Fate and Translocation of (Nano)Particulate Matter in the Gastrointestinal Tract

  • Andreas FreyEmail author
  • Katrin Ramaker
  • Niels Röckendorf
  • Barbara Wollenberg
  • Ingmar Lautenschläger
  • Gabriella Gébel
  • Artur Giemsa
  • Markus Heine
  • Denise Bargheer
  • Peter Nielsen
Part of the NanoScience and Technology book series (NANO)


Nanoscience has flourished with increasing use of nanoparticles in many products. The particles enter the environment and affect both biotic and abiotic components of the ecosystem. Via the water supply and the food chain, humans could be affected by ingesting those particles. In this chapter, we will discuss mechanisms by which nanoparticles or their constituents can be translocated from the gastrointestinal tract, what their fate may be and how relevant this is for human health.


  1. 1.
    Piccinno, F., Gottschalk, F., Seeger, S., Nowack, B.: Industrial production quantities and uses of ten engineered nanomaterials in Europe and the world. J. Nanopart. Res. 14, 1109 (2012). Scholar
  2. 2.
    Ostiguy, C., Roberge, B., Woods, C., Soucy, B.: Engineered Nanoparticles: Current Knowledge about OHS Risks and Prevention Measures, 2nd edn. Institut de recherche Robert-Sauvé en santé et en sécurité du travail (2010). ISBN 2896314792, 9782896314799.
  3. 3.
    Griffin, S., Masood, M.I., Nasim, M.J., Sarfraz, M., Ebokaiwe, A.P., Schäfer, K.-H., Keck, C.M., Jacob, C.: Natural nanoparticles: a particular matter inspired by Nature. Antioxidants 7, 3 (2018). Scholar
  4. 4.
    Boccuni, F., Ferrante, R., Tombolini, F., Lega, D., Antonini, A., Alvino, A., Pingue, P., Beltram, F., Sorba, L., Piazza, V., Gemmi, M., Porcari, A., Iavicoli, S.: Workers’ exposure to nano-objects with different dimensionalities in R&D laboratories: measurement strategy and field studies. Int. J. Mol. Sci. 19, 349–377 (2018). Scholar
  5. 5.
    Kirch, J., Guenther, M., Doshi, N., Schaefer, U.F., Schneider, M., Mitragotri, S., Lehr, C.-M.: Mucociliary clearance of micro- and nanoparticles is independent of size, shape and charge—an ex vivo and in silico approach. J. Control Rel. 159, 128–134 (2012). Scholar
  6. 6.
    Pan, K., Zhong, Q.: Organic nanoparticles in foods: fabrication, characterization and utilization. Annu. Rev. Food Sci. Technol. 7, 245–266 (2016). Scholar
  7. 7.
    Sekhon, B.S.: Food nanotechnology—an overview. Nanotechnol. Sci. Appl. 3, 1–15 (2010). Scholar
  8. 8.
    Herbst, E.F.G.: Das Lymphgefäßsystem und seine Verrichtungen, pp. 333–337, Göttingen (1844)Google Scholar
  9. 9.
    Hirsch, R.: Über das Vorkommen von Stärkekörnern im Blut und im Urin. Z. Exp. Path. Ther. 3, 390 (1906)CrossRefGoogle Scholar
  10. 10.
    Volkheimer, G.: Detection of starch in tissue and urine after oral starch intake. Dtsch Gesundheitsw 15, 1298–1302 (1960)Google Scholar
  11. 11.
    Jani, P.U., Florence, A.T., McCarthy, D.E.: Further histological evidence of the gastrointestinal absorption of polystyrene nanospheres in the rat. Int. J. Pharm. 84, 245–252 (1992). Scholar
  12. 12.
    Alpar, H.O., Field, W.N., Hyde, R., Lewis, D.A.: The transport of microspheres from the gastro-intestinal tract to inflammatory air pouches in the rat. J. Pharm. Pharmacol. 41, 194–196 (1989). Scholar
  13. 13.
    Payne, J.M., Sansom, B.F., Garner, R.J., Thomson, A.R., Miles, B.J.: Uptake of small resin particles (1-5 µ diameter) by the alimentary canal of the calf. Nature 188, 586–587 (1960). Scholar
  14. 14.
    Pontefract, R.D., Cunningham, H.M.: Penetration of asbestos through the digestive tract of rats. Nature 243, 352–353 (1973). Scholar
  15. 15.
    Sanders, E., Ashworth, C.T.: A study of particulate intestinal absorption and hepatocellular uptake: Use of polystyrene latex particle. Exp. Cell Res. 22, 137–145 (1961). Scholar
  16. 16.
    Hodges, G.M., Carr, E.A., Hazzard, R.A., O’Reilly, C., Carr, K.E.: A commentary on morphological and quantitative aspects of microparticle translocation across the gastrointestinal mucosa. J. Drug Target. 3, 57–60 (1995). Scholar
  17. 17.
    Ebel, J.P.: A method for quantifying particle absorption from the small intestine of the mouse. Pharm. Res. 7, 848–851 (1990). Scholar
  18. 18.
    Limpanussorn, J., Simon, L., Dayan, A.D.D.: Transepithelial transport of large particles in rat: a new model for the quantitative study of particle uptake. J. Pharm. Pharmacol. 50, 753–760 (1998). Scholar
  19. 19.
    Powell, J.J., Faria, N., Thomas-McKay, E., Pele, L.C.: Origin and fate of dietary nanoparticles and microparticles in the gastrointestinal tract. J. Autoimmun. 34, J226–J233 (2010). Scholar
  20. 20.
    Fröhlich, E., Mercuri, A., Wu, S., Salar-Behzadi, S.: Measurements of deposition, lung surface area and lung fluid for simulation of inhaled compounds. Front. Pharmacol. 7, 181 (2016). Scholar
  21. 21.
    Squier, C.A., Kremer, M.J.: Biology of oral mucosa and esophagus. J. Natl. Cancer Inst. Monogr. 29, 7–15 (2001). Scholar
  22. 22.
    Squier, C.A.: The permeability of keratinized and nonkeratinized oral epithelium to horseradish peroxidase. J. Ultrastruct. Res. 43, 160–177 (1973). Scholar
  23. 23.
    Squier, C.A.: The permeability of oral mucosa. Crit. Rev. Oral Biol. Med. 2, 13–32 (1991)CrossRefGoogle Scholar
  24. 24.
    Ramaker, K., Bade, S., Röckendorf, N., Meckelein, B., Vollmer, E., Schulz, H., Fröschle, G.-W., Frey, A.: Absence of the epithelial glycocalyx as potential tumor marker for the early detection of colorectal cancer. PLoS ONE 11, e0168801 (2016).
  25. 25.
    Bullen, T.F., Forrest, S., Campbell, F., Dodson, A.R., Hershman, M.J., Pritchard, D.M., Turner, J.R., Montrose, M.H., Watson, A.J.M.: Characterization of epithelial cell shedding from human small intestine. Lab. Invest. 86, 1052–1063 (2006). Scholar
  26. 26.
    Madara, J.L.: Maintenance of the macromolecular barrier at cell extrusion sites in intestinal epithelium: physiological rearrangement of tight junctions. J. Mem. Biol. 116, 177–184 (1990)CrossRefGoogle Scholar
  27. 27.
    Marchiando, A.M., Shen, L., Graham, W.V., Edelblum, K.L., Duckworth, C.A., Guan, Y., Montrose, M.H., Turner, J.R., Watson, A.J.M.: The epithelial barrier is maintained by in vivo tight junction expansion during pathologic intestinal epithelial shedding. Gastroenterology 140, 1208–1218 (2011). Scholar
  28. 28.
    Watson, A.J.M., Chu, S., Sieck, L., Gerasimenko, O., Bullen, T., Campbell, F., McKenna, M., Rose, T., Montrose, M.H.: Epithelial barrier function in vivo is sustained despite gaps in epithelial layers. Gastroenterology 129, 902–912 (2005). Scholar
  29. 29.
    Frey, A., Giannasca, K.T., Weltzin, R., Giannasca, P.J., Reggio, H., Lencer, W.I., Neutra, M.R.: Role of the glycocalyx in regulating access of microparticles to apical plasma membranes of intestinal epithelial cells: implications for microbial attachment and oral vaccine targeting. J. Exp. Med. 184, 1045–1059 (1996). Scholar
  30. 30.
    Pelasayed, T., Bergström, J.H., Gustafsson, J.K., Ermund, A., Birchenough, G.M.H., Schütte, A., van der Post, S., Svensson, F., Rodríguez-Piñeiro, A.M., Nyström, E.E.L., Wising, C., Johansson, M.E.V., Hansson, G.C.: The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol. Rev. 260, 8–20 (2014). Scholar
  31. 31.
    Johansson, M.E.V., Sjövall, H., Hansson, G.C.: The gastrointestinal mucus system in health and disease. Nat. Rev. Gastroenterol. Hepatol. 10, 352–361 (2013). Scholar
  32. 32.
    Neutra, M.R., Forstner, J.F.: Gastrointestinal mucus: synthesis, secretion, and function. In: Johnson, L.R. (ed.) Physiology of the Gastrointestinal Tract. Raven Press: New York, NY, U.S.A, (1987)Google Scholar
  33. 33.
    Johansson, M.E.V., Phillipson, M., Petersson, J., Velcich, A., Holm, L., Hansson, G.C.: The inner of the two MUC2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl. Acad. Sci. U.S.A. 105, 15064–15069 (2008). Scholar
  34. 34.
    Busch, A.E., Herzer, T., Waldegger, S., Schmidt, F., Palacin, M., Biber, J., Markovich, D., Murer, H., Lang, F.: Opposite directed currents induced by the transport of dibasic and neutral amino acids in Xenopus oocytes expressing the protein rBAT. J. Biol. Chem. 269, 25581–25586 (1994)Google Scholar
  35. 35.
    Palacín, M., Kanai, Y.: The ancillary proteins of HATs: SLC3 family of amino acid transporters. Pflugers Arch. Eur. J. Physiol. 447, 490–494 (2004). Scholar
  36. 36.
    Howard, A., Hirst, B.H.: The glycine transporter GLYT1 in human intestine: expression and function. Biol. Pharm. Bull. 34, 784–788 (2011). Scholar
  37. 37.
    Pramod, A.B., Foster, J., Carvelli, L., Henry, L.K.: SLC6 transporters: structure, function, regulation, disease association and therapeutics. Mol. Asp. Med. 34, 197–219 (2013). Scholar
  38. 38.
    Bröer, A., Klingel, K., Kowalczuk, S., Rasko, J.E.J., Cavanaugh, J., Bröer, S.: Molecular cloning of mouse amino acid transport system B0, a neutral amino acid transporter related to Hartnup Disorder. J. Biol. Chem. 279, 24467–24476 (2004). Scholar
  39. 39.
    Takanaga, H., Mackenzie, B., Suzuki, Y., Hediger, M.A.: Identification of mammalian proline transporter SIT1 (SLC6A20) with characteristics of classical System Imino. J. Biol. Chem. 280, 8974–8984 (2005). Scholar
  40. 40.
    Thwaites, D.T., Anderson, C.M.H.: The SLC36 family of proton-coupled amino acid transporters and their potential role in drug transport. Br. J. Pharmacol. 164, 1802–1816 (2011). Scholar
  41. 41.
    Douard, V., Ferraris, R.P.: Regulation of the fructose transporter GLUT5 in health and disease. Am. J. Physiol. 295, E227–E237 (2008). Scholar
  42. 42.
    Wright, E.M.: Glucose transport families SLC5 and SLC50. Mol. Asp. Med. 34, 183–196 (2013). Scholar
  43. 43.
    Wright, E.M., Turk, E.: The sodium/glucose cotransport family SLC5. Pflugers Arch. Eur. J. Physiol. 447, 510–518 (2004).
  44. 44.
    Barley, N.F., Howard, A., O’Callaghan, D., Legon, S., Walters, J.R.F.: Epithelial calcium transporter expression in human duodenum. Am. J. Physiol. 280, G285–G290 (2001). Scholar
  45. 45.
    Vesey, D.A.: Transport pathways for cadmium in the intestine and kidney proximal tubule: focus on the interaction with essential metals. Toxicol. Lett. 198, 13–19 (2010). Scholar
  46. 46.
    Mackenzie, B., Hediger, M.A.: SLC11 family of H + -coupled metal-ion transporters NRAMP1 and DMT1. Pflugers Arch. Eur. J. Physiol. 447, 571–579 (2004). Scholar
  47. 47.
    Hashimoto, A., Kambe, T.: Mg, Zn and Cu transport proteins: a brief overview from physiological and molecular perspectives. J. Nutr. Sci. Vitaminol. 61, S116–S118 (2015). Scholar
  48. 48.
    Voets, T., Nilius, B., Hoefs, S., van der Kemp, A.W.C.M., Droogmans, G., Bindels, R.J.M., Hoenderop, J.G.J.: TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J. Biol. Chem. 279, 19–25 (2004). Scholar
  49. 49.
    Reboul, E.: Vitamin E bioavailability: mechanisms of intestinal absorption in the spotlight. Antioxidants 6, 95 (2017). Scholar
  50. 50.
    Reboul, E., Borel, P.: Proteins involved in uptake, intracellular transport and basolateral secretion of fat-soluble vitamins and carotenoids by mamalian enterocytes. Prog. Lipid Res. 50, 388–402 (2011). Scholar
  51. 51.
    Anderson, C.M., Stahl, A.: SLC27 fatty acid transport proteins. Mol. Asp. Med. 34, 516–528 (2013). Scholar
  52. 52.
    Daniel, H., Kottra, G.: The proton oligopeptide cotransporter family SLC15 in physiology and pharmacology. Pflugers Arch. Eur. J. Physiol. 447, 610–618 (2004). Scholar
  53. 53.
    May, J.M.: The SLC23 family of ascorbate transportes: ensuring that you get and keep your daily dose of vitamin C. Br. J. Pharmacol. 164, 1793–1801 (2011). Scholar
  54. 54.
    Yonezawa, A., Inui, K.: Novel riboflavin transporter family RFVT/SLC52: identification, nomenclature, functional characterization and genetic diseases of RFVT/SLC52. Mol. Asp. Med. 34, 693–701 (2013). Scholar
  55. 55.
    Zhao, R., Goldman, I.D.: Folate and thiamine transporters mediated by facilitative carriers (SLC19A1-3 and SLC46A1) and folate receptors. Mol. Asp. Med. 34, 373–385 (2013). Scholar
  56. 56.
    Ganapathy, V., Smith, S.B., Prasad, P.D.: SLC19: the folate/thiamine transporter family. Pflugers Arch. Eur. J. Physiol. 447, 641–646 (2004). Scholar
  57. 57.
    Roth, M., Obaidat, A., Hagenbuch, B.: OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Brit. J. Pharmacol. 165, 1260–1287 (2012). Scholar
  58. 58.
    Bargheer, D., Giemsa, A., Freund, B., Heine, M., Waurisch, C., Stachowski, G.M., Hickey, S.G., Eychmüller, A., Heeren, J., Nielsen, P.: The distribution and degradation of radiolabeled superparamagnetic iron oxide nanoparticles and quantum dots in mice. Beilstein J. Nanotechnol. 6, 111–123 (2015). Scholar
  59. 59.
    Heinrich, H.C.: Diagnostik, Ätiologie und Therapie des Eisenmangels unter besonderer Berücksichtigung der 59Fe-Retentionsmessung im Gesamtkörper-Radioaktivitätsdetektor. Der Nuklearmediziner 137, 137–269 (1983)Google Scholar
  60. 60.
    Bruns, O.T., Ittrich, H., Peldschus, K., Kaul, M.G., Tromsdorf, U.I., Lauterwasser, J., Nikolic, M.S., Mollwitz, B., Merkel, M., Bigall, N.C., Sapra, S., Reimer, R., Hohenberg, H., Weller, H., Eychmüller, A., Adam, G., Beisiegel, U., Heeren, J.: Real-time magnetic resonance imaging and quantification of lipoprotein metabolism in vivo using nanocrystals. Nat. Nanotechnol. 4, 193–201 (2009). Scholar
  61. 61.
    Kottwitz, K., Laschinsky, N., Fischer, R., Nielsen, P.: Absorption, excretion and retention of 51Cr from labelled Cr-(III)-picolinate in rats. Biometals 22, 289–295 (2009). Scholar
  62. 62.
    Chen, N., He, Y., Su, Y., Li, X., Huang, Q., Wang, H., Zhang, X., Tai, R., Fan, C.: The cytotoxicity of cadmium-based quantum dots. Biomaterials 33, 1238–1244 (2012). Scholar
  63. 63.
    Cho, S.J., Maysinger, D., Jain, M., Röder, B., Hackbarth, S., Winnik, F.M.: Long-term exposure of CdTe quantum dots causes functional impairments in live cells. Langmuir 23, 1974–1980 (2007). Scholar
  64. 64.
    Hardman, R.: A toxicological review of quantum dots: toxicity depends on physicochemical and environmental factors. Environ. Health Perspect. 114, 165–172 (2006). Scholar
  65. 65.
    Hoshino, A., Hanada, S., Yamamoto, K.: Toxicity of nanocrystal quantum dots: the relevance of surface modifications. Arch. Toxicol. 85, 707–720 (2011). Scholar
  66. 66.
    Winnik, F.M., Maysinger, D.: Quantum dot cytotoxicity and ways to reduce it. Acc. Chem. Res. 46, 672–680 (2013). Scholar
  67. 67.
    Zheng, X., Tian, J., Weng, L., Wu, L., Jin, Q., Zhao, J., Wang, L.: Cytotoxicity of cadmium-containing quantum dots based on a study using a microfluidic chip. Nanotechnology 23, 055102 (2012). Scholar
  68. 68.
    Loginova, Y.F., Dezhurov, S.V., Zherdeva, V.V., Kazachkina, N.I., Wakstein, M.S., Savitsky, A.P.: Biodistribution and stability of CdSe core quantum dots in mouse digestive tract following per os administration: Advantages of double polymer/silica coated nanocrystals. Biochem. Biophys. Res. Commun. 419, 54–59 (2012). Scholar
  69. 69.
    Mohs, A.M., Duan, H., Kairdolf, B.A., Smith, A.M., Nie, S.: Proton-resistant quantum dots: stability in gastrointestinal fluids and implications for oral delivery of nanoparticle agents. Nano Res. 2, 500–508 (2009).
  70. 70.
    Mancini, M.C., Kairdolf, B.A., Smith, A.M., Nie, S.: Oxidative quenching and degradation of polymer-encapsulated quantum dots: new insights into the long term fate and toxicity of nanocrystals in-vivo. J. Am. Chem. Soc. 130, 10836–10837 (2008). Scholar
  71. 71.
    Smith, A.M., Duan, H., Rhyner, M.N., Ruan, G., Nie, S.: A systematic examination of surface coatings on the optical and chemical properties of semiconductor quantum dots. Phys. Chem. Chem. Phys. 8, 3895–3903 (2006). Scholar
  72. 72.
    Min, K.S., Sano, E., Ueda, H., Sakazaki, F., Yamada, K., Takano, M., Tanaka, K.: Dietary deficiency of calcium and/or iron, an age-related risk factor for renal accumulation of cadmium in Mice. Biol. Pharm. Bull. 38, 1557–1563 (2015)CrossRefGoogle Scholar
  73. 73.
    Hauck, T.S., Anderson, R.E., Fischer, H.C., Newbigging, S., Chan, W.C.W.: In vivo quantum-dot toxicity assessment. Small 6, 138–144 (2010). Scholar
  74. 74.
    Rzigalinski, B.A., Strobl, J.S.: Cadmium-containing nanoparticles: perspectives on pharmacology and toxicology of quantum dots. Toxicol. Appl. Pharmacol. 238, 280–288 (2009). Scholar
  75. 75.
    Tsoi, K.M., Dai, Q., Alman, B.A., Chan, W.C.: Are quantum dots toxic? Exploring the discrepancy between cell culture and animal studies. Acc. Chem. Res. 46, 662–671 (2013). Scholar
  76. 76.
    Liu, Y., Li, Y., Liu, K., Shen, J.: Exposing to cadmium stress cause profound toxic effect on microbiota of the mice intestinal tract. PLoS ONE 9, e85323 (2014). Scholar
  77. 77.
    Breton, J., Daniel, C., Dewulf, J., Pothion, S., Froux, N., Sauty, M., Thomas, P., Pot, B., Foligné, B.: Gut microbiota limits heavy metals burden caused by chronic oral exposure. Toxicol. Lett. 222, 132–138 (2013). Scholar
  78. 78.
    Zhai, Q., Yin, R., Yu, L., Wang, G., Tian, F., Yu, R., Zhao, J., Liu, X., Chen, Y.Q., Zhang, H., Chen, W.: Screening of lactic acid bacteria with potential protective effects against cadmium toxicity. Food Control 54, 23–30 (2015). Scholar
  79. 79.
    Breton, J., Massart, S., Vandamme, P., De Brandt, E., Pot, B., Foligné, B.: Ecotoxicology inside the gut: impact of heavy metals on the mouse microbiome. BMC Pharmacol. Toxicol. 14, 62 (2013). Scholar
  80. 80.
    Tiwari, R., Singh, R.D., Khan, H., Gangopadhyay, S., Mittal, S., Singh, V., Arjaria, N., Shankar, J., Roy, S.K., Singh, D., Srivastava, V.: Oral subchronic exposure to silver nanoparticles causes renal damage through apoptotic impairment and necrotic cell death. Nanotoxicology 11, 671–686 (2017). Scholar
  81. 81.
    Nielsen, P.: Chelation therapy for heavy metals. In: Crichton, R., Ward, R.J., Hider, R.C., (eds.) Metal Chelation in Medicine. The Royal Society of Chemistry (2016).
  82. 82.
    Lo, D.D.: Vigilance or subversion? Constitutive and inducible M cells in mucosal tissues. Trends Immunol. 39, 185–195 (2017). Scholar
  83. 83.
    Mantis, N.J., Frey, A., Neutra, M.R.: Accessibility of glycolipid and oligosaccharide epitopes on rabbit villus and follicle-associated epithelium. Am. Physiol. 278, G915–G923 (2000). Scholar
  84. 84.
    Bonnardel, J., Da Silva, C., Henri, S., Tamoutounour, S., Chasson, L., Montaña-Sanchis, F., Gorvel, J.-P., Lelouard, H.: Innate and adaptive immune functions of Peyer’s patch monocyte-derived cells. Cell Rep. 11, 770–784 (2015).
  85. 85.
    Neutra, M.R., Frey, A., Kraehenbuhl, J.-P.: Epithelial M cells: gateways for mucosal infection and immunization. Cell 86, 345–348 (1996). Scholar
  86. 86.
    Rescigno, M., Urbano, M., Valzasina, B., Francolini, M., Rotta, G., Bonasio, R., Granucci, F., Kraehenbuhl, J.-P., Ricciardi-Castagnoli, P.: Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat. Immunol. 2, 361–367 (2001). Scholar
  87. 87.
    Jung, C., Hugot, J.-P., Barreau, F.: Peyer’s patches: the immune sensors of the intestine. Int. J. Inflamm. 2010, 823710 (2010). Scholar
  88. 88.
    Knoop, K.A., Kumar, N., Butler, B.R., Sakthivel, S.K., Taylor, R.T., Nochi, T., Akiba, H., Yagita, H., Kiyono, H., Williams, I.R.: RANKL is necessary and sufficient to initiate development of antigen-sampling M cells in the intestinal epitelium. J. Immunol. 183, 5738–5747 (2009). Scholar
  89. 89.
    Kanaya, T., Ohno, H.: The mechanisms of M cell differentiation. Biosci. Microbiota Food Health 33, 91–97 (2014). Scholar
  90. 90.
    Jang, M.H., Kweon, M.-N., Iwatani, K., Yamamoto, M., Terahara, K., Sasakawa, C., Suzuki, T., Nochi, T., Yokota, Y., Rennert, P.D., Hiroi, T., Tamagawa, H., Iijima, H., Kunisawa, J., Yuki, Y., Kiyono, H.: Intestinal villous M cells: an antigen entry site in the mucosal epithelium. Proc. Natl. Acad. Sci. U.S.A 101, 6110–6115 (2004).
  91. 91.
    Lelouard, H., Fallet, M., De Boris, B., Méresse, S., Gorvel, J.-P.: Peyer’s patch dendritic cells sample antigens by extending dendrites through M-cell specific transcellular pores. Gastroenterology 142, 592–601 (2012). Scholar
  92. 92.
    Pelasayed, T., Gustafsson, J.K., Gustafsson, I.J., Ermund, A., Hansson, G.C.: Carbachol-induced MUC-17 endocytosis is concomitant with NHE3 internalization and CFTR membrane recruitment in enterocytes. Am. J. Physiol. 305, C457–C467 (2013). Scholar
  93. 93.
    Silveira, J.R., Raymond, G.J., Hughson, A.G., Race, R.E., Sim, V.L., Hayes, S.F., Caughy, B.: The most infectious prion particles. Nature 437, 257–261 (2005). Scholar
  94. 94.
    Bade, S., Frey, A.: Potential of active and passive immunizations for the prevention and therapy of transmissible spongiform encephalopathies. Expert Rev. Vaccines 6, 153–168 (2007). Scholar
  95. 95.
    Donaldson, D.S., Kobayashi, A., Ohno, H., Yagita, H., Williams, I.R., Mabbott, N.A.: M cell-depletion blocks oral prion disease pathogenesis. Mucosal Immunol. 5, 216–225 (2012). Scholar
  96. 96.
    Donaldson, D.S., Sehgal, A., Rios, D., Williams, I.R., Mabbott, N.A.: Increased abundance of M cells in the gut epithelium dramatically enhances oral prion disease susceptibility. PLoS Pathog. 12, e1006075 (2016). Scholar
  97. 97.
    Ermak, T.H., Dougherty, E.P., Bhagat, H.R., Kabok, Z., Papp, J.: Uptake and transport of copolymer biodegradable microspheres by rabbit Peyer’s patch M cells. Cell Tissue Res. 279, 433–436 (1995). Scholar
  98. 98.
    Foged, C., Brodin, B., Frokjaer, S., Sundblad, A.: Particle size and surface charge affect particle uptake by human dendritic cells in an in vitro model. Int. J. Pharm. 298, 315–322 (2005). Scholar
  99. 99.
    Gebert, A., Steinmetz, I., Fassbender, S., Wendlandt, K.-H.: Antigen transport into Peyer’s patches: Increased uptake by constant numbers of M cells. Am. J. Pathol. 164, 65–72 (2004).
  100. 100.
    Jepson, M., Simmons, N.L., O’Hagan, D.T., Hirst, B.H.: Comparison of poly(DL-lactide-co-glycolide) and polystyrene microsphere targeting to intestinal M cells. J. Drug Target. 1, 245–249 (1993). Scholar
  101. 101.
    Jepson, M.A., Simmons, N.L., Savidge, T.C., James, P.S., Hirst, B.H.: Selective binding and transcytosis of latex microspheres by rabbit intestinal M cells. Cell Tissue Res. 271, 399–405 (1993). Scholar
  102. 102.
    Pappo, J., Ermak, T.H.: Uptake and translocation of fluorescent latex particles by rabbit Peyer’s patch follicle epithelium: a quantitative model for M cell uptake. Clin. Exp. Immunol. 76, 144–148 (1989)Google Scholar
  103. 103.
    Berg, R.D.: Bacterial translocation from the gastrointestinal tract. Trends Microbiol. 3, 149–154 (1995). Scholar
  104. 104.
    Gewirtz, A.T., Navas, T.A., Lyons, S., Godowski, P.G., Madara, J.L.: Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J. Immunol. 167, 1882–1885 (2001). Scholar
  105. 105.
    Husebye, E.: The pathogenesis of gastrointestinal bacterial overgrowth. Chemotherapy 51(Suppl1), 1–22 (2005).
  106. 106.
    Berkes, J., Viswanathan, V.K., Savkovic, S.D., Hecht, G.: Intestinal epithelial responses to enteric pathogens: effects on the tight junction barrier, ion transport, and inflammation. Gut 52, 439–451 (2003).
  107. 107.
    Mukiza, C.N., Dubreuil, J.D.: Escherichia coli heat-stable toxin b impairs intestinal barrier function by altering tight junction proteins. Infect. Immun. 81, 2819–2827 (2013). Scholar
  108. 108.
    Ugalde-Silva, P., Gonzalez-Lugo, O., Navarro-Garcia, F.: Tight junction disruption induced by type 3 secretion system effectors injected by enteropathogenic and enterohemorrhagic Escherichia coli. Front. Cell Infect. Mirobiol. 6, 87 (2016). Scholar
  109. 109.
    Freeman, H.J.: Spontaneous free perforation of the small intestine in adults. World J. Gastroenterol. 20, 9990–9997 (2014). Scholar
  110. 110.
    Laukoetter, M.G., Nava, P., Nusrat, A.: Role of the intestianal barrier in inflammatory bowel disease. World J. Gastroenterol. 14, 401–407 (2008). Scholar
  111. 111.
    Schmitz, H., Barmeyer, C., Fromm, M., Runkel, N., Foss, H.-D., Bentzel, C.J., Rieken, E.-O., Schulzke, J.-D.: Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis. Gastroenterology 116, 301–309 (1999). Scholar
  112. 112.
    Lechuga, S., Ivanov, A.I.: Disruption of the epithelial barrier during intestinal inflammation: quest for new molecules and mechanisms. Biochim. Biophys. Acta 1864, 1183–1194 (2017). Scholar
  113. 113.
    Lautenschläger, C., Schmidt, C., Lehr, C.-M., Fischer, D., Stallmach, A.: PEG-functionalized microparticles selectively target inflamed mucosa in inflammatory bowel disease. Eur. J. Pharm. Biopharm. 85, 578–586 (2013). Scholar
  114. 114.
    Champion, J.A., Mitragotri, S.: Role of target geometry in phagocytosis. Proc. Natl. Acad. Sci. U.S.A. 103, 4930–4934 (2006). Scholar
  115. 115.
    Docter, D., Westmeier, D., Markiewicz, M., Stolte, S., Knauer, S.K., Staubert, R.H.: The nanoparticle biomolecule corona: lessons learned—challenge accepted? Chem. Soc. Rev. 44, 6094–6121 (2015). Scholar
  116. 116.
    Lundqvist, M., Stigler, J., Elia, G., Lynch, I., Cedervall, T., Dawson, K.A.: Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc. Natl. Acad. Sci. U.S.A. 105, 14265–14270 (2008). Scholar
  117. 117.
    Saptarshi, S.R., Duschi, A., Lopata, A.L.: Interaction of nanoparticles with proteins: relation to bio-reactivity of the nanoparticle. J. Nanobiotech. 11, 26 (2013). Scholar
  118. 118.
    Parsons, B.N., Campbell, B.J., Wigley, P.: Soluble plantain nonstarch polysaccharides, although increasing caecal load, reduce systemic invasion of Salmonella gallinarum in the chicken. Lett. Appl. Microbiol. 60, 347–351 (2014). Scholar
  119. 119.
    Parsons, B.N., Wigley, P., Simpson, H.L., Williams, J.M., Humphrey, S., Salisbury, A.-M., Watson, A.J.M., Fry, S.C., O’Brien, D., Roberts, C.L., O’Kennedy, N., Keita, A.V., Söderholm, J.D., Rhodes, J.M., Campbell, B.J.: Dietary Supplementation with soluble plantain non-starch polysaccharides inhibits intestinal invasion of Salmonella typhimurium in the chicken. PLoS ONE 9, e87658 (2014). Scholar
  120. 120.
    Roberts, C.L., Keita, A.V., Duncan, S.H., O’Kennedy, N., Söderholm, J.D., Rhodes, J.M., Campbell, B.J.: Translocation of Crohn’s disease Escherichia coli across M-cells: contrasting effects of soluble plant fibres and emulsifiers. Gut 59, 1331–1339 (2010). Scholar
  121. 121.
    Roberts, C.L., Keita, A.V., Parsons, B.N., Prorok-Hamon, M., Knight, P., Winstanley, C., O’Kennedy, N., Söderholm, J.D., Rhodes, J.M., Campbell, B.J.: Soluble plantain fibre blocks adhesion and M-cell translocation of intestinal pathogens. J. Nutr. Biochem. 24, 97–103 (2013). Scholar
  122. 122.
    Hochella Jr., M.F., Spencer, M.G., Jones, K.L.: Nanotechnology: nature’s gift or scientists’ brainchild? Environ. Sci. Nano 2, 114–119 (2015). Scholar
  123. 123.
    Sharma, V.K., Filip, J., Zboril, R., Varma, R.S.: Natural inorganic nanoparticles—formation, fate, and toxicity in the environment. Chem. Soc. Rev. 44, 8410–8423 (2015). Scholar
  124. 124.
    Griffin, S., Masood, M.I., Nasim, M.J., Sarfraz, M., Ebokaiwe, A.P., Schäfer, K.-H., Keck, C.M., Jacob, C.: Natural nanoparticles: a particular matter inspired by Nature. Antioxidants 7, 3 (2018). Scholar
  125. 125.
    Strambeanu, N., Demetrovici, L., Dragos, D.: Natural sources of nanoparticles. In: Lungu, M. et al. (eds.) Nanoparticles’ Promises and Risks. Springer International Publishing Switzerland (2015).
  126. 126.
    Dykman, L.A., Khlebtsov, N.G.: Gold nanoparticles in biology and medicine: recent advances and prospects. Acta Naturae 3, 34–55 (2011)Google Scholar
  127. 127.
    Zhang, X.F., Liu, Z.G., Shen, W., Gurunathan, S.: Silver nanoparticles: synthesis, characterization, properties, applications, and therapeutic approaches. Int. J. Mol. Sci. 17, 1534 (2016).
  128. 128.
    Ali, A., Zafar, H., Zia, M., ul Haq, I., Phull, A.R., Ali, J.S., Hussain, A.: Synthesis, characterization, applications, and challenges of iron oxide nanoparticles. Nanotechnol. Sci. Appl. 9, 49–67 (2016). Scholar
  129. 129.
    Valizadeh, A., Mikaeili, H., Samiei, M., Farkhani, S.M., Zarghami, N., Kouhi, M., Akbarzadeh, A., Davaran, S.: Quantum dots: synthesis, bioapplications, and toxicity. Nanoscale Res. Lett. 7, 480 (2012). Scholar
  130. 130.
    Pan, K., Zhong, Q.: Organic nanoparticles in foods: fabrication, characterization and utilization. Annu. Rev. Food Sci. Technol. 7, 245–266 (2016). Scholar
  131. 131.
    Marcaccio, M., Paolucci, F., eds.: Making and exploiting fullerenes, graphene, and carbon nanotubes. Springer, Berlin, Heidelberg (2014).
  132. 132.
    Nasir, S., Hussein, M.Z., Zainal, Z., Yusof, N.A.: Carbon-based nanomaterials/allotropes: a glimpse of their synthesis, properties and some applications. Materials 11, 295 (2018). Scholar
  133. 133.
    Feltracco, M., Barbaro, E., Contini, D., Zangrando, R., Toscano, G., Battistel, D., Barbante, C., Gambaro, A.: Photo-oxidation products of α-pinene in coarse, fine and ultrafine aerosol: a new high sensitive HPLC-MS/MS method. Atmos. Environ. 180, 149–155 (2018). Scholar
  134. 134.
    Kerminen, V.-M.: Roles of SO2 and secondary organics in the growth of nanometer particles in the lower atmosphere. J. Aerosol Sci. 30, 1069–1078 (1999). Scholar
  135. 135.
    Tu, P., Johnston, M.V.: Particle size dependence of biogenic secondary organic aerosol molecular composition. Atmos. Chem. Phys. 17, 7593–7603 (2017).
  136. 136.
    Lindner, K., Ströbele M., Schlick, S., Webering, S., Jenckel, A., Kopf, J., Danov, O., Sewald, K., Buj, C., Creutzenberg, O., Tillmann, T., Pohlmann, G., Ernst, H., Ziemann, C., Hüttmann, G., Heine, H., Bockhorn, H., Hansen, T., König, P., Fehrenbach, H.: Biological effects of carbon black nanoparticles are changed by surface coating with polycyclic aromatic hydrocarbons. Part. Fibre Toxicol. 14, 8 (2017).
  137. 137.
    Ginoux, P., Chin, M., Tegen, I., Prospero, J.M., Holben, B., Dubovik, O., Lin, S.-J.: Sources and distributions of dust aerosols simulated with GOCART model. J. Geophys. Res. 106, 20255–20273 (2001). Scholar
  138. 138.
    D’Andrea, S.D., Häkkinen, S.A.K., Westervelt, D.M., Kuang, C., Levin, E.J.T., Kanawade, V.P., Leaitch, W.R., Spracklen, D.V., Riipinen, I., Pierce, J.R.: Understanding global secondary organic aerosol amount and size-resolved condensational behavior. Atmos. Chem. Phys. 13, 11519–11534 (2013).
  139. 139.
    Taghavi, S.M., Momenpour, M., Azarian, M., Ahmadian, M., Souri, F., Taghavi, S.A., Sadeghain, M., Karchani, M.: Effects of nanoparticles on the environment and outdoor workplaces. Electron. Physician 5, 706–712 (2013). Scholar
  140. 140.
    Rivero, P.J., Urrutia, A., Goicoechea, J., Arregui, F.J.: Nanomaterials for functional textiles and fibers. Nanoscale Res. Lett. 10, 501 (2015). Scholar
  141. 141.
    Blackford, D.B., Simons, G.R.: Particle size analysis of carbon black. Part. Charact. 4, 112–117 (1987). Scholar
  142. 142.
    ICBA International Carbon Black Association. Carbon Black User’s Guide. (2016)
  143. 143.
    SCCS Scientific Committee on Consumer Safety and Chaudhry Q. Opinion of the Scientific Committee on Consusmer Safety (SCCS)—Second revision of the opinion on carbon black, nano-form, in cosmetic products. Regul. Toxicol. Pharmacol. 79, 103–104 (2016).
  144. 144.
    Suryanto, B.H.R., Zhao, C.: Surface-oxidized carbon black as a catalyst for the water oxidation and alcohol oxidation reactions. Chem. Commun. 52, 6439–6442 (2016). Scholar
  145. 145.
    Yuan, L., Lu, X.-H., Xiao, X., Zhai, T., Dai, J., Zhang, F., Hu, B., Wang, X., Gong, L., Chen, J., Hu, C., Tong, Y., Zhou, J., Wang, Z.L.: Flexible solid-state supercapacitors based on carbon nanoparticles/MnO2 nanorods hybrid structure. ACS Nano 6, 656–661 (2012). Scholar
  146. 146.
    Yuan, L., Tao, Y., Chen, J., Dai, J., Song, T., Ruan, M., Ma, Z., Gong, L., Liu, K., Zhang, X., Hu, X., Zhou, J., Wang, Z.L.: Carbon nanoparticles on carbon fabric for flexible and high-performance field emitters. Adv. Funct. Mater. 21, 2150–2154 (2011). Scholar
  147. 147.
    Posthuma-Trumpie, G.A., Wichers, J.H., Koets, M., Berendsen, L.B.J.M., van Amerongen, A.: Amorphous carbon nanoparticles: a versatile label for diagnostic (immuno)assays. Anal. Bioanal. Chem. 402, 593–600 (2012). Scholar
  148. 148.
    Rosic, J.S., Conte, M., Muncan, J., Matija, L., Koruga, D.: Characterization of fullerenes thin film on glasses by UV/VIS/NIR and opto-magnetic imaging spectroscopy. FME Trans. 42, 172–176 (2014). Scholar
  149. 149.
    Gatti, T., Menna, E., Meneghetti, M., Maggini, M., Petrozza, A., Lamberti, F.: The renaissance of fullerenes with perovskite solar cells. Nano Energy 41, 84–100 (2017). Scholar
  150. 150.
    Liu, L., Niu, Z., Chen, J.: Unconventional supercapacitors from nanocarbon-based electrode materials to device configurations. Chem. Soc. Rev. 45, 4340–4363 (2016). Scholar
  151. 151.
    Lv, T., Liu, M., Zhu, D., Gan, L., Chen, T.: Nanocarbon-based materials for flexible all-solid-state supercapacitors. Adv. Mater. 2018, 1705489 (2018). Scholar
  152. 152.
    Yong, Y., Zhou, Q., Li, X., Lv, S.: The H60Si6C54 heterofullerene as high-capacity storage medium. AIP Adv. 6, 075321 (2016). Scholar
  153. 153.
    Yoon, M., Yang, S., Hicke, C., Wang, E., Geohegan, D., Zhang, Z.: Calcium as the superior coating metal in functionalization of carbon fullerenes for high-capacity hydrogen storage. Phys. Rev. Lett. 100, 206806 (2008). Scholar
  154. 154.
    Yoon, M., Yang, S., Wang, E., Zhang, Z.: Charged fullerenes as high-capacity hydrogen storage media. Nano Lett. 7, 2578–2583 (2007). Scholar
  155. 155.
    Al-Jumaili, A., Alancherry, S., Bazaka, K., Jacob, M.V.: Review on the antimicrobial properties of carbon nanostructures. Materials 10, 1066 (2017). Scholar
  156. 156.
    Teradal, N.L., Jelinek, R.: Carbon nanomaterials in biological studies and biomedicine. Adv. Healthc. Mater. 6, 1700574 (2017). Scholar
  157. 157.
    De Smet, R., Demoor, T., Verschuere, S., Dullaers, M., Ostroff, G.R., Leclerq, G., Allais, L., Pilette, C., Dierendonck, M., De Geest, B.G., Cuvelier, C.A.: β-Glucan microparticles are good candidates for mucosal antigen delivery in oral vaccination. J. Control Rel. 172, 671–678 (2013). Scholar
  158. 158.
    des Rieux, A., Fievez, A., Garinot, M., Schneider, Y.-J., Préat, V.: Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach. J. Control Rel. 116, 1–27 (2006).
  159. 159.
    Zhu, Q., Talton, J., Zhang, G., Cunningham, T., Wang, Z., Waters, R.C., Kirk, J., Eppler, B., Klinman, D.M., Sui, Y., Gagnon, S., Belyakov, I.M., Mumper, R.J., Berzofsky, J.A.: Large intestine-targeted, nanoparticle-releasing oral vaccine to control genitorectal viral infection. Nat. Med. 18, 1291–1297 (2012). Scholar
  160. 160.
    Fonte, P., Nogueira, T., Gehm, C., Ferreira, D., Sarmento, B.: Chitosan-coated solid lipid nanoparticles enhance the oral absorption of insulin. Drug Deliv. Transl. Res. 1, 299–308 (2011). Scholar
  161. 161.
    Ren, T., Wang, Q., Xu, Y., Cong, L., Gou, J., Tao, X., Zhang, Y., He, H., Yin, T., Zhang, H., Zhang, Y., Tang, X.: Enhanced oral absorption and anticancer efficacy of cabazitaxel by overcoming intestinal mucus and epithelium barriers using surface polyethylene oxide (PEO) decorated positively charged polymer-lipid hybrid nanoparticles. J. Control Rel. 269, 423–438 (2018). Scholar
  162. 162.
    Sun, S., Liang, N., Gong, X., An, W., Kawashima, Y., Cui, F., Yan, P.: Multifunctional composite microcapsules for oral delivery of insulin. Int. J. Mol. Sci. 18, 54 (2017). Scholar
  163. 163.
    Niu, Z., Conejos-Sánchez, I., Griffin, B.T., O’Driscoll, C.M., Alonso, M.J.: Lipid-based nanocarriers for oral peptide delivery. Adv. Drug Deliv. Rev. 106 Part B, 337–354 (2016). Scholar
  164. 164.
    Sheng, Y., He, H., Zou, H.: Poly(lactic acid) nanoparticles coated with combined WGA and water-soluble chitosan for mucosal delivery of β-galactosidase. Drug Deliv. 21, 370–378 (2014). Scholar
  165. 165.
    Yin, Y.S., Chen, D.W., Qiao, M.X., Wei, X.Y., Hu, H.Y.: Lectin-conjugated PLGA nanoparticles loaded with thymopentin: ex vivo bioadhesion and in vivo biodistribution. J. Control Rel. 123, 27–38 (2007). Scholar
  166. 166.
    Menzel, C., Bernkop-Schnürch, A.: Enzyme decorated drug carriers: targeted swords to cleave and overcome the mucus barrier. Adv. Drug Deliv. Rev. 124, 164–174 (2018). Scholar
  167. 167.
    Frøkjær, J.B., Drewes, A.M., Gregersen, H.: Imaging of the gastrointestinal tract-novel technologies. World J. Gastroenterol. 15, 160–168 (2009). Scholar
  168. 168.
    Stark, D.D., Weissleder, R., Elizondo, G., Hahn, P.F., Saini, S., Todd, L.E., Wittenberg, J., Ferrucci, J.T.: Superparamagnetic iron oxide: clinical application as a contrast agent for MR imaging of the liver. Radiology 168, 297–301 (1988). Scholar
  169. 169.
    Shokrollahi, H.: Contrast agents for MRI. Mater. Sci. Eng. C 33, 4485–4497 (2013). Scholar
  170. 170.
    Li, W., Tutton, S., Vu, A.T., Pierchala, L., Li, B.S.Y., Lewis, J.M., Prasad, P.V., Edelman, R.R.: First-pass contrast-enhanced magnetic resonance angiography in humans using ferumoxytol, a novel ultrasmall superparamagnetic iron oxide (USPIO)-based blood pool agent. J. Magn. Reson. Imaging 21, 46–52 (2005). Scholar
  171. 171.
    Frisch, A., Walter, T.C., Hamm, B., Denecke, T.: Efficacy of oral contrast agents for upper gastrointestinal signal suppression in MRCP: A systematic review of the literature. Acta Radiol. Open 6, 2058460117727315 (2017). Scholar
  172. 172.
    Maccioni, F., Bruni, A., Viscido, A., Colaiacomo, M.C., Cocco, A., Montesani, C., Caprilli, R., Marini, M.: MR imaging in patients with Crohn disease: value of T2- versus T1-weighted gadolinium-enhanced MR sequences with use of an oral superparamagnetic contrast agent. Radiology 238, 517–530 (2006). Scholar
  173. 173.
    Gleich, B., Weizenecker, J.: Tomographic imaging using the nonlinear response of magnetic particles. Nature 435, 1214–1217 (2005). Scholar
  174. 174.
    Salamon, J., Hofmann, M., Jung, C., Kaul, M.G., Werner, F., Them, K., Reimer, R., Nielsen, P., vom Scheidt, A., Adam, G., Knopp, T., Ittrich, H.: Magnetic particle/magnetic resonance imaging: In-Vitro MPI-guided real time catheter tracking and 4D angioplasty using a road map and blood pool tracer approach. PLoS ONE 11, e0156899 (2016). Scholar
  175. 175.
    Yu, E.Y., Chandrasekharan, P., Berzon, R., Tay, Z.W., Zhou, X.Y., Khandhar, A.P., Ferguson, R.M., Kemp, S.J., Zheng, B., Goodwill, P.W., Wendland, M.F., Krishnan, K.M., Behr, S., Carter, J., Conolly, S.M.: Magnetic particle imaging for highly sensitive, quantitative, and safe in vivo gut bleed detection in a murine model. ACS Nano 11, 12067–12076 (2017). Scholar
  176. 176.
    Gamboa, J.M., Leong, K.W.: In vitro and in vivo models for the study of oral delivery of nanoparticles. Adv. Drug Deliv. Rev. 65, 800–810 (2013). Scholar
  177. 177.
    Buhrke, T., Lengler, I., Lampen, A.: Analysis of proteomic changes induced upon cellular differentiation of the human intestinal cell line Caco-2. Dev. Growth Differ. 53, 411–426 (2011). Scholar
  178. 178.
    Hidalgo, I.J., Raub, T.J., Borchardt, R.T.: Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology 96, 736–749 (1989)CrossRefGoogle Scholar
  179. 179.
    Sinnecker, H., Ramaker, K., Frey, A.: Coating with luminal gut-constituents alters adherence of nanoparticles to intestinal epithelial cells. Beilstein J. Nanotechnol. 5, 2308-2315 (2014).
  180. 180.
    Béduneau, A., Tempesta, C., Fimbel, S., Pellequer, Y., Jannin, V., Demarne, F., Lamprecht, A.: A tunable Caco-2/HT29-MTX co-culture model mimicking variable permeabilities of the human intestine obtained by an original seeding procedure. Eur. J. Pharm. Biopharm. 87, 290–298 (2014). Scholar
  181. 181.
    Mahler, G.J., Shuler, M.L., Glahn, R.P.: Characterization of Caco-2 and HT29-MTX cocultures in an in vitro digestion/cell culture model used to predict iron bioavailability. J. Nutr. Biochem. 20, 494–502 (2009). Scholar
  182. 182.
    Kernéis, S., Bogdanova, A., Kraehenbuhl, J.-P., Pringault, E.: Conversion by Peyer’s patch lymphocytes of human enterocytes into M cells that transport bacteria. Science 277, 949–952 (1997). Scholar
  183. 183.
    Ahmad, T., Gogarty, M., Walsh, E.G., Brayden, D.J.: A comparison of three Peyer’s patch “M-like” cell culture models: particle uptake, bacterial interaction and epithelial histology. Eur. J. Pharm. Biopharm. 119, 426–436 (2017).
  184. 184.
    des Rieux, A., Fievez, V., Théate, I., Mast, J., Préat, V., Schneider, Y.-J.: An improved in vitro model of human intestinal follicle-associated epithelium to study nanoparticle transport by M cells. Eur. J. Pharm. Sci. 30, 380–391 (2007).
  185. 185.
    Gullberg, E., Leonard, M., Karlsson, J., Hopkins, A.M., Brayden, D., Baird, A.W., Artursson, P.: Expression of specific markers and particle transport in a new human intestinal M cell model. Biochim. Biophys. Res. Commun. 279, 808–813 (2000). Scholar
  186. 186.
    Schimpel, C., Teubl, B., Absenger, M., Meindl, C., Fröhlich, E., Leitinger, G., Zimmer, A., Roblegg, E.: Development of an advanced intestinal in vitro triple culture permeability model to study transport of nanoparticles. Mol. Pharm. 11, 808–818 (2014). Scholar
  187. 187.
    Hilgers, A.R., Conradi, R.A., Burton, P.S.: Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa. Pharm. Res. 7, 902–910 (1990). Scholar
  188. 188.
    Beloqui, A., des Lieux, A., Préat, V.: Mechanisms of transport of polymeric and lipidic nanoparticles across the intestinal barrier. Adv. Drug Deliv. Rev. 106, Part B, 242–255 (2016).
  189. 189.
    He, B., Lin, P., Jia, Z., Du, W., Qu, W., Yuan, L., Dai, W., Zhang, H., Wang, X., Wang, J., Zhang, X., Zhang, Q.: The transport mechanisms of polymer nanoparticles in Caco-2 epithelial cells. Biomaterials 34, 6082–6098 (2013). Scholar
  190. 190.
    Russel-Jones, G.J., Arthur, L., Walker, H.: Vitamin B12-mediated transport of nanoparticles across Caco-2 cells. Int. J. Pharm. 179, 247–255 (1999). Scholar
  191. 191.
    Sheng, J., Han, L., Qin, J., Ru, G., Li, R., Wu, L., Cui, D., Yang, P., He, Y., Wang, J.: N-Trimethyl chitosan chloride-coated PLGA nanoparticles overcoming multiple barriers to oral insulin absorption. ACS Appl. Mater. Interfaces 7, 15430–15441 (2015). Scholar
  192. 192.
    Luo, Y., Teng, Z., Li, Y., Wang, Q.: Solid lipid nanoparticles for oral drug delivery: Chitosan coating improves stability, controlled delivery, mucoadhesion and cellular uptake. Carbohydr. Polym. 122, 221–229 (2015). Scholar
  193. 193.
    Araújo, F., Shrestha, N., Shahbazi, M.-A., Fonte, P., Mäkilä, E.M., Salonen, J.J., Hirvonen, J.T., Granja, P.L., Santos, H.A., Sarmento, B.: The impact of nanoparticles on the mucosal translocation and transport of GLP-1 across the intestinal epithelium. Biomaterials 35, 9199–9207 (2014). Scholar
  194. 194.
    Lichtenstein, D., Ebmeyer, J., Meyer, T., Behr, A.-C., Kästner, C., Böhmert, L., Juling, S., Nieman, B., Fahrenson, C., Selve, S., Thünemann, A.F., Meijer, J., Estrela-Lopis, I., Braeuning, A., Lampen, A.: It takes more than a coating to get nanoparticles through the intestinal barrier in vitro. Eur. J. Pharm. Biopharm. 118, 21–29 (2017). Scholar
  195. 195.
    Giannasca, K.T., Giannasca, P.J., Neutra, M.R.: Adherence of Salmonella typhimurium to Caco-2 cells: identification of a glycoconjugate receptor. Infect. Immun. 64, 135–145 (1996)Google Scholar
  196. 196.
    Jahn, K.A., Biazik, J.M., Braet, F.: GM1 Expression in Caco-2 cells: characterisation of a fundamental passage-dependent transformation of a cell line. J. Pharmaceut. Sci. 100, 3751–3762 (2011). Scholar
  197. 197.
    Behrens, I., Vila Pena, A.I., Alonso, M.J., Kissel, T.: Comparative uptake studies of bioadhesive and non-bioadhesive nanoparticles in human intestinal cell lines and rats: the effect of mucus on particle adsorption and transport. Pharm. Res. 19, 1185–1193 (2002). Scholar
  198. 198.
    Ke, Z., Guo, H., Zhu, X., Jin, Y., Huang, Y.: Efficient peroral delivery of insulin via vitamin B12 modified trimethyl chitosan nanoparticles. J. Pharm. Pharm. Sci. 18, 155–170 (2015)CrossRefGoogle Scholar
  199. 199.
    Yoshida, T., Yoshioka, Y., Takahashi, H., Misato, K., Mori, T., Hirai, T., Nagano, K., Abe, Y., Mukai, Y., Kamada, H., Tsunoda, S., Nabeshi, H., Yoshikawa, T., Higashisaka, K., Tsutsumi, Y.: Intestinal absorption and biological effects of orally administered amorphous silica particles. Nanoscale Res. Lett. 9, 532–538 (2014). Scholar
  200. 200.
    Wiwattanapatapee, R., Carreño-Gomez, B., Malik, N., Duncan, R.: Anionic PAMAM dendrimers rapidly cross adult rat intestine in vitro: a potential oral delivery system? Pharm. Res. 17, 991–998 (2000).
  201. 201.
    Lautenschläger, I., Dombrowski, H., Frerichs, I., Kuchenbecker, S.C., Bade, S., Schultz, H., Zabel, P., Scholz, J., Weiler, N., Uhlig, S.: A model of the isolated perfused rat small intestine. Am. J. Physiol. 298, G304–G313 (2010). Scholar
  202. 202.
    Sinnecker, H., Krause, T., Koelling, S., Lautenschläger, I., Frey, A.: The gut wall provides an effective barrier against nanoparticle uptake. Beilstein J. Nanotechnol. 5, 2092–2101 (2014). Scholar
  203. 203.
    Bergin, I.L., Witzmann, F.A.: Nanoparticle toxicity by the gastrointestinal route: evidence and knowledge gaps. Int. J. Biomed. Nanosci. Nanotechnol. 3, 163–210 (2013). Scholar
  204. 204.
    Delie, F.: Evaluation of nano- and microparticle uptake by the gastrointestinal tract. Adv. Drug Deliv. Rev. 34, 221–233 (1998). Scholar
  205. 205.
    Bölke, T., Krapf, L., Orzekowsky-Schroeder, R., Vossmeyer, T., Dimitrijevic, J., Weller, H., Schüth, A., Klinger, A., Hüttmann, G., Gebert, A.: Data-adaptive image-denoising for detecting and quantifying nanoparticle entry in mucosal tissues through intravital 2-photon microscopy. Beilstein J. Nanotechnol. 5, 2016–2025 (2014). Scholar
  206. 206.
    Lee, C.-M., Lee, T.K., Kim, D.-I., Kim, Y.-R., Kim, M.-K., Jeong, H.-J., Sohn, M.-H., Lim, S.T.: Optical imaging of absorption and distribution of RITC-SiO2 nanoparticles after oral administration. Int. J. Nanomed. 9(Suppl 2), 243–250 (2014). Scholar
  207. 207.
    Howe, S.E., Lickteig, D.J., Plunkett, K.N., Ryerse, J.S., Konjufca, V.: The uptake of soluble and particulate antigens by epithelial cells in the mouse small intestine. PLoS ONE 9, e86656 (2014). Scholar
  208. 208.
    Loeschner, K., Hadrup, N., Qvortrup, K., Larsen, A., Gao, X., Vogel, U., Mortensen, A., Lam, H.R., Larsen, E.H.: Distribution of silver in rats following 28 days of repeated oral exposure to silver nanoparticles or silver acetate. Part. Fibre Toxicol. 8, 18 (2011). Scholar
  209. 209.
    Jani, P., Halbert, G.W., Langridge, J., Florence, A.T.: Nanoparticle uptake by the rat gastrointestinal mucosa: quantitation and particle size dependency. J. Pharm. Pharmacol. 42, 821–826 (1990). Scholar
  210. 210.
    Geraets, L., Oomen, A.G., Krystek, P., Jaobsen, N.R., Wallin, H., Laurentie, M., Verharen, H.W., Brandon, E.F.A., de Jong, W.H.: Tissue distribution and elimination after oral and intravenous administration of different titanium dioxide nanoparticles in rats. Part. Fibre Toxicol. 11, 30 (2014). Scholar
  211. 211.
    Janer, G., Mas del Molino, E., Fernández-Rosas, E., Fernández, A., Vázquez-Campos, S.: Cell uptake and oral absorption of titanium dioxide nanoparticles. Toxicol. Lett. 228, 103–110 (2014).
  212. 212.
    Jovanovic, B.: Critical review of public health regulations of titanium dioxide, a human food additive. Integr. Environ. Assess. Manag. 11, 10–20 (2015). Scholar
  213. 213.
    Böckmann, J., Lahl, H., Eckert, T., Unterhalt, B.: Titan-Blutspiegel vor und nach Belastungsversuchen mit Titandioxid. Pharmazie 55, 140–143 (2000)Google Scholar
  214. 214.
    Jones, K., Morton, J., Smith, I., Jurkschat, K., Harding, A.-H., Evans, G.: Human in vivo and in vitro studies on gastrointestinal absorption of titanium dioxide nanoparticles. Toxicol. Lett. 233, 95–101 (2015). Scholar
  215. 215.
    Pele, L.C., Thoree, V., Bruggraber, S.F.A., Koller, D., Thompson, R.P.H., Lomer, M.C., Powell, J.J.: Pharmaceutical/food grade titanium dioxide particles are absorbed into the bloodstream of human volunteers. Part. Fibre Toxicol. 12, 26 (2015). Scholar
  216. 216.
    Rompelberg, C., Heringa, M.B., van Donkersgoed, G., Drijvers, J., Roos, A., Westenbrink, S., Peters, R., van Bemmel, G., Brand, W., Oomen, A.G.: Oral intake of added titanium dioxide and its nanofraction from food products, food supplements and toothpaste by the Dutch population. Nanotoxicology 10, 1404–1414 (2016). Scholar
  217. 217.
    Weir, A., Westerhoff, P., Fabricius, L., Hristovski, K., von Goertz, N.: Titanium dioxide nanoparticles in food and personal care products. Environ. Sci. Technol. 46, 2242–2250 (2012). Scholar
  218. 218.
    Jani, P.U., McCarthy, D.E., Florence, A.: Titanium dioxide (rutile) particle uptake from the rat GI tract and translocation to systemic organs after oral administration. Int. J. Pharm. 105, 157–168 (1994). Scholar
  219. 219.
    Hummel, T.Z., Kindermann, A., Stokkers, P.C.F., Benninga, M.A., ten Kate, F.J.W.: Exogenous pigment in Peyer’s patches of children suspected of having IBD. J. Pediatr. Gastroenterol. Nutr. 58, 477–480 (2014). Scholar
  220. 220.
    Shepherd, N.A., Crocker, P.R., Smith, A.P., Levison, D.A.: Exogenous pigment in Peyer’s patches. Human Pathol. 18, 50–54 (1987). Scholar
  221. 221.
    Feliu, N., Docter, D., Heine, M., Del Pino, P., Ashraf, S., Kolosnjaj-Tabi, J., Macchiarini, P., Nielsen, P., Alloyeau, D., Gazeau, F., Stauber, R.H., Parak, W.J.: In vivo degeneration and the fate of inorganic nanoparticles. Chem. Soc. Rev. 45, 2440–2457 (2016). Scholar
  222. 222.
    Carambia, A., Freund, B., Schwinge, D., Bruns, O.T., Salmen, S.C., Ittrich, H., Reimer, R., Heine, M., Huber, S., Waurisch, C., Eychmüller, A., Wraith, D.C., Korn, T., Nielsen, P., Weller, H., Schramm, C., Lüth, S., Lohse, A.W., Heeren, J., Herkel, J.: Nanoparticle-based autoantigen delivery to Treg-inducing liver sinusoidal endothelial cells enables control of autoimmunity in mice. J. Hepatol. 62, 1349–1356 (2015). Scholar
  223. 223.
    Jung, C.S.L., Heine, M., Freund, B., Reimer, R., Koziolek, E.J., Kaul, M.G., Kording, F., Schumacher, U., Weller, H., Nielsen, P., Adam, G., Heeren, J., Ittrich, H.: Quantitative activity measurements of brown adipose tissue at 7 T magnetic resonance imaging after application of triglyceride-rich lipoprotein 59Fe-superparamagnetic iron oxide nanoparticle: intravenous versus intraperitoneal approach. Invest. Radiol. 51, 194–202 (2016). Scholar
  224. 224.
    Wang, Y., Zhao, Y., Cui, Y., Zhao, Q., Zhang, Q., Musetti, S., Kinghorn, K.A., Wang, S.: Overcoming multiple gastrointestinal barriers by bilayer modified hollow mesoporous silica nanocarriers. Acta Biomater. 65, 405–416 (2018). Scholar
  225. 225.
    Bartelt, A., Bruns, O.T., Reimer, R., Hohenberg, H., Ittrich, H., Peldschus, K., Kaul, M.G., Tromsdorf, U.I., Weller, H., Waurisch, C., Eychmüller, A., Gordts, P.L.S.M., Rinninger, F., Bruegelmann, K., Freund, B., Nielsen, P., Merkel, M., Heeren, J.: Brown adipose tissue activity controls triglyceride clearance. Nat. Med. 17, 200–205 (2011). Scholar
  226. 226.
    Freund, B., Tromsdorf, U.I., Bruns, O.T., Heine, M., Giemsa, A., Bartelt, A., Salmen, S.C., Raabe, N., Heeren, J., Ittrich, H., Reimer, R., Hohenberg, H., Schumacher, U., Weller, H., Nielsen, P.: A simple and widely applicable method to 59Fe-radiolabel monodisperse superparamagnetic iron oxide nanoparticles for in vivo quantification studies. ACS Nano 6, 7318–7325 (2012). Scholar
  227. 227.
    Kreyling, W.G., Hirn, S., Möller, W., Schleh, C., Wenk, A., Celik, G., Lipka, J., Schäffler, M., Haberl, N., Johnston, B.D., Sperling, R., Schmid, G., Simon, U., Parak, W.J., Semmler-Behnke, M.: Air-blood barrier translocation of tracheally instilled gold nanoparticles inversely depends on particle size. ACS Nano 8, 222–233 (2014). Scholar
  228. 228.
    Schleh, C., Semmler-Behnke, M., Lipka, J., Wenk, A., Hirn, S., Schäffler, M., Schmid, G., Simon, U., Kreyling, W.G.: Size and surface charge of gold nanoparticles determine absorption across intestinal barriers and accumulation in secondary target organs after oral administration. Nanotoxicology 6, 36–46 (2012). Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Andreas Frey
    • 1
    Email author
  • Katrin Ramaker
    • 1
  • Niels Röckendorf
    • 1
  • Barbara Wollenberg
    • 2
  • Ingmar Lautenschläger
    • 3
  • Gabriella Gébel
    • 4
  • Artur Giemsa
    • 4
  • Markus Heine
    • 4
  • Denise Bargheer
    • 4
  • Peter Nielsen
    • 4
  1. 1.Division of Mucosal Immunology and DiagnosticsResearch Center BorstelBorstelGermany
  2. 2.Department of Ear, Nose and ThroatUniversity Hospital Schleswig-HolsteinLübeckGermany
  3. 3.Clinic for Anesthesiology and Operative Intensive Care MedicineUniversity Hospital Schleswig-HolsteinKielGermany
  4. 4.Institute of Biochemisty and Molecular Cell BiologyUniversity Medical Center EppendorfHamburgGermany

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