRefGoogle Scholar
  12. 12.
    Caravan P, Ellison JJ, McMurry TJ, Lauffer RB (1999) Gadolinium(III) chelates as MRI contrast agents: structure, dynamics and applications. Chem Rev 99:2293–2352CrossRefGoogle Scholar
  13. 13.
    Werner EJ, Datta A, Jocher CJ, Raymond KN (2008) High-relaxivity MRI contrast agents: where coordination chemistry meets medical imaging. Angew Chem Int Ed 47:8568–8580CrossRefGoogle Scholar
  14. 14.
    Yan GP, Robinson L, Hogg P (2007) Magnetic resonance imaging contrast agents: overview and perspectives. Radiography 13:e5–e19CrossRefGoogle Scholar
  15. 15.
    Kim J, Piao Y, Hyeon T (2009) Multifunctional nanostructured materials for multimodal imaging, and simultaneous imaging and therapy. Chem Soc Rev 38:372–390CrossRefGoogle Scholar
  16. 16.
    Lux F, Sancey L, Bianchi A, Crémillieux Y, Roux S, Tillement O (2015) Gadolinium-based nanoparticles for theranostic MRI-radiosensitization. Nanomedicine 10:1801–1815CrossRefGoogle Scholar
  17. 17.
    Xiong R, Cheng L, Tian Y, Tang W, Xu K, Yuan Y, Hu A (2016) Hyperbranched polyethylenimine based polyamine-N-oxide-carboxylate chelates of gadolinium for high relaxivity MRI contrast agents. RSC Adv 6:28063–28068CrossRefGoogle Scholar
  18. 18.
    Dewi N, Peng M, Yanagie H (2016) In vivo evaluation of neutron capture therapy effectivity using calcium phosphate-based nanoparticles as Gd-DTPA delivery agent. J Cancer Res Clin 142:1–9CrossRefGoogle Scholar
  19. 19.
    Liu Y, Zhang N (2012) Gadolinium loaded nanoparticles in theranostic magnetic resonance imaging. Biomaterials 33:5363–5375CrossRefGoogle Scholar
  20. 20.
    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
  21. 21.
    Caravan P (2006) Strategies for increasing the sensitivity of gadolinium based MRI contrast agents. Chem Soc Rev 35:512–523CrossRefGoogle Scholar
  22. 22.
    Yan L, Shen L, Zhou H, Wu C, Zhao Y, Wang L, Fang X, Zhang G, Xu J, Yang W (2016) Combination of the fluorescent conjugated polymer and 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid gadolinium chelate as an agent for dual-modal imaging. Tetrahedron 72:8578–8583CrossRefGoogle Scholar
  23. 23.
    Zhu Y, Zhu M, Liu P, Xia L, Wu Y, Xie J (2017) Two Gd(III) coordination polymers based on a flexible tricarboxylate: syntheses, structures, luminescence and catalytic properties. J Mol Struct 1130:26–32CrossRefGoogle Scholar
  24. 24.
    Ferreira MF, Mousavi B, Ferreira PM, Martins CIO, Helm L, Martins JA, Geraldes CFGC (2012) Gold nanoparticles functionalised with stable, fast water exchanging Gd3+ chelates as high relaxivity contrast agents for MRI. Dalton Trans 41:5472–5475CrossRefGoogle Scholar
  25. 25.
    Kobayashi Y, Nozawa T, Nakagawa T, Gonda K, Takeda M, Ohuchi N (2012) Fabrication and fluorescence properties of multilayered core–shell particles composed of quantum dot, gadolinium compound, and silica. J Mater Sci 47:1852–1859. doi:10.1007/s10853-011-5972-z CrossRefGoogle Scholar
  26. 26.
    Li Y-Y, Yan B, Li Q-P (2013) Bifunctional heterometallic Ln3+ − Gd3+(Ln = Eu, Tb) hybrid silica microspheres: luminescence and MRI contrast agent property. Dalton Trans 42:1678–1686CrossRefGoogle Scholar
  27. 27.
    Aríñez-Soriano J, Albalad J, Carné-Sánchez A, Bonnet CS, Busqué F, Lorenzo J, Juanhuix J, Terban MW, Imaz I, Tóth É, Maspoch D (2016) pH-responsive relaxometric behaviour of coordination polymer nanoparticles made of a stable macrocyclic gadolinium chelate. Chem–A Eur J 22:13162–13170CrossRefGoogle Scholar
  28. 28.
    Guo C, Hu J, Bains A, Pan D, Luo K, Li N, Gu Z (2016) The potential of peptide dendron functionalized and gadolinium loaded mesoporous silica nanoparticles as magnetic resonance imaging contrast agents. J Mater Chem B 4:2322–2331CrossRefGoogle Scholar
  29. 29.
    Tang Z, He C, Tian H, Ding J, Hsiao BS, Chu B, Chen X (2016) Polymeric nanostructured materials for biomedical applications. Prog Polym Sci 60:86–128CrossRefGoogle Scholar
  30. 30.
    Kim KS, Park W, Hu J, Bae YH, Na K (2014) A cancer-recognizable MRI contrast agents using pH-responsive polymeric micelle. Biomaterials 35:337–343CrossRefGoogle Scholar
  31. 31.
    Hu X, Liu G, Yang L, Wang X, Liu S (2014) Cell-penetrating hyperbranched polyprodrug amphiphiles for synergistic reductive milieu-triggered drug release and enhanced magnetic resonance signals. J Am Chem Soc 137:362–368CrossRefGoogle Scholar
  32. 32.
    Frangville C, Li Y, Billotey C, Talham DR, Taleb J, Roux P, Marty JD, Mingotaud C (2016) Assembly of double-hydrophilic block copolymers triggered by gadolinium ions: new colloidal MRI contrast agents. Nano Lett 16:4069–4073CrossRefGoogle Scholar
  33. 33.
    Huang CH, Tsourkas A (2013) Gd-based macromolecules and nanoparticles as magnetic resonance contrast agents for molecular imaging. Curr Top Med Chem 13:411–421CrossRefGoogle Scholar
  34. 34.
    Botta M, Tei L (2012) Relaxivity enhancement in macromolecular and nanosized GdIII-based MRI contrast agents. Eur J Inorg Chem 12:1945–1960CrossRefGoogle Scholar
  35. 35.
    Cheng Z, Thorek DLJ, Tsourkas A (2010) Gadolinium-conjugated dendrimer nanoclusters as a tumor-targeted T1 magnetic resonance imaging contrast agent. Angew Chem Int Ed 49:346–350CrossRefGoogle Scholar
  36. 36.
    Luo K, Liu G, Zhang X, She W, He B, Nie Y, Li L, Wu Y, Zhang Z, Gong Q, Gao F, Song B, Ai H, Gu Z (2009) Functional l-lysine dendritic macromolecules as liver-imaging probes. Macromol Biosci 9:1227–1236CrossRefGoogle Scholar
  37. 37.
    Guo C, Sun L, She W, Li N, Jiang L, Luo K, Gong Q, Gu Z (2016) A dendronized heparin–gadolinium polymer self-assembled into a nanoscale system as a potential magnetic resonance imaging contrast agent. Polym Chem 7:2531–2541CrossRefGoogle Scholar
  38. 38.
    Tong G, Fang Z, Huang G, Jing Y, Dai S, Jiang Q, Zhang C, Feng S-T, Li Z-P (2016) Gadolinium/DOTA functionalized poly(ethylene glycol)-block-poly(acrylamide-co-acrylonitrile) micelles with synergistically enhanced cellular uptake for cancer theranostics. RSC Adv 6:50534–50542CrossRefGoogle Scholar
  39. 39.
    Esser L, Truong NP, Karagoz B, Moffat BA, Boyer C, Quinn JF, Whittaker MR, Davis TP (2016) Gadolinium-functionalized nanoparticles for application as magnetic resonance imaging contrast agents via polymerization-induced self-assembly. Polym Chem 7:7325–7337CrossRefGoogle Scholar
  40. 40.
    Cao Y, Liu M, Zhang K, Zu G, Kuang Y, Tong X, Xiong D, Pei R (2017) Poly(glycerol) used for constructing mixed polymeric micelles as T1 MRI contrast agent for tumor-targeted imaging. Biomacromol 18:150–158CrossRefGoogle Scholar
  41. 41.
    Shetty AN, Pautler R, Ghagahda K, Rendon D, Gao H, Starosolski Z, Bhavane R, Patel C, Annapragada A, Yallampalli C, Lee W (2016) A liposomal Gd contrast agent does not cross the mouse placental barrier. Sci Rep 6:27863CrossRefGoogle Scholar
  42. 42.
    Ravoori MK, Singh S, Bhavane R, Sood AK, Anvari B, Bankson J, Annapragada A, Kundra V (2016) Multimodal magnetic resonance and near-infrared-fluorescent imaging of intraperitoneal ovarian cancer using a dual-mode-dual-gadolinium liposomal contrast agent. Sci Rep 6:38991CrossRefGoogle Scholar
  43. 43.
    Yoshioka N, Nishide H, Tsuchida E (1987) Complexation of gadolinium ion with poly(methacrylic acid)s and magnetic properties of the complexes. Inorg Chim Acta 128:135–138CrossRefGoogle Scholar
  44. 44.
    Michinobu T, Sasao N, Nishide H (2004) Microparticles of poly(methacrylic acid)–gadolinium ion complex and their magnetic force microscopic images. J Polym Sci, Part A: Polym Chem 42:1912–1918CrossRefGoogle Scholar
  45. 45.
    Reynolds CH, Annan N, Beshah K, Huber JH, Shaber SH, Lenkinski RE, Wortman JA (2000) Gadolinium-loaded nanoparticles: new contrast agents for magnetic resonance imaging. J Am Chem Soc 122:8940–8945CrossRefGoogle Scholar
  46. 46.
    Qiao A, Jing L, Meng Y, Wan J, Li D, Wang C, Chen C, Jia G (2015) Multifunctional magnetic Gd3+-based coordination polymer nanoparticles: combination of magnetic resonance and multispectral optoacoustic detections for tumor-targeted imaging in vivo. Small 11:5675–5686CrossRefGoogle Scholar
  47. 47.
    Gong P, Chen Z, Chen Y, Wang W, Wang X, Hu A (2011) High-relaxivity MRI contrast agents prepared from miniemulsion polymerization using gadolinium(III)-based metallosurfactants. Chem Commun 47:4240–4242CrossRefGoogle Scholar
  48. 48.
    Chen K-J, Wolahan SM, Wang H, Hsu C-H, Chang H-W, Durazo A, Hwang L-P, Garcia MA, Jiang ZK, Wu L, Lin Y-Y, Tseng H-R (2011) A small MRI contrast agent library of gadolinium(III)-encapsulated supramolecular nanoparticles for improved relaxivity and sensitivity. Biomaterials 32:2160–2165CrossRefGoogle Scholar
  49. 49.
    Courant T, Roullin VG, Cadiou C, Callewaert M, Andry MC, Portefaix C, Hoeffel C, de Goltstein MC, Port M, Laurent S, LV Elst, Muller R, Molinari M, Chuburu F (2012) Hydrogels incorporating GdDOTA: towards highly efficient dual T1/T2 MRI contrast agents. Angew Chem Int Ed 51:9119–9122CrossRefGoogle Scholar
  50. 50.
    Russo M, Bevilacqua P, Netti PA, Torino E (2016) A microfluidic platform to design crosslinked hyaluronic acid nanoparticles (cHANPs) for enhanced MRI. Sci Rep 6:37906-1-10Google Scholar
  51. 51.
    Sun L, Li X, Wei X, Luo Q, Guan P, Wu M, Zhu H, Luo K, Gong Q (2016) Stimuli-responsive biodegradable hyperbranched polymer-gadolinium conjugates as efficient and biocompatible nanoscale magnetic resonance imaging contrast agents. ACS Appl Mater Interfaces 8:10499–10512CrossRefGoogle Scholar
  52. 52.
    Anbazhagan R, Su Y-A, Tsai H-C, Jeng R-J (2016) MoS2–Gd chelate magnetic nanomaterials with core-shell structure used as contrast agents in in vivo magnetic resonance imaging. ACS Appl Mater Interfaces 8:1827–1835CrossRefGoogle Scholar
  53. 53.
    Sambhudevan S, Shankar B, Saritha A, Joseph K, Philip J, Saravanan T (2016) Development of X-ray protective garments from rare earth-modified natural rubber composites. J Elastom Plast. doi:10.1177/0095244316676866 Google Scholar
  54. 54.
    Liu L, He L, Yang C, Zhang W, Jin RG, Zhang LQ (2004) In situ reaction and radiation protection properties of Gd (AA)3/NR composites. Macromol Rapid Commun 25:1197–1202CrossRefGoogle Scholar
  55. 55.
    Wu W, Zhai Y, Zhang Y, Ren W (2014) Mechanical and microwave absorbing properties of in situ prepared hydrogenated acrylonitrile–butadiene rubber/rare earth acrylate composites. Compos B Eng 56:497–503CrossRefGoogle Scholar
  56. 56.
    Sasaki M, Shibata E (2005) Enhancement effects and relaxivities of gadolinium-DTPA at 1.5 versus 3 Tesla: a phantom study. Magn Reson Med Sci 4:145–149CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Xu Dong
    • 1
  • Yuxue Ding
    • 1
  • Pan Wu
    • 1
  • Changchun Wang
    • 1
  • Christian G. Schäfer
    • 1
  1. 1.State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, and Laboratory of Advanced MaterialsFudan UniversityShanghaiChina

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