Cellular Uptake Mechanisms and Detection of Nanoparticle Uptake by Advanced Imaging Methods

  • Kleanthis Fytianos
  • Fabian BlankEmail author
  • Loretta Müller
Part of the NanoScience and Technology book series (NANO)


The specific mechanism, of uptake of a nanoparticle by a cell and the subcellular localisation are of great importance regarding the potential effect of the nanomaterial inside the cell. In order to study health risks and the potential of a nanoparticle to be used in biomedical applications, cellular internalization has to be investigated in great detail. This chapter highlights most relevant routes of nanoparticle uptake and includes current approaches for the visualization of particle uptake at the nano-level.


  1. 1.
    Beddoes, C.M., Case, C.P., Briscoe, W.H.: Understanding nanoparticle cellular entry: a physicochemical perspective. Adv. Colloid Interface Sci. 48–68 (2015).
  2. 2.
    Abbas, K., Cydzik, I., Del Torchio, R., Farina, M., Forti, E., Gibson, N., et al.: Radiolabelling of TiO2 nanoparticles for radiotracer studies. J Nanopart. Res. 12, 2435–2443 (2010). Scholar
  3. 3.
    Maynard, A.D., Aitken, R.J., Butz, T., Colvin, V., Donaldson, K., Oberdörster, G., et al.: Safe handling of nanotechnology. Nature 444, 267–269 (2006). Scholar
  4. 4.
    Nel, A., Xia, T., Mädler, L., Li, N.: Toxic potential of materials at the nanolevel. Science 622–627 (2006).
  5. 5.
    Service, R.F.: Priorities needed for nano-risk research and development. Science. 45 (2006).
  6. 6.
    Barnard, A.S.: Nanohazards: Knowledge is our first defence. Nat. Mater. 5, 245–248 (2006). Scholar
  7. 7.
    Handy, R.D., Von Der Kammer, F., Lead, J.R., Hassellöv, M., Owen, R., Crane, M.: The ecotoxicology and chemistry of manufactured nanoparticles. Ecotoxicology 287–314 (2008).
  8. 8.
    Linse, S., Cabaleiro-Lago, C., Xue, W.-F., Lynch, I., Lindman, S., Thulin, E., et al.: Nucleation of protein fibrillation by nanoparticles. Proc. Natl. Acad. Sci. 104, 8691–8696 (2007). Scholar
  9. 9.
    Lunov, O., Zablotskii, V., Syrovets, T., Röcker, C., Tron, K., Nienhaus, G.U., et al.: Modeling receptor-mediated endocytosis of polymer-functionalized iron oxide nanoparticles by human macrophages. Biomaterials 32, 547–555 (2011). Scholar
  10. 10.
    Lunov, O., Syrovets, T., Röcker, C., Tron, K., Ulrich Nienhaus, G., Rasche, V., et al.: Lysosomal degradation of the carboxydextran shell of coated superparamagnetic iron oxide nanoparticles and the fate of professional phagocytes. Biomaterials 31, 9015–9022 (2010). Scholar
  11. 11.
    Yameen, B., Choi, W.I., Vilos, C., Swami, A., Shi, J., Farokhzad, O.C.: Insight into nanoparticle cellular uptake and intracellular targeting. J Control Release. 190, 485–499 (2014). Scholar
  12. 12.
    Treuel, L., Jiang, X., Nienhaus, G.U.: New views on cellular uptake and trafficking of manufactured nanoparticles. J. R. Soc. Interface 10, 20120939–20120939 (2013). Scholar
  13. 13.
    AshaRani, P.V., Mun, G.L.K., Hande, M.P., Valiyaveettil, S.: Cytotoxicity and genotoxicity of silver nanoparticles in human cells. ACS Nano 3, 279–290 (2009). Scholar
  14. 14.
    Chithrani, B.D., Ghazani, A.A., Chan, W.C.W.: Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Lett. 6, 662–668 (2006). Scholar
  15. 15.
    Rejman, J., Oberle, V., Zuhorn, I.S., Hoekstra, D.: Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochem J. 377, 159–169 (2004).
  16. 16.
    Labhasetwar, V., Song, C., Humphrey, W., Shebuski, R., Levy, R.J.: Arterial uptake of biodegradable nanoparticles: effect of surface modifications. J. Pharm. Sci. 87, 1229–1234 (1998). Scholar
  17. 17.
    Arbab, A.S., Bashaw, L.A., Miller, B.R., Jordan, E.K., Lewis, B.K., Kalish, H., et al.: Characterization of biophysical and metabolic properties of cells labeled with superparamagnetic iron oxide nanoparticles and transfection agent for cellular MR imaging. Radiology 229, 838–846 (2003). Scholar
  18. 18.
    Sun, X., Rossin, R., Turner, J.L., Becker, M.L., Joralemon, M.J., Welch, M.J., et al.: An assessment of the effects of shell cross-linked nanoparticle size, core composition, and surface PEGylation on in vivo biodistribution. Biomacromolecules 6, 2541–2554 (2005). Scholar
  19. 19.
    Nativo, P., Prior, I.A., Brust, M.: Uptake and intracellular fate of surface-modified gold nanoparticles. ACS Nano 2, 1639–1644 (2008). Scholar
  20. 20.
    Holzapfel, V., Lorenz, M., Weiss, C.K., Schrezenmeier, H., Landfester, K., Mailänder, V.: Synthesis and biomedical applications of functionalized fluorescent and magnetic dual reporter nanoparticles as obtained in the miniemulsion process. J. Phys. Condens. Matter. 18 (2006).
  21. 21.
    Rajendran, L., Knölker, H.-J., Simons, K.: Subcellular targeting strategies for drug design and delivery. Nat. Rev. Drug Discov. 9, 29–42 (2010). Scholar
  22. 22.
    Huang, J.G., Leshuk, T., Gu, F.X.: Emerging nanomaterials for targeting subcellular organelles. Nano Today 478–492 (2011).
  23. 23.
    Kettiger, H., Schipanski, A., Wick, P., Huwyler, J.: Engineered nanomaterial uptake and tissue distribution: from cell to organism. Int. J. Nanomed. 3255–3269 (2013).
  24. 24.
    Aderem, A., Underhill, D.M.: Mechanisms of phagocytosis in macrophages. Annu. Rev. Immunol. 17, 593–623 (1999). Scholar
  25. 25.
    Hillaireau, H., Couvreur, P.: Nanocarriers’ entry into the cell: relevance to drug delivery. Cell. Mol. Life Sci. 66, 2873–2896 (2009). Scholar
  26. 26.
    Silverstein, S.C.: Phagocytosis of microbes: insights and prospects. Trends Cell Biol. 5, 141–142 (1995). Scholar
  27. 27.
    Owens, D.E., Peppas, N.A.: Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int. J. Pharm. 93–102 (2006).
  28. 28.
    Underhill, D.M., Goodridge, H.S.: Information processing during phagocytosis. Nat. Rev. Immunol. 492–502 (2012).
  29. 29.
    Rabinovitch, M.: Professional and non-professional phagocytes: an introduction. Trends Cell Biol. 5, 85–87 (1995). Scholar
  30. 30.
    Dobrovolskaia, M.A., Mcneil, S.E.: Immunological properties of engineered nanomaterials. Nat. Nanotechnol. 2, 469–478 (2007)CrossRefGoogle Scholar
  31. 31.
    Conner, S.D., Schmid, S.L.: Regulated portals of entry into the cell. Nature. 422, 37–44 (2003).
  32. 32.
    Falcone, S., Cocucci, E., Podini, P., Kirchhausen, T., Clementi, E., Meldolesi, J.: Macropinocytosis: regulated coordination of endocytic and exocytic membrane traffic events. J. Cell Sci. 119, 4758–4769 (2006). Scholar
  33. 33.
    Mercer, J., Helenius, A.: Virus entry by macropinocytosis. Nat. Cell Biol. 510–520 (2009).
  34. 34.
    Kolb-Mäurer, A., Wilhelm, M., Weissinger, F., Bröcker, E.-B., Goebel, W.: Interaction of human hematopoietic stem cells with bacterial pathogens. Blood 100, 3703–3709 (2002). Scholar
  35. 35.
    Fiorentini, C., Falzano, L., Fabbri, A., Stringaro, A., Logozzi, M., Travaglione, S., et al.: Activation of rho GTPases by cytotoxic necrotizing factor 1 induces macropinocytosis and scavenging activity in epithelial cells. Mol. Biol. Cell 12, 2061–2073 (2001). Scholar
  36. 36.
    Steinman, R.M., Swanson, J.: The endocytic activity of dendritic cells. J Exp Med. United States 182, 283–288 (1995)CrossRefGoogle Scholar
  37. 37.
    Sallusto, F., Cella, M., Danieli, C., Lanzavecchia, A.: Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. J. Exp. Med. 182, 389–400 (1995).
  38. 38.
    Kerr, M.C., Teasdale, R.D.: Defining macropinocytosis. Traffic 364–371 (2009).
  39. 39.
    Rima, W., Sancey, L., Aloy, M.T., Armandy, E., Alcantara, G.B., Epicier, T., et al.: Internalization pathways into cancer cells of gadolinium-based radiosensitizing nanoparticles. Biomaterials 34, 181–195 (2013). Scholar
  40. 40.
    Kumari, S., Mg, S., Mayor, S.: Endocytosis unplugged: multiple ways to enter the cell. Cell Res. 256–275 (2010).
  41. 41.
    Kirchhausen, T.: Clathrin. Annu. Rev. Biochem. 69, 699–727 (2000). Scholar
  42. 42.
    Sandvig, K., Pust, S., Skotland, T., van Deurs, B.: Clathrin-independent endocytosis: mechanisms and function. Curr. Opin. Cell Biol. 413–420 (2011).
  43. 43.
    Ford, M.G.J., Mills, I.G., Peter, B.J., Vallis, Y., Praefcke, G.J.K., Evans, P.R., et al.: Curvature of clathrin-coated pits driven by epsin. Nature 419, 361–366 (2002). Scholar
  44. 44.
    Capraro, B.R., Shi, Z., Wu, T., Chen, Z., Dunn, J.M., Rhoades, E., et al.: Kinetics of endophilin N-BAR domain dimerization and membrane interactions. J. Biol. Chem. 288, 12533–12543 (2013). Scholar
  45. 45.
    Tebar, F., Bohlander, S.K., Sorkin, A.: Clathrin assembly lymphoid myeloid leukemia (CALM) protein: localization in endocytic-coated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic. Mol. Biol. Cell 10, 2687–2702 (1999). Scholar
  46. 46.
    Marsh, M., McMahon, H.T.: The structural era of endocytosis. Science 215–220 (1999).
  47. 47.
    Stowell, M.H., Marks, B., Wigge, P., McMahon, H.T.: Nucleotide-dependent conformational changes in dynamin: evidence for a mechanochemical molecular spring. Nat. Cell Biol. 1, 27–32 (1999). Scholar
  48. 48.
    Harush-Frenkel, O., Rozentur, E., Benita, S., Altschuler, Y.: Surface charge of nanoparticles determines their endocytic and transcytotic pathway in polarized MDCK cells. Biomacromol 9, 435–443 (2008). Scholar
  49. 49.
    Oh, P., Borgström, P., Witkiewicz, H., Li, Y., Borgström, B.J., Chrastina, A., et al.: Live dynamic imaging of caveolae pumping targeted antibody rapidly and specifically across endothelium in the lung. Nat. Biotechnol. 25, 327–337 (2007). Scholar
  50. 50.
    Wang, Z., Tiruppathi, C., Minshall, R.D., Malik, A.B.: Size and dynamics of caveolae studied using nanoparticles in living endothelial cells. ACS Nano 3, 4110–4116 (2009). Scholar
  51. 51.
    Hommelgaard, A.M., Roepstorff, K., Vilhardt, F., Torgersen, M.L., Sandvig, K., van Deurs, B.: Caveolae: stable membrane domains with a potential for internalization. Traffic 720–724 (2005).
  52. 52.
    Howes, M.T., Kirkham, M., Riches, J., Cortese, K., Walser, P.J., Simpson, F., et al.: Clathrin-independent carriers form a high capacity endocytic sorting system at the leading edge of migrating cells. J. Cell Biol. 190, 675–691 (2010). Scholar
  53. 53.
    Parton, R.G., Simons, K.: The multiple faces of caveolae. Nat. Rev. Mol. Cell Biol. 185–194 (2007).
  54. 54.
    Pelkmans, L., Püntener, D., Helenius, A.: Local actin polymerization and dynamin recruitment in SV40-induced internalization of caveolae. Science (80-) 296, 535–539 (2002).
  55. 55.
    Hayer, A., Stoeber, M., Ritz, D., Engel, S., Meyer, H.H., Helenius, A.: Caveolin-1 is ubiquitinated and targeted to intralumenal vesicles in endolysosomes for degradation. J. Cell Biol. 191, 615–629 (2010). Scholar
  56. 56.
    Parton, R.G., Howes, M.T.: Revisiting caveolin trafficking: the end of the caveosome. J. Cell Biol. 439–441 (2010).
  57. 57.
    Gratton, S.E.A., Ropp, P.A., Pohlhaus, P.D., Luft, J.C., Madden, V.J., Napier, M.E., et al.: The effect of particle design on cellular internalization pathways. Proc. Natl. Acad. Sci. 105, 11613–11618 (2008). Scholar
  58. 58.
    Sandvig, K., Torgersen, M.L., Raa, H.A., Van Deurs, B.: Clathrin-independent endocytosis: from nonexisting to an extreme degree of complexity. Histochem. Cell Biol. 267–276 (2008).
  59. 59.
    Robertson, A.S., Smythe, E., Ayscough, K.R.: Functions of actin in endocytosis. Cellu. Mol. Life Sci. 2049–2065 (2009).
  60. 60.
    Rothen-Rutishauser, B., Mühlfeld, C., Blank, F., Musso, C., Gehr, P.: Translocation of particles and inflammatory responses after exposure to fine particles and nanoparticles in an epithelial airway model. Part Fibre Toxicol. 4 (2007).
  61. 61.
    Rothen-Rutishauser, B., Schurch, S., Gehr, P.: Interaction of particles with membranes. In: Donaldson, K., Borm, P. (eds.) Particle Toxicology, pp. 139–160. CRC Press, Tyler & Francis Group, Boca Raton, FL (2007)Google Scholar
  62. 62.
    Xu, S., Olenyuk, B.Z., Okamoto, C.T., Hamm-Alvarez, S.F.: Targeting receptor-mediated endocytotic pathways with nanoparticles: rationale and advances. Adv. Drug Deliv. Rev. 65, 121–138 (2013). Scholar
  63. 63.
    Low, P.S., Kularatne, S.A.: Folate-targeted therapeutic and imaging agents for cancer. Curr. Opin. Chem. Biol. 13, 256–262 (2009). Scholar
  64. 64.
    Muller, C., Schibli, R.: Prospects in folate receptor-targeted radionuclide therapy. Front Oncol. 3, 249 (2013). Scholar
  65. 65.
    Xia, W., Hilgenbrink, A.R., Matteson, E.L., Lockwood, M.B., Cheng, J.X., Low, P.S.: A functional folate receptor is induced during macrophage activation and can be used to target drugs to activated macrophages. Blood 113, 438–446 (2009). Scholar
  66. 66.
    Ross, J.F., Wang, H., Behm, F.G., Mathew, P., Wu, M., Booth, R., et al.: Folate receptor type beta is a neutrophilic lineage marker and is differentially expressed in myeloid leukemia. Cancer 85, 348–357 (1999).
  67. 67.
    Low, P.S., Henne, W.A., Doorneweerd, D.D.: Discovery and development of folic-acid-based receptor targeting for imaging and therapy of cancer and inflammatory diseases. Acc. Chem. Res. 41, 120–129 (2008). Scholar
  68. 68.
    Zhao, X., Li, H., Lee, R.J.: Targeted drug delivery via folate receptors. Expert Opin. Drug Deliv. 5, 309–319 (2008). Scholar
  69. 69.
    Werner, M.E., Karve, S., Sukumar, R., Cummings, N.D., Copp, J.A., Chen, R.C., et al.: Folate-targeted nanoparticle delivery of chemo- and radiotherapeutics for the treatment of ovarian cancer peritoneal metastasis. Biomaterials 32, 8548–8554 (2011). Scholar
  70. 70.
    Ponka, P., Lok, C.N.: The transferrin receptor: role in health and disease. Int. J. Biochem. Cell. Biol. 31, 1111–1137 (1999).
  71. 71.
    Sadat Tabatabaei Mirakabad, F., Nejati-Koshki, K., Akbarzadeh, A., Yamchi, M.R., Milani, M., Zarghami, N., et al.: PLGA-based nanoparticles as cancer drug delivery systems. Asian Pac. J. Cancer Prev. 15, 517–535 (2014)Google Scholar
  72. 72.
    Danhier, F., Feron, O., Preat, V.: To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J. Control Release 148, 135–146 (2010). Scholar
  73. 73.
    van der Meel, R., Vehmeijer, L.J., Kok, R.J., Storm, G., van Gaal, E.V.: Ligand-targeted particulate nanomedicines undergoing clinical evaluation: current status. Adv. Drug Deliv. Rev. 65, 1284–1298 (2013). Scholar
  74. 74.
    Mirghani, H., Amen, F., Moreau, F., Guigay, J., Hartl, D.M., Lacau St Guily, J.: Oropharyngeal cancers: relationship between epidermal growth factor receptor alterations and human papillomavirus status. Eur. J. Cancer 50, 1100–1111 (2014).
  75. 75.
    Holbro, T., Civenni, G., Hynes, N.E.: The ErbB receptors and their role in cancer progression. Exp. Cell Res. 284, 99–110 (2003).
  76. 76.
    Lurje, G., Lenz, H.J.: EGFR signaling and drug discovery. Oncology 77, 400–410 (2009). Scholar
  77. 77.
    Harris, R.C., Chung, E., Coffey, R.J.: EGF receptor ligands. Exp. Cell Res. 284, 2–13 (2003).
  78. 78.
    Tseng, C.L., Su, W.Y., Yen, K.C., Yang, K.C., Lin, F.H.: The use of biotinylated-EGF-modified gelatin nanoparticle carrier to enhance cisplatin accumulation in cancerous lungs via inhalation. Biomaterials 30, 3476–3485 (2009). Scholar
  79. 79.
    Rajasekaran, A.K., Anilkumar, G., Christiansen, J.J.: Is prostate-specific membrane antigen a multifunctional protein? Am. J. Physiol. Cell Physiol. 288, C975–C981 (2005). Scholar
  80. 80.
    Schulke, N., Varlamova, O.A., Donovan, G.P., Ma, D., Gardner, J.P., Morrissey, D.M., et al.: The homodimer of prostate-specific membrane antigen is a functional target for cancer therapy. Proc. Natl. Acad. Sci. U.S.A. 100, 12590–12595 (2003). Scholar
  81. 81.
    Hrkach, J., Von Hoff, D., Mukkaram Ali, M., Andrianova, E., Auer, J., Campbell, T., et al.: Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci. Trans. Med. 4, 128ra39 (2012).
  82. 82.
    Tucker, G.C.: Integrins: molecular targets in cancer therapy. Curr. Oncol. Rep. 8, 96–103 (2006).
  83. 83.
    Gottschalk, K.E., Kessler, H.: The structures of integrins and integrin-ligand complexes: implications for drug design and signal transduction. Angew. Chem. Int. Ed. Engl. 41, 3767–3774 (2002).;2-TCrossRefGoogle Scholar
  84. 84.
    Eliceiri, B.P., Cheresh, D.A.: Role of alpha v integrins during angiogenesis. Cancer J. 6(Suppl 3), S245–9 (2000).
  85. 85.
    Brooks, P.C., Stromblad, S., Sanders, L.C., von Schalscha, T.L., Aimes, R.T., Stetler-Stevenson, W.G., et al.: Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alphavbeta3. Cell 85, 683–693 (1996).
  86. 86.
    Liu, S.: Radiolabeled cyclic RGD peptides as integrin alpha(v)beta(3)-targeted radiotracers: maximizing binding affinity via bivalency. Bioconjug. Chem. 20, 2199–2213 (2009). Scholar
  87. 87.
    Auzzas, L., Zanardi, F., Battistini, L., Burreddu, P., Carta, P., Rassu, G., et al.: Targeting alphavbeta3 integrin: design and applications of mono- and multifunctional RGD-based peptides and semipeptides. Curr. Med. Chem. 17, 1255–1299 (2010).
  88. 88.
    Graf, N., Bielenberg, D.R., Kolishetti, N., Muus, C., Banyard, J., Farokhzad, O.C., et al.: alpha(V)beta(3) integrin-targeted PLGA-PEG nanoparticles for enhanced anti-tumor efficacy of a Pt(IV) prodrug. ACS Nano 6, 4530–4539 (2012). Scholar
  89. 89.
    Brambell, F.W.: The transmission of immune globulins from the mother to the foetal and newborn young. Proc. Nutr. Soc. 28, 35–41 (1969).
  90. 90.
    Pridgen, E.M., Alexis, F., Kuo, T.T., Levy-Nissenbaum, E., Karnik, R., Blumberg, R.S., et al.: Transepithelial transport of Fc-targeted nanoparticles by the neonatal fc receptor for oral delivery. Sci. Transl. Med. 5, 213ra167 (2013).
  91. 91.
    Goldberg, M., Gomez-Orellana, I.: Challenges for the oral delivery of macromolecules. Nat. Rev. Drug Discov. 2, 289–295 (2003). Scholar
  92. 92.
    Borner, M.M., Schoffski, P., de Wit, R., Caponigro, F., Comella, G., Sulkes, A., et al.: Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomised crossover trial in advanced colorectal cancer. Eur. J. Cancer 38, 349–358 (2002).
  93. 93.
    Priem, B., Tian, C., Tang, J., Zhao, Y., Mulder, W.J.: Fluorescent nanoparticles for the accurate detection of drug delivery. Expert Opin. Drug Deliv. 12, 1881–1894 (2015). Scholar
  94. 94.
    Wei, Q., Qi, H., Luo, W., Tseng, D., Ki, S.J., Wan, Z., et al.: Fluorescent imaging of single nanoparticles and viruses on a smart phone. ACS Nano 7, 9147–9155 (2013). Scholar
  95. 95.
    Jin, S., Hu, Y., Gu, Z., Liu, L., Wu, H.-C.: Application of quantum dots in biological imaging. J. Nanomater. 2011, 1–13 (2011). Scholar
  96. 96.
    He, X., Ma, N.: An overview of recent advances in quantum dots for biomedical applications. Coll. Surf. B Biointerfaces 124, 118–131 (2014). Scholar
  97. 97.
    Michalet, X., Pinaud, F.F., Bentolila, L.A., Tsay, J.M., Doose, S., Li, J.J., et al.: Quantum dots for live cells, in vivo imaging, and diagnostics. Science 307, 538–544 (2005). Scholar
  98. 98.
    Bagalkot, V., Zhang, L., Levy-Nissenbaum, E., Jon, S., Kantoff, P.W., Langery, R., et al.: Quantum dot-aptamer conjugates for synchronous cancer imaging, therapy, and sensing of drug delivery based on Bi-fluorescence resonance energy transfer. Nano Lett. 7, 3065–3070 (2007). Scholar
  99. 99.
    Fontes, A., de Lira, R.B., Seabra, M.A.B.L., da Silva, T.G., Castro Neto, A.G., Santos, B.S.: Quantum dots in biomedical research, biomedical engineering—technical applications in medicine [Internet]. In: Hudak, R. (ed.) InTech. (2012)
  100. 100.
    England, C.G., Huang, J.S., James, K.T., Zhang, G., Gobin, A., Frieboes, H.B.: Detection of phosphatidylcholine-coated gold nanoparticles in orthotopic pancreatic adenocarcinoma using hyperspectral imaging. PLoS One 10 (2015).
  101. 101.
    Guggenheim, E.J., Khan, A., Pike, J., Chang, L., Lynch, I., Rappoport JZ. Comparison of confocal and super-resolution reflectance imaging of metal oxide nanoparticles. PLoS One 11 (2016).
  102. 102.
    Repenko, T., Rix, A., Ludwanowski, S., Go, D., Kiessling, F., Lederle, W., et al.: Bio-degradable highly fluorescent conjugated polymer nanoparticles for bio-medical imaging applications. Nat. Commun. 8 (2017).
  103. 103.
    Wolfbeis, O.S.: An overview of nanoparticles commonly used in fluorescent bioimaging. Chem. Soc. Rev. 44, 4743–4768 (2015). Scholar
  104. 104.
    Chen, X., Cui, J., Sun, H., Mullner, M., Yan, Y., Noi, K.F., et al.: Analysing intracellular deformation of polymer capsules using structured illumination microscopy. Nanoscale 8, 11924–11931 (2016). Scholar
  105. 105.
    Fytianos, K., Rodriguez-Lorenzo, L., Clift, M.J.D., Blank, F., Vanhecke, D., von Garnier, C., et al.: Uptake efficiency of surface modified gold nanoparticles does not correlate with functional changes and cytokine secretion in human dendritic cells in vitro. Nanomed. Nanotechnol. Biol. Med. 11 (2015).
  106. 106.
    Lehmann, A.D., Parak, W.J., Zhang, F., Ali, Z., Röcker, C., Nienhaus, G.U., et al.: Fluorescent-magnetic hybrid nanoparticles induce a dose-dependent increase in proinflammatory response in lung cells in vitro correlated with intracellular localization. Small 6, 753–762 (2010)CrossRefGoogle Scholar
  107. 107.
    Blom, R.A.M., Amacker, M., Moser, C., van Dijk, R.M., Bonetti, R., Seydoux, E., et al.: Virosome-bound antigen enhances DC-dependent specific CD4+T cell stimulation, inducing a Th1 and Treg profile in vitro. Nanomed. Nanotechnol. Biol. Med. 13 (2017).
  108. 108.
    Seydoux, E., Rothen-Rutishauser, B., Nita, I.M., Balog, S., Gazdhar, A., Stumbles, P.A., et al.: Size-dependent accumulation of particles in lysosomes modulates dendritic cell function through impaired antigen degradation. Int. J. Nanomed. 9 (2014).
  109. 109.
    Hemmerich, P.H., von Mikecz, A.H.: Defining the subcellular interface of nanoparticles by live-cell imaging. PLoS One 8 (2013).
  110. 110.
    De Los, S.C., Chang, C.-W., Mycek, M.-A., Cardullo, R.A.: FRAP, FLIM, and FRET: detection and analysis of cellular dynamics on a molecular scale using fluorescence microscopy. Mol. Reprod. Dev. 82, 587–604 (2015). Scholar
  111. 111.
    Basuki, J.S., Duong, H.T.T., Macmillan, A., Erlich, R.B., Esser, L., Akerfeldt, M.C., et al.: Using fluorescence lifetime imaging microscopy to monitor theranostic nanoparticle uptake and intracellular doxorubicin release. ACS Nano 7, 10175–10189 (2013). Scholar
  112. 112.
    Welsher, K., Yang, H.: Multi-resolution 3D visualization of the early stages of cellular uptake of peptide-coated nanoparticles. Nat. Nanotechnol. 9, 198–203 (2014). Scholar
  113. 113.
    Van Der Zwaag, D., Vanparijs, N., Wijnands, S., De Rycke, R., De Geest, B.G., Albertazzi, L.: Super resolution imaging of nanoparticles cellular uptake and trafficking. ACS Appl. Mater. Interfaces 8, 6391–6399 (2016). Scholar
  114. 114.
    Bon, P., Bourg, N., Lécart, S., Monneret, S., Fort, E., Wenger, J., et al.: Three-dimensional nanometre localization of nanoparticles to enhance super-resolution microscopy. Nat. Commun. 6 (2015).
  115. 115.
    Peuschel, H., Ruckelshausen, T., Cavelius, C., Kraegeloh, A.: Quantification of internalized silica nanoparticles via STED microscopy. Biomed. Res. Int. 2015 (2015).
  116. 116.
    Rodriguez-Lorenzo, L., Fytianos, K., Blank, F., Von Garnier, C., Rothen-Rutishauser, B., Petri-Fink, A.: Fluorescence-encoded gold nanoparticles: library design and modulation of cellular uptake into dendritic cells. Small 10, 1341–1350 (2014). Scholar
  117. 117.
    Clift, M.J.D., Fytianos, K., Vanhecke, D., Hočevar, S., Petri-Fink, A., Rothen-Rutishauser, B.: A novel technique to determine the cell type specific response within an in vitro co-culture model via multi-colour flow cytometry. Sci. Rep. 7, 434 (2017). Scholar
  118. 118.
    Mills, N., Rnqvist, H.T., Gonzalez, M., Vink, E., Robinson, S., Soderberg, S., et al.: Ischaemic and thrombotic effects of dilute diesel exhaust inhalation in patients with coronary heart disease: mechanisms for the adverse cardiovascular effects of air pollution. Heart 93, A9–A9 (2007)Google Scholar
  119. 119.
    Clark, R.T.: Imaging flow cytometry enhances particle detection sensitivity for extracellular vesicle analysis. Nat. Methods. Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved; 12 (2015).
  120. 120.
    Vanhecke, D., Rodriguez-Lorenzo, L., Clift, M.J.D., Blank, F., Petri-Fink, A., Rothen-Rutishauser, B.: Quantification of nanoparticles at the single-cell level: an overview about state-of-the-art techniques and their limitations. Nanomedicine 9 (2014).

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Kleanthis Fytianos
    • 1
  • Fabian Blank
    • 1
    Email author
  • Loretta Müller
    • 2
    • 3
  1. 1.Respiratory Medicine, Department of BioMedical Research (DBMR)University of BernBernSwitzerland
  2. 2.University Children’s Hospital BaselBaselSwitzerland
  3. 3.Department of Pediatrics, InselspitalBern University HospitalBernSwitzerland

Personalised recommendations