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In vitro and in vivo investigations of upconversion and NIR emitting Gd2O3:Er3+,Yb3+ nanostructures for biomedical applications

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Abstract

The use of an “over 1000-nm near-infrared (NIR) in vivo fluorescence bioimaging” system based on lanthanide containing inorganic nanostructures emitting in the visible and NIR range under 980-nm excitation is proposed. It may overcome problems of currently used biomarkers including color fading, phototoxicity and scattering. Gd2O3:Er3+,Yb3+ nanoparticles and nanorods showing upconversion and NIR emission are synthesized and their cytotoxic behavior is investigated by incubation with B-cell hybridomas and macrophages. Surface modification with PEG-b-PAAc provides the necessary chemical durability reducing the release of toxic Gd3+ ions. NIR fluorescence microscopy is used to investigate the suitability of the nanostructures as NIR–NIR biomarkers. The in vitro uptake of bare and modified nanostructures by macrophages is investigated by confocal laser scanning microscopy. In vivo investigations revealed nanostructures in liver, lung, kidneys and spleen a few hours after injection into mice, while most of the nanostructures have been removed from the body after 24 h.

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References

  1. Hong YL, Fan HS, Li B, Guo B, Liu M, Zhang XD. Fabrication, biological effects, and medical applications of calcium phosphate nanoceramics. Mater Sci Eng R. 2010;70:225–42.

    Article  Google Scholar 

  2. Madurantakam PA, Cost CP, Simpson DG, Bowlin GL. Science of nanofibrous scaffold fabrication: strategies for next generation tissue-engineering scaffolds. Nanomedicine. 2009;4:193–206.

    Article  CAS  Google Scholar 

  3. Poinern GEJ, Fawcett D, Ng YJ, Ali N, Brundavanam RK, Jiang ZT. Nanoengineering a biocompatible inorganic scaffold for skin wound healing. J Biomed Nanotechnol. 2010;6(Special issue):497–510.

    Article  CAS  Google Scholar 

  4. Kallinteri P, Higgins S, Hutcheon GA, St Pourcain CB, Garnett MC. Novel functionalized biodegradable polymers for nanoparticle drug delivery systems. Biomacromolecules. 2005;6:1885–94.

    Article  CAS  Google Scholar 

  5. Kreuter J, Shamenkov D, Petrov V, Ramge P, Cychutek K, Koch-Brandt C, Alyautdin R. Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier. J Drug Target. 2002;10:317–25.

    Article  CAS  Google Scholar 

  6. Hughes GA. Nanostructure-mediated drug delivery. Nanomedicine. 2005;1:22–30.

    Article  CAS  Google Scholar 

  7. Tosi G, Costantino L, Rivasi F, Ruozi B, Leo E, Vergoni AV, Tacchi R, Bertolini A, Vandelli MA, Forni F. Targeting the central nervous system: in vivo experiments with peptide-derivatized nanoparticles loaded with Loperamide and Rhodamine-123. J Control Release. 2007;122:1–9.

    Article  CAS  Google Scholar 

  8. Ravi Kumar MNV. Nano and microparticles as controlled drug delivery devices. J Pharm Pharm Sci. 2000;3:234–58.

    CAS  Google Scholar 

  9. Yan E, Fu Y, Wang X, Ding Y, Qian H, Wang CH, Hu Y, Jiang X. Hollow chitosan-silica nanospheres for doxorubicin delivery to cancer cells with enhanced antitumor effect in vivo. J Mater Chem. 2011;21:3147–55.

    Article  CAS  Google Scholar 

  10. Rosenblum LT, Kosaka N, Mitsunaga M, Choyke PL, Kobayashi H. In vivo molecular imaging using nanomaterials: general in vivo characteristics of nano-sized reagents and applications for cancer diagnosis (review). Mol Membr Biol. 2010;27:274–85.

    Article  CAS  Google Scholar 

  11. Corr SA, Rakovich YP, Gun’ko YK. Multifunctional magnetic-fluorescent nanocomposites for biomedical applications. Nanoscale Res Lett. 2008;3:87–104.

    Article  CAS  Google Scholar 

  12. Pautler M, Brenner S. Nanomedicine: promises and challenges for the future of public health. Int J Nanomed. 2010;5:803–9.

    Google Scholar 

  13. Portney NG, Ozkan M. Nano-oncology: drug delivery, imaging, and sensing. Anal Bioanal Chem. 2006;384:620–30.

    Article  CAS  Google Scholar 

  14. Kotov NA, Winter JO, Clements IP, Jan E, Timko BP, Campidelli S, Pathak S, Mazzatenta A, Lieber CM, Prato M, Bellamkonda RV, Silva GA, Wong Shi Kam N, Patolsky F, Ballerini L. Nanomaterials for neural interfaces. Adv Mater. 2009;21:3970–4004.

    Article  CAS  Google Scholar 

  15. Shaner NC, Lin MZ, McKeown MR, Steinbach PA, Hazelwood KL, Davidson MW, Tsien RY. Improving the photostability of bright monomeric orange and red fluorescent proteins. Nat Methods. 2008;5:545–51.

    Article  CAS  Google Scholar 

  16. Chudakov DM, Matz MV, Lukyanov S, Lukyanov KA. Fluorescent proteins and their applications in imaging living cells and tissues. Physiol Rev. 2010;90:1103–63.

    Article  CAS  Google Scholar 

  17. Michalet X, Pinaud FF, Bentolila LA, Tsay JM, Doose S, Li JJ, Sundaresan G, Wu AM, Gambhir SS, Weiss S. Science. 2005;307:538–44.

    Article  CAS  Google Scholar 

  18. Sharma P, Brown S, Walter G, Santra S, Moudgil B. Nanoparticles for bioimaging. Adv Colloid Interface Sci. 2006;123–126:471–85.

    Article  Google Scholar 

  19. Lu Z, Zhu Z, Zheng X, Qiao Y, Guo J, Li CM. Biocompatible fluorescence-enhanced ZrO2-CdTe quantum dot nanocomposite for in vitro cell imaging. Nanotechnology. 2011;22:155604.

    Article  Google Scholar 

  20. Vela J, Htoon H, Chen Y, Park YS, Ghosh Y, Goodwin PM, Werner JH, Wells NP, Casson JL, Hollingsworth JA. Effect of shell thickness and composition on blinking suppression and the blinking mechanism in ‘giant’ CdSe/CdS nanocrystal quantum dots. Biophotonics. 2010;3:706–17.

    Article  CAS  Google Scholar 

  21. Frantsuzov PA, Marcus RA. Explanation of quantum dot blinking without the long-lived trap hypothesis. Phys Rev B. 2005;72:155321.

    Article  Google Scholar 

  22. Cotton S. Lanthanide and actinide chemistry. Chichester: Wiley; 2006.

    Book  Google Scholar 

  23. Hanaoka K. Development of responsive lanthanide-based magnetic resonance imaging and luminescent probes for biological applications. Chem Pharm Bull. 2010;58:1283–94.

    Article  CAS  Google Scholar 

  24. Andraud C, Maury O. Lanthanide complexes for nonlinear optics: from fundamental aspects to applications. Eur J Inorg Chem. 2009;29–30:4357–71.

    Article  Google Scholar 

  25. Das GK, Heng BC, Ng SC, White T, Loo JSC, D’Silva L, Padmanabhan P, Bhakoo KK, Selvan ST, Tan TTY. Gadolinium oxide ultranarrow nanorods as multimodal contrast agents for optical and magnetic resonance imaging. Langmuir. 2010;26:8959–65.

    Article  CAS  Google Scholar 

  26. Pang M, Liu D, Lei Y, Song S, Feng J, Fan W, Zhang H. Rare-earth-doped bifunctional alkaline-earth metal fluoride nanocrystals via a facile microwave-assisted process. Inorg Chem. 2011;50:5327–9.

    Article  CAS  Google Scholar 

  27. Kamimura M, Miyamoto D, Saito Y, Soga K, Nagasaki Y. Design of poly(ethylene glycol)/streptavidin coimmobilized upconversion nanophosphors and their application to fluorescence biolabeling. Langmuir. 2008;24:8864–70.

    Article  CAS  Google Scholar 

  28. Xiong L, Chen Z, Tian Q, Cao T, Xu C, Li F. High contrast upconversion luminescence targeted imaging in vivo using peptide-labeled nanophosphors. Anal Chem. 2009;81:8687–94.

    Article  CAS  Google Scholar 

  29. Anderson RR, Parrish JA. The optics of human skin. J Invest Dermatol. 1981;77:13–9.

    Article  CAS  Google Scholar 

  30. Hilderbrand SA, Shao F, Salthouse C, Mahmood U, Weissleder R. Upconverting luminescent nanomaterials: application to in vivo bioimaging. Chem Commun. 2009;28:4188–90.

    Article  Google Scholar 

  31. Nyk M, Kumar R, Ohulchanskyy TY, Bergey EJ, Prasad PN. High contrast in vitro and in vivo photoluminescence bioimaging using near infrared to near infrared up-conversion in Tm3+ and Yb3+ doped fluoride nanophosphors. Nano Lett. 2008;8:3834–8.

    Article  CAS  Google Scholar 

  32. Kumar R, Nyk M, Ohulchanskyy TY, Flask CA, Prasad PN. Combined optical and MR bioimaging using rare earth ion doped NaYF4 nanocrystals. Adv Funct Mater. 2009;19:853–9.

    Article  CAS  Google Scholar 

  33. Chen G, Ohulchanskyy TY, Law WC, Agren H, Prasad PN. Monodisperse NaYbF4: Tm3+/NaGdF4 core/shell nanocrystals with near-infrared to near-infrared upconversion photoluminescence and magnetic resonance properties. Nanoscale. 2011;3:2003–8.

    Article  CAS  Google Scholar 

  34. Zhou J, Sun Y, Du X, Xiong L, Hu H, Li F. Dual-modality in vivo imaging using rare-earth nanocrystals with near-infrared to near-infrared (NIR-to-NIR) upconversion luminescence and magnetic resonance properties. Biomaterials. 2010;31:3287–95.

    Article  CAS  Google Scholar 

  35. Troyan SL, Kianzad V, Gibbs-Strauss SL, Gioux S, Matsui A, Oketokoun R, Ngo L, Khamene A, Azar F, Frangioni JV. The FLARE intraoperative near-infrared fluorescence imaging system: a first-in-human clinical trial in breast cancer sentinel lymph node mapping. Ann Surg Oncol. 2009;16:2943–52.

    Article  Google Scholar 

  36. Vahrmeijer AL, Frangioni JV. Seeing the invisible during surgery. Br J Surg. 2011;98:749–50.

    Article  CAS  Google Scholar 

  37. Soga K, Tokuzen K, Tsuji K, Yamano T, Hyodo H, Kishimoto H. NIR bioimaging: development of liposome-encapsulated, rare-earth-doped Y2O3 nanoparticles as fluorescent probes. Eur J Inorg Chem. 2010;18:2673–7.

    Article  Google Scholar 

  38. Hemmer E, Yamanao T, Kishimoto H, Soga K. Gadolinium-containing inorganic nanostructures for biomedical applications: cytotoxic aspects. In: IEEE Explore, proceedings of the international conference on nanoscience and nanotechnology (ICONN), Sydney, Australia; 2010. p. 225–9.

  39. Singh S, Bhat MK. Carboplatin induces apoptotic cell death through downregulation of constitutively active nuclear factor-jB in human HPV-18 E6-positive HEp-2 cells. Biochem Biophys Res Commun. 2004;318:346–53.

    Article  CAS  Google Scholar 

  40. Farrer RA, Butterfield FL, Chen VW, Fourkas JT. Highly efficient multiphoton-absorption-induced luminescence from gold nanoparticles. Nano Lett. 2005;5:1139–42.

    Article  CAS  Google Scholar 

  41. Matijevic E, Hsu WP. Preparation and properties of monodispersed colloidal particles of lanthanide compounds. J Colloid Interface Sci. 1987;118:506–23.

    Article  CAS  Google Scholar 

  42. Park IY, Kim D, Lee J, Lee SH, Kim KJ. Effects of urea concentration and reaction temperature on morphology of gadolinium compounds prepared by homogeneous precipitation. Mater Chem Phys. 2007;106:149–57.

    Article  CAS  Google Scholar 

  43. Wang Y, Bai X, Liu T, Dong B, Xu L, Liu Q, Song H. Solvothermal synthesis and luminescence properties of monodisperse Gd2O3:Eu3+ and Gd2O3:Eu3+@SiO2 nanospheres. J Solid State Chem. 2010;183:2779–85.

    Article  CAS  Google Scholar 

  44. Mu Q, Chen T, Wang Y. Synthesis, characterization and photoluminescence of lanthanum hydroxide nanorods by a simple route at room temperature. Nanotechnology. 2009;20:345602.

    Article  Google Scholar 

  45. Lin S, Dong X, Jia R, Yuan Y. Controllable synthesis and luminescence property of LnPO4 (Ln = La, Gd, Y) nanocrystals. J Mater Sci Mater Electron. 2010;21:38–44.

    Article  CAS  Google Scholar 

  46. Du G, Van Tendeloo G. Preparation and structure analysis of Gd(OH)3 nanorods. Nanotechnology. 2005;16:595–7.

    Article  CAS  Google Scholar 

  47. Wang X, Li Y. Synthesis and characterization of lanthanide hydroxide single-crystal nanowires. Angew Chem Int Ed. 2002;41:4790–3.

    Article  CAS  Google Scholar 

  48. Wang X, Li Y. Solution-based routes to transition-metal oxide one-dimensional nanostructures. Pure Appl Chem. 2006;78:45–64.

    Article  CAS  Google Scholar 

  49. Ma L, Chen WX, Zhao J, Zheng YF. Synthesis of Pr(OH)3 and Pr6O11 nanorods by microwave-assisted method: effects of concentration of alkali and microwave heating time. J Cryst Growth. 2007;303:590–6.

    Article  CAS  Google Scholar 

  50. Venkatachalam N, Saito Y, Soga K. Synthesis of Er3+ doped Y2O3 nanophosphors. J Am Ceram Soc. 2009;92:1006–10.

    Article  CAS  Google Scholar 

  51. Günther A, Bender P, Birringer R. Rotational diffusion of magnetic nickel nanorods in colloidal dispersions. J Phys Condens Matter. 2011;23:325103.

    Article  Google Scholar 

  52. Mahler H-C, Jiskoot W. Analysis of aggregates and particles in protein pharmaceuticals. Hoboken: Wiley; 2012. p. 44.

    Book  Google Scholar 

  53. Soga K, Okumura Y, Tsuji K, Venkatachalam N. Effect of K3PO4 addition as sintering inhibitor during calcination of Y2O3 nanoparticles. J Phys Conf Ser. 2009;191:012003.

    Article  Google Scholar 

  54. Wang X, Li Y. Rare-earth-compound nanowires, nanotubes, and fullerene-like nanoparticles: synthesis, characterization, and properties. Chem Eur J. 2003;9:5627–35.

    Article  CAS  Google Scholar 

  55. Hemmer E, Yamano T, Kishimoto H, Soga K. Cytotoxicity of Gd2O3:Ln3+ nanostructures and their potential as biomarkers. In: Meyer G, editor. Proceedings of the 7th international conference on f elements, ICfE-7, Terrae Rarae; 2009. p. 1–10.

  56. Dong Y, Feng SS. Methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) nanoparticles for controlled delivery of anticancer drugs. Biomaterials. 2004;25:2843–9.

    Article  CAS  Google Scholar 

  57. Xie J, Xu C, Kohler N, Hou Y, Sun S. Controlled PEGylation of monodisperse Fe3O4 nanoparticles for reduced non-specific uptake by macrophage cells. Adv Mater. 2007;19:3163–6.

    Article  CAS  Google Scholar 

  58. Sheng Y, Yuan Y, Liu C, Tao X, Shan X, Xu F. In vitro macrophage uptake and in vivo biodistribution of PLA-PEG nanoparticles loaded with hemoglobin as blood substitutes: effect of PEG content. J Mater Sci Mater Med. 2009;20:188–891.

    Article  Google Scholar 

  59. Bazile D, Prud’Homme C, Bassoullet MT, Marlard M, Spenlehauer G, Veillard M. Stealth Me.PEG-PLA nanoparticles avoid uptake by the mononuclear phagocytes system. J Pharm Sci. 1995;84:493–8.

    Article  CAS  Google Scholar 

  60. Wu H, Liu G, Zhuang Y, Wu D, Zhang H, Yang H, Hu H, Yang S. The behavior after intravenous injection in mice of multiwalled carbon nanotube/Fe3O4 hybrid MRI contrast agents. Biomaterials. 2011;32:4867–76.

    Article  CAS  Google Scholar 

  61. Al Faraj A, Fauvelle F, Luciani N, Lacroix G, Levy M, Crémillieux Y, Canet-Soulas E. In vivo biodistribution and biological impact of injected carbon nanotubes using magnetic resonance techniques. Int J Nanomed. 2011;6:351–61.

    Article  CAS  Google Scholar 

  62. Tasciotti E, Godin B, Martinez JO, Chiappini C, Bhavane R, Liu X, Ferrari M. Near-infrared imaging method for the in vivo assessment of the biodistribution of nanoporous silicon particles. Mol Imaging. 2011;10:56–68.

    CAS  Google Scholar 

  63. Gratton SEA, Williams S, Napier ME, Pohlhaus PD, Zhou Z, Wiles KB, Maynor BW, Shen C, Olafsen T, Samulski ET, DeSimone JM. The pursuit of a scalable nanofabrication platform for the use in material and life science applications. Acc Chem Res. 2008;41:1685–95.

    Article  CAS  Google Scholar 

  64. Sadauskas E, Wallin H, Stoltenberg M, Vogel U, Doering P, Larsen A, Danscher G. Kupffer cells are central in the removal of nanoparticles from the organism. Particle Fibre Toxicol. 2007;4:10.

    Article  Google Scholar 

  65. Kryza D, Taleb J, Janier M, Marmuse L, Miladi I, Bonazza P, Louis C, Perriat P, Roux S, Tillement O, Billotey C. Biodistribution study of nanometric hybrid gadolinium oxide particles as a multimodal SPECT/MR/optical imaging and theragnostic agent. Bioconjug Chem. 2011;22:1145–52.

    Article  CAS  Google Scholar 

  66. Tu C, Ma X, House A, Kauzlarich SM, Louie AY. PET imaging and biodistribution of silicon quantum dots in mice. ACS Med Chem Lett. 2011;2:285–8.

    Article  CAS  Google Scholar 

  67. Nagayama S, Ogawara K, Fukuoka Y, Higaki K, Kimura T. Time-dependent changes in opsonin amount associated on nanoparticles alter their hepatic uptake characteristics. Int J Pharm. 2007;342:215–21.

    Article  CAS  Google Scholar 

  68. Arnida, Janát-Amsbury MM, Ray A, Peterson CM, Ghandehari H. Geometry and surface characteristics of gold nanoparticles influence their biodistribution and uptake by macrophages. Eur J Pharm Biopharm. 2011;77:417–23.

    Article  CAS  Google Scholar 

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Acknowledgment

This work was partly supported by Matching Fund Subsidy from MEXT (Ministry of Education, Culture, Sports, Science and Technology), 2006–2010 and 2009–2013. The authors thank Dr. Lionel Vayssieres (WPI Center for Materials NanoArchitectonics (MANA), National Institute for Materials Science (NIMS), Tsukuba, Japan) for scientific discussion and provision of the zeta-potential equipment.

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Correspondence to Eva Hemmer.

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Hemmer, E., Takeshita, H., Yamano, T. et al. In vitro and in vivo investigations of upconversion and NIR emitting Gd2O3:Er3+,Yb3+ nanostructures for biomedical applications. J Mater Sci: Mater Med 23, 2399–2412 (2012). https://doi.org/10.1007/s10856-012-4671-x

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