Methods for Detection and Visualization of CPPs

  • Ülo LangelEmail author


There are numerous reports available on the methods of studies of internalization, mechanisms and localization of CPPs and CPP/cargo conjugates. Here, the most frequently used methods for that will be briefly summarize, some recent reviews are available on the topics (Holm et al. 2011; Uusna et al. 2015; Margus et al. 2015; Madani and Gräslund 2015; Wimley 2015; Sagan et al. 2015; Brock 2014; Gräslund and Mäler 2011; Herrera et al. 2016; Holm et al. 2006).


Methods Visualization Fluorescence HPLC Mass-spectrometry Microscopy 


  1. Abraham, P., & Maliekal, T. T. (2017). Single cell biology beyond the era of antibodies: Relevance, challenges, and promises in biomedical research. Cellular and Molecular Life Sciences, 74, 1177–1189.PubMedCrossRefPubMedCentralGoogle Scholar
  2. Adams, S., & Tsien, R. (2006). Imaging the influx of cell-penetrating peptides into the cytosol of individual cells. In Ü. Langel (Ed.), Handbook of cell-penetrating peptides (2nd ed., pp. 505–512). Boca Raton, London, New York: CRC Press/Taylor & Francis.CrossRefGoogle Scholar
  3. Adams, S. R., & Tsien, R. Y. (2008). Preparation of the membrane-permeant biarsenicals FlAsH-EDT2 and ReAsH-EDT2 for fluorescent labeling of tetracysteine-tagged proteins. Nature Protocols, 3, 1527–1534.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Arukuusk, P., Pärnaste, L., Margus, H., Eriksson, N. K., Vasconcelos, L., Padari, K., et al. (2013a). Differential endosomal pathways for radically modified peptide vectors. Bioconjugate Chemistry, 24, 1721–1732.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Arukuusk, P., Pärnaste, L., Oskolkov, N., Copolovici, D. M., Margus, H., Padari, K., et al. (2013b). New generation of efficient peptide-based vectors, NickFects, for the delivery of nucleic acids. Biochimica et Biophysica Acta, 1828, 1365–1373.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Aubry, S., Burlina, F., Dupont, E., Delaroche, D., Joliot, A., Lavielle, S., et al. (2009). Cell-surface thiols affect cell entry of disulfide-conjugated peptides. The FASEB Journal, 23, 2956–2967.PubMedCrossRefPubMedCentralGoogle Scholar
  7. Aussedat, B., Sagan, S., Chassaing, G., Bolbach, G., & Burlina, F. (2006). Quantification of the efficiency of cargo delivery by peptidic and pseudo-peptidic Trojan carriers using MALDI-TOF mass spectrometry. Biochimica et Biophysica Acta, 1758, 375–383.PubMedCrossRefPubMedCentralGoogle Scholar
  8. Balayssac, S., Burlina, F., Convert, O., Bolbach, G., Chassaing, G., & Lequin, O. (2006). Comparison of penetratin and other homeodomain-derived cell-penetrating peptides: Interaction in a membrane-mimicking environment and cellular uptake efficiency. Biochemistry, 45, 1408–1420.PubMedCrossRefPubMedCentralGoogle Scholar
  9. Barnett, E. M., Zhang, X., Maxwell, D., Chang, Q., & Piwnica-Worms, D. (2009). Single-cell imaging of retinal ganglion cell apoptosis with a cell-penetrating, activatable peptide probe in an in vivo glaucoma model. Proceedings of the National Academy of Sciences of the U S A, 106, 9391–9396.CrossRefGoogle Scholar
  10. Basak, S., & Chattopadhyay, K. (2014). Studies of protein folding and dynamics using single molecule fluorescence spectroscopy. Physical Chemistry Chemical Physics: PCCP, 16, 11139–11149.PubMedCrossRefPubMedCentralGoogle Scholar
  11. Bechara, C., Pallerla, M., Zaltsman, Y., Burlina, F., Alves, I. D., Lequin, O., et al. (2013). Tryptophan within basic peptide sequences triggers glycosaminoglycan-dependent endocytosis. The FASEB Journal, 27, 738–749.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Bi, X., Wang, C., Dong, W., Zhu, W., & Shang, D. (2014). Antimicrobial properties and interaction of two Trp-substituted cationic antimicrobial peptides with a lipid bilayer. The Journal of Antibiotics (Tokyo), 67, 361–368.CrossRefGoogle Scholar
  13. Biswas, S., Dodwadkar, N. S., Deshpande, P. P., Parab, S., & Torchilin, V. P. (2013). Surface functionalization of doxorubicin-loaded liposomes with octa-arginine for enhanced anticancer activity. European Journal of Pharmaceutics and Biopharmaceutics, 84, 517–525.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Bonner, W., Hulett, H., Sweet, R., & Herzenberg, L. (1972). Fluorescence Activated Cell Sorting. Review of Scientific Instruments, 43, 404–409.PubMedCrossRefPubMedCentralGoogle Scholar
  15. Brock, R. (2014). The uptake of arginine-rich cell-penetrating peptides: Putting the puzzle together. Bioconjugate Chemistry, 25, 863–868.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Bu, X., Zhu, T., Ma, Y., & Shen, Q. (2015). Co-administration with cell penetrating peptide enhances the oral bioavailability of docetaxel-loaded nanoparticles. Drug Development and Industrial Pharmacy, 41, 764–771.PubMedCrossRefPubMedCentralGoogle Scholar
  17. Burlina, F., Sagan, S., Bolbach, G., & Chassaing, G. (2005). Quantification of the cellular uptake of cell-penetrating peptides by MALDI-TOF mass spectrometry. Angewandte Chemie (International ed. in English), 44, 4244–4247.CrossRefGoogle Scholar
  18. Burlina, F., Sagan, S., Bolbach, G., & Chassaing, G. (2006). A direct approach to quantification of the cellular uptake of cell-penetrating peptides using MALDI-TOF mass spectrometry. Nature Protocols, 1, 200–205.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Busetto, S., Trevisan, E., Patriarca, P., & Menegazzi, R. (2004). A single-step, sensitive flow cytofluorometric assay for the simultaneous assessment of membrane-bound and ingested Candida albicans in phagocytosing neutrophils. Cytometry A, 58, 201–206.PubMedCrossRefPubMedCentralGoogle Scholar
  20. Cardo, L., Thomas, S. G., Mazharian, A., Pikramenou, Z., Rappoport, J. Z., Hannon, M. J., et al. (2015). Accessible synthetic probes for staining actin inside platelets and megakaryocytes by employing lifeact peptide. ChemBioChem, 16, 1680–1688.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Cardoso, A. M., Trabulo, S., Cardoso, A. L., Lorents, A., Morais, C. M., Gomes, P., et al. (2012). S4(13)-PV cell-penetrating peptide induces physical and morphological changes in membrane-mimetic lipid systems and cell membranes: Implications for cell internalization. Biochimica et Biophysica Acta, 1818, 877–888.PubMedCrossRefPubMedCentralGoogle Scholar
  22. Cerrato, C. P., Lehto, T., & Langel, Ü. (2014). Peptide-based vectors: Recent developments. Biomol Concepts, 5, 479–488.PubMedCrossRefPubMedCentralGoogle Scholar
  23. Cheung, J. C., Kim Chiaw, P., Deber, C. M., & Bear, C. E. (2009). A novel method for monitoring the cytosolic delivery of peptide cargo. Journal of Controlled Release, 137, 2–7.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Child, H. W., del Pino, P. A., de la Fuente, J. M., Hursthouse, A. S., Stirling, D., Mullen, M., et al. (2011). Working together: The combined application of a magnetic field and penetratin for the delivery of magnetic nanoparticles to cells in 3D. ACS Nano, 5, 7910–7919.PubMedCrossRefPubMedCentralGoogle Scholar
  25. Chiu, J. Z., Tucker, I. G., & McDowell, A. (2016). Quantification of Cell-Penetrating Peptide Associated with Polymeric Nanoparticles Using Isobaric-Tagging and MALDI-TOF MS/MS. Journal of the American Society for Mass Spectrometry, 27, 1891–1894.PubMedCrossRefPubMedCentralGoogle Scholar
  26. Chiu, J. Z., Tucker, I. G., McLeod, B. J., & McDowell, A. (2015). Arginine-tagging of polymeric nanoparticles via histidine to improve cellular uptake. European Journal of Pharmaceutics and Biopharmaceutics, 89, 48–55.PubMedCrossRefPubMedCentralGoogle Scholar
  27. Chlanda, P., & Krijnse Locker, J. (2017). The sleeping beauty kissed awake: New methods in electron microscopy to study cellular membranes. Biochemical Journal, 474, 1041–1053.PubMedCrossRefPubMedCentralGoogle Scholar
  28. Console, S., Marty, C., Garcia-Echeverria, C., Schwendener, R., & Ballmer-Hofer, K. (2003). Antennapedia and HIV transactivator of transcription (TAT) “protein transduction domains” promote endocytosis of high molecular weight cargo upon binding to cell surface glycosaminoglycans. Journal of Biological Chemistry, 278, 35109–35114.PubMedCrossRefPubMedCentralGoogle Scholar
  29. Copolovici, D. M., Langel, K., Eriste, E., & Langel, Ü. (2014). Cell-penetrating peptides: Design, synthesis, and applications. ACS Nano, 8, 1972–1994.PubMedCrossRefPubMedCentralGoogle Scholar
  30. Delaroche, D., Aussedat, B., Aubry, S., Chassaing, G., Burlina, F., Clodic, G., et al. (2007). Tracking a new cell-penetrating (W/R) nonapeptide, through an enzyme-stable mass spectrometry reporter tag. Analytical Chemistry, 79, 1932–1938.PubMedCrossRefPubMedCentralGoogle Scholar
  31. Ding, C., Wu, K., Wang, W., Guan, Z., Wang, L., Wang, X., et al. (2017). Synthesis of a cell penetrating peptide modified superparamagnetic iron oxide and MRI detection of bladder cancer. Oncotarget, 8, 4718–4729.PubMedGoogle Scholar
  32. Dixon, J. E., Osman, G., Morris, G. E., Markides, H., Rotherham, M., Bayoussef, Z., et al. (2016). Highly efficient delivery of functional cargoes by the synergistic effect of GAG binding motifs and cell-penetrating peptides. Proceedings of the National Academy of Sciences of the U S A, 113, 5.CrossRefGoogle Scholar
  33. Dowaidar, M., Abdelhamid, H. N., Hallbrink, M., Freimann, K., Kurrikoff, K., Zou, X., et al. (2017a). Magnetic nanoparticle assisted self-assembly of cell penetrating peptides-oligonucleotides complexes for gene delivery. Scientific Reports, 7, 9159.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Dowaidar, M., Abdelhamid, H., Hällbrink, M., Zou, X. & Langel, Ü. (2017b). Graphene oxide mediated cell penetrating peptides for oligonucleotides delivery. manuscript.Google Scholar
  35. Drin, G., Cottin, S., Blanc, E., Rees, A. R., & Temsamani, J. (2003). Studies on the internalization mechanism of cationic cell-penetrating peptides. Journal of Biological Chemistry, 278, 31192–31201.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Dupont, E., Prochiantz, A., & Joliot, A. (2007). Identification of a signal peptide for unconventional secretion. Journal of Biological Chemistry, 282, 8994–9000.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Ehrenberg, M., Cronvall, E., & Rigler, R. (1971). Fluorescence of proteins interacting with nucleic acids. Correction for light absorption. FEBS Letters, 18, 199–203.PubMedCrossRefPubMedCentralGoogle Scholar
  38. El Chamy Maluf, S., Dal Mas, C., Oliveira, E. B., Melo, P. M., Carmona, A. K., Gazarini, M. L., et al. (2016). Inhibition of malaria parasite Plasmodium falciparum development by crotamine, a cell penetrating peptide from the snake venom. Peptides, 78, 11–16.PubMedPubMedCentralCrossRefGoogle Scholar
  39. El-Andaloussi, S., Järver, P., Johansson, H. J., & Langel, Ü. (2007). Cargo-dependent cytotoxicity and delivery efficacy of cell-penetrating peptides: A comparative study. Biochemical Journal, 407, 285–292.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Elmlund, D., Le, S. N., & Elmlund, H. (2017). High-resolution cryo-EM: The nuts and bolts. Current Opinion in Structural Biology, 46, 1–6.PubMedCrossRefPubMedCentralGoogle Scholar
  41. Elmquist, A., & Langel, Ü. (2003). In vitro uptake and stability study of pVEC and its all-D analog. Biological Chemistry, 384, 387–393.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Ezzat, K., Helmfors, H., Tudoran, O., Juks, C., Lindberg, S., Padari, K., et al. (2012). Scavenger receptor-mediated uptake of cell-penetrating peptide nanocomplexes with oligonucleotides. The FASEB Journal, 26, 1172–1180.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Fernandes, R., Smyth, N. R., Muskens, O. L., Nitti, S., Heuer-Jungemann, A., Ardern-Jones, M. R., et al. (2015). Interactions of skin with gold nanoparticles of different surface charge, shape, and functionality. Small (Weinheim an der Bergstrasse, Germany), 11, 713–721.CrossRefGoogle Scholar
  44. Fernandez-Carneado, J., Kogan, M. J., van Mau, N., Pujals, S., Lopez-Iglesias, C., Heitz, F., et al. (2005). Fatty acyl moieties: Improving Pro-rich peptide uptake inside HeLa cells. Journal of Peptide Research, 65, 580–590.PubMedCrossRefPubMedCentralGoogle Scholar
  45. Fischer, R., Kohler, K., Fotin-Mleczek, M., & Brock, R. (2004). A stepwise dissection of the intracellular fate of cationic cell-penetrating peptides. Journal of Biological Chemistry, 279, 12625–12635.PubMedCrossRefPubMedCentralGoogle Scholar
  46. Fischer, R., Waizenegger, T., Kohler, K., & Brock, R. (2002). A quantitative validation of fluorophore-labelled cell-permeable peptide conjugates: Fluorophore and cargo dependence of import. Biochimica et Biophysica Acta, 31, 365–374.CrossRefGoogle Scholar
  47. Fleissner, F., Putz, S., Schwendy, M., Bonn, M., & Parekh, S. H. (2017). Measuring Intracellular Secondary Structure of a Cell-Penetrating Peptide in Situ. Analytical Chemistry, 89, 11310–11317.PubMedCrossRefPubMedCentralGoogle Scholar
  48. Floren, A., Mäger, I., & Langel, Ü. (2011). Uptake kinetics of cell-penetrating peptides. Methods in Molecular Biology, 683, 117–128.PubMedCrossRefPubMedCentralGoogle Scholar
  49. Freimann, K., Arukuusk, K., Kurrikoff, K., Vasconselos, L. D. F., Veiman, K.-L., Uusna, et al. (2016). Optimization of in vivo pDNA gene delivery with NickFect peptide vectors. Journal of Controlled Release, 241, 135–143.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Freire, J. M., Veiga, A. S., Rego De Figueiredo, I., De La Torre, B. G., Santos, N. C., Andreu, D., et al. (2014). Nucleic acid delivery by cell penetrating peptides derived from dengue virus capsid protein: Design and mechanism of action. FEBS Journal, 281, 191–215.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Fuchs, S. M., & Raines, R. T. (2004). Pathway for polyarginine entry into mammalian cells. Biochemistry, 43, 2438–2444.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Gehne, S., Sydow, K., Dathe, M., & Kumke, M. U. (2013). Characterization of cell-penetrating lipopeptide micelles by spectroscopic methods. The Journal of Physical Chemistry B, 117, 14215–14225.PubMedCrossRefPubMedCentralGoogle Scholar
  53. Gemmill, K. B., Muttenthaler, M., Delehanty, J. B., Stewart, M. H., Susumu, K., Dawson, P. E., et al. (2013). Evaluation of diverse peptidyl motifs for cellular delivery of semiconductor quantum dots. Analytical and Bioanalytical Chemistry, 405, 6145–6154.PubMedCrossRefPubMedCentralGoogle Scholar
  54. Ghisaidoobe, A. B., & Chung, S. J. (2014). Intrinsic tryptophan fluorescence in the detection and analysis of proteins: A focus on Forster resonance energy transfer techniques. International Journal of Molecular Sciences, 15, 22518–22538.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Giepmans, B. N., Adams, S. R., Ellisman, M. H., & Tsien, R. Y. (2006). The fluorescent toolbox for assessing protein location and function. Science, 312, 217–224.PubMedCrossRefPubMedCentralGoogle Scholar
  56. Gräslund, A., & Mäler, L. (2011). Testing membrane interactions of CPPs. Methods in Molecular Biology, 683, 33–40.PubMedCrossRefPubMedCentralGoogle Scholar
  57. Gupta, A., Mandal, D., Ahmadibeni, Y., Parang, K., & Bothun, G. (2011). Hydrophobicity drives the cellular uptake of short cationic peptide ligands. European Biophysics Journal, 40, 727–736.PubMedCrossRefPubMedCentralGoogle Scholar
  58. Hällbrink, M., Floren, A., Elmquist, A., Pooga, M., Bartfai, T., & Langel, Ü. (2001). Cargo delivery kinetics of cell-penetrating peptides. Biochimica et Biophysica Acta, 1515, 101–109.CrossRefGoogle Scholar
  59. Hassane, F. S., Abes, R., el Andaloussi, S., Lehto, T., Sillard, R., Langel, Ü., et al. (2011). Insights into the cellular trafficking of splice redirecting oligonucleotides complexed with chemically modified cell-penetrating peptides. Journal of Controlled Release, 153, 163–172.PubMedCrossRefPubMedCentralGoogle Scholar
  60. Hauff, S. J., Raju, S. C., Orosco, R. K., Gross, A. M., Diaz-Perez, J. A., Savariar, E., et al. (2014). Matrix-metalloproteinases in head and neck carcinoma-cancer genome atlas analysis and fluorescence imaging in mice. Otolaryngology—Head and Neck Surgery, 151, 612–618.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Henriques, S. T., & Castanho, M. A. (2004). Consequences of nonlytic membrane perturbation to the translocation of the cell penetrating peptide pep-1 in lipidic vesicles. Biochemistry, 43, 9716–9724.PubMedCrossRefPubMedCentralGoogle Scholar
  62. Henriques, S. T., Melo, M. N., & Castanho, M. A. (2007). How to address CPP and AMP translocation? Methods to detect and quantify peptide internalization in vitro and in vivo (Review). Molecular Membrane Biology, 24, 173–184.PubMedCrossRefPubMedCentralGoogle Scholar
  63. Herbig, M. E., Fromm, U., Leuenberger, J., Krauss, U., Beck-Sickinger, A. G., & Merkle, H. P. (2005). Bilayer interaction and localization of cell penetrating peptides with model membranes: A comparative study of a human calcitonin (hCT)-derived peptide with pVEC and pAntp(43-58). Biochimica et Biophysica Acta, 1712, 197–211.CrossRefGoogle Scholar
  64. Herbig, M. E., Weller, K. M., & Merkle, H. P. (2007). Reviewing biophysical and cell biological methodologies in cell-penetrating peptide (CPP) research. Critical Reviews in Therapeutic Drug Carrier Systems, 24, 203–255.PubMedCrossRefPubMedCentralGoogle Scholar
  65. Herrera, A. I., Tomich, J. M., & Prakash, O. (2016). Membrane Interacting Peptides: A Review. Current Protein and Peptide Science, 17, 827–841.PubMedCrossRefPubMedCentralGoogle Scholar
  66. Hilinski, G. J., Kim, Y. W., Hong, J., Kutchukian, P. S., Crenshaw, C. M., Berkovitch, S. S., et al. (2014). Stitched alpha-helical peptides via bis ring-closing metathesis. Journal of the American Chemical Society, 136, 12314–12322.PubMedCrossRefPubMedCentralGoogle Scholar
  67. Holm, T., el Andaloussi, S., & Langel, Ü. (2011). Comparison of CPP uptake methods. Methods in Molecular Biology, 683, 207–217.PubMedPubMedCentralCrossRefGoogle Scholar
  68. Holm, T., Johansson, H., Lundberg, P., Pooga, M., Lindgren, M., & Langel, Ü. (2006). Studying the uptake of cell-penetrating peptides. Nature Protocols, 1, 1001–1005.PubMedCrossRefPubMedCentralGoogle Scholar
  69. Hortolà, P. (2005). SEM examination of human erythrocytes in uncoated bloodstains on stone: Use of conventional as environmental-like SEM in a soft biological tissue (and hard inorganic material). Journal of Microscopy, 218, 94–103.PubMedCrossRefPubMedCentralGoogle Scholar
  70. Hu, Q., Gao, X., Gu, G., Kang, T., Tu, Y., Liu, Z., et al. (2013). Glioma therapy using tumor homing and penetrating peptide-functionalized PEG-PLA nanoparticles loaded with paclitaxel. Biomaterials, 34, 5640–5650.PubMedCrossRefPubMedCentralGoogle Scholar
  71. Illien, F., Rodriguez, N., Amoura, M., Joliot, A., Pallerla, M., Cribier, S., et al. (2016). Quantitative fluorescence spectroscopy and flow cytometry analyses of cell-penetrating peptides internalization pathways: Optimization, pitfalls, comparison with mass spectrometry quantification. Scientific Reports, 6, Doi: 10.1038.Google Scholar
  72. Jing, X., Foged, C., Martin-Bertelsen, B., Yaghmur, A., Knapp, K. M., Malmsten, M., et al. (2016). Delivery of siRNA complexed with palmitoylated alpha-peptide/beta-peptoid cell-penetrating peptidomimetics: Membrane interaction and structural characterization of a lipid-based nanocarrier system. Molecular Pharmaceutics, 13, 1739–1749.PubMedCrossRefPubMedCentralGoogle Scholar
  73. Jones, S. W., Christison, R., Bundell, K., Voyce, C. J., Brockbank, S. M., Newham, P., et al. (2005). Characterisation of cell-penetrating peptide-mediated peptide delivery. British Journal of Pharmacology, 145, 1093–1102.PubMedPubMedCentralCrossRefGoogle Scholar
  74. Kadkhodayan, S., Sadat, S. M., Irani, S., Fotouhi, F., & Bolhassani, A. (2016). Generation of GFP native protein for detection of its intracellular uptake by cell-penetrating peptides. Folia Biologica, 62, 103–109.Google Scholar
  75. Klein, T., Buhr, E. & Georg Frase, C. (2012). Chapter 6—TSEM: A review of scanning electron microscopy in transmission mode and its applications. In: Peter, W. H. (Ed.) Advances in imaging and electron physics. Elsevier.Google Scholar
  76. Kochurani, K. J., Suganya, A. A., Nair, M. G., Louis, J. M., Majumder, A., Kumar, S. K., et al. (2015). Live detection and purification of cells based on the expression of a histone chaperone, HIRA, using a binding peptide. Scientific Reports, 5.Google Scholar
  77. Koren, E., Apte, A., Sawant, R. R., Grunwald, J., & Torchilin, V. P. (2011). Cell-penetrating TAT peptide in drug delivery systems: Proteolytic stability requirements. Drug Delivery, 18, 377–384.PubMedPubMedCentralCrossRefGoogle Scholar
  78. Krpetic, Z., Saleemi, S., Prior, I. A., See, V., Qureshi, R., & Brust, M. (2011). Negotiation of intracellular membrane barriers by TAT-modified gold nanoparticles. ACS Nano, 5, 5195–5201.PubMedCrossRefPubMedCentralGoogle Scholar
  79. Lakowicz, J. R. (2006). Principles of fluorescence spectroscopy. New York: Springer.CrossRefGoogle Scholar
  80. Larochelle, J. R., Cobb, G. B., Steinauer, A., Rhoades, E., & Schepartz, A. (2015). Fluorescence correlation spectroscopy reveals highly efficient cytosolic delivery of certain penta-arg proteins and stapled peptides. Journal of the American Chemical Society, 137, 2536–2541.PubMedPubMedCentralCrossRefGoogle Scholar
  81. Liu, M., Guo, Y. M., Wang, P., Guo, X. J., Yang, J. L., Wang, S. C., et al. (2007). Characteristics and in vitro imaging study of matrix metalloproteinase-2 targeting activable cell-penetrating peptide. Zhonghua Yi Xue Za Zhi, 87, 233–239.PubMedPubMedCentralGoogle Scholar
  82. Liu, B. R., Lo, S. Y., Liu, C. C., Chyan, C. L., Huang, Y. W., Aronstam, R. S., et al. (2013a). Endocytic trafficking of nanoparticles delivered by cell-penetrating peptides comprised of nona-arginine and a penetration accelerating sequence. PLoS ONE, 8, e67100.PubMedPubMedCentralCrossRefGoogle Scholar
  83. Liu, Y., Xia, X., Xu, L., & Wang, Y. (2013b). Design of hybrid beta-hairpin peptides with enhanced cell specificity and potent anti-inflammatory activity. Biomaterials, 34, 237–250.PubMedPubMedCentralCrossRefGoogle Scholar
  84. Liu, L., Zhang, H., Song, D., & Wang, Z. (2018). An upconversion nanoparticle-based fluorescence resonance energy transfer system for effectively sensing caspase-3 activity. Analyst, 143, 761–767.PubMedCrossRefPubMedCentralGoogle Scholar
  85. Lundberg, M., & Johansson, M. (2001). Is VP22 nuclear homing an artifact? Nature Biotechnology, 19, 713–714.PubMedCrossRefPubMedCentralGoogle Scholar
  86. Lundberg, M., & Johansson, M. (2002). Positively Charged DNA-Binding Proteins Cause Apparent Cell Membrane Translocation. Biochemical and Biophysical Research Communications, 291, 367–371.PubMedPubMedCentralCrossRefGoogle Scholar
  87. Lundin, P., Johansson, H., Guterstam, P., Holm, T., Hansen, M., Langel, Ü., et al. (2008). Distinct uptake routes of cell-penetrating peptide conjugates. Bioconjugate Chemistry, 19, 2535–2542.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Madani, F., & Gräslund, A. (2015). Investigating membrane interactions and structures of CPPs. Methods in Molecular Biology, 1324, 73–87.PubMedPubMedCentralCrossRefGoogle Scholar
  89. Mäe, M., Myrberg, H., Jiang, Y., Paves, H., Valkna, A., & Langel, Ü. (2005). Internalisation of cell-penetrating peptides into tobacco protoplasts. Biochimica et Biophysica Acta, 1669, 101–107.PubMedCrossRefPubMedCentralGoogle Scholar
  90. Magde, D., Elson, E. L., & Webb, W. W. (1974). Fluorescence correlation spectroscopy. II. An Experimental Realization. Biopolymers, 13, 29–61.PubMedPubMedCentralGoogle Scholar
  91. Mäger, I., Eiriksdottir, E., Langel, K., el Andaloussi, S., & Langel, Ü. (2010). Assessing the uptake kinetics and internalization mechanisms of cell-penetrating peptides using a quenched fluorescence assay. Biochimica et Biophysica Acta, 1798, 338–343.PubMedPubMedCentralCrossRefGoogle Scholar
  92. Magzoub, M., Eriksson, L. E., & Graslund, A. (2003). Comparison of the interaction, positioning, structure induction and membrane perturbation of cell-penetrating peptides and non-translocating variants with phospholipid vesicles. Biophysical Chemistry, 103, 271–288.CrossRefGoogle Scholar
  93. Magzoub, M., Oglecka, K., Pramanik, A., Eriksson, G., & Gräslund, A. (2005). Membrane perturbation effects of peptides derived from the N-termini of unprocessed prion proteins. Biochimica et Biophysica Acta, 1716, 126–136.PubMedPubMedCentralCrossRefGoogle Scholar
  94. Malatesta, M. (2016). Transmission electron microscopy for nanomedicine: Novel applications for long-established techniques. European Journal of Histochemistry, 60.Google Scholar
  95. Mano, M., Teodosio, C., Paiva, A., Simoes, S., & Pedroso DE Lima, M. C. (2005). On the mechanisms of the internalization of S4(13)-PV cell-penetrating peptide. Biochemical Journal, 390, 603–612.PubMedPubMedCentralCrossRefGoogle Scholar
  96. Margus, H., Arukuusk, P., Langel, U., & Pooga, M. (2016). Characteristics of cell-penetrating peptide/nucleic acid nanoparticles. Molecular Pharmaceutics, 13, 172–179.CrossRefGoogle Scholar
  97. Margus, H., Juks, C., & Pooga, M. (2015). Unraveling the mechanisms of peptide-mediated delivery of nucleic acids using electron microscopy. Methods in Molecular Biology, 1324, 149–162.PubMedCrossRefPubMedCentralGoogle Scholar
  98. Margus, H., Padari, K., & Pooga, M. (2013). Insights into cell entry and intracellular trafficking of peptide and protein drugs provided by electron microscopy. Advanced Drug Delivery Reviews, 65, 1031–1038.PubMedCrossRefPubMedCentralGoogle Scholar
  99. Marinova, Z., Vukojevic, V., Surcheva, S., Yakovleva, T., Cebers, G., Pasikova, N., et al. (2005). Translocation of dynorphin neuropeptides across the plasma membrane. A putative mechanism of signal transmission. Journal of Biological Chemistry, 280, 26360–26370.CrossRefGoogle Scholar
  100. Maxwell, D., Chang, Q., Zhang, X., Barnett, E. M., & Piwnica-Worms, D. (2009). An improved cell-penetrating, caspase-activatable, near-infrared fluorescent peptide for apoptosis imaging. Bioconjugate Chemistry, 20, 702–709.PubMedPubMedCentralCrossRefGoogle Scholar
  101. Medina, D. X., Householder, K. T., Ceton, R., Kovalik, T., Heffernan, J. M., Shankar, R. V., et al. (2017). Optical barcoding of PLGA for multispectral analysis of nanoparticle fate in vivo. Journal of Controlled Release, 2, 30091–30093.Google Scholar
  102. Mendez Ardoy, A., Lostale-Seijo, I. & Montenegro, J. (2018). Where in the cell is our cargo? Current methods to study intracellular cytosolic localization. Chembiochem.Google Scholar
  103. Miao, J., Guo, H., Chen, F., Zhao, L., He, L., Ou, Y., et al. (2016). Antibacterial effects of a cell-penetrating peptide isolated from kefir. Journal of Agriculture and Food Chemistry, 22, 22.Google Scholar
  104. Moller, L. H., Gabel-Jensen, C., Franzyk, H., Bahnsen, J. S., Sturup, S., & Gammelgaard, B. (2014). Quantification of pharmaceutical peptides using selenium as an elemental detection label. Metallomics, 6, 1639–1647.PubMedCrossRefPubMedCentralGoogle Scholar
  105. Mueller, J., Kretzschmar, I., Volkmer, R., & Boisguerin, P. (2008). Comparison of cellular uptake using 22 CPPs in 4 different cell lines. Bioconjugate Chemistry, 19, 2363–2374.PubMedCrossRefPubMedCentralGoogle Scholar
  106. Mukherjee, D., Kundu, N., Chakravarty, L., Behera, B., Chakrabarti, P., Sarkar, N. & Maiti, T. K. (2017). Membrane perturbation through novel cell-penetrating peptides influences intracellular accumulation of imatinib mesylate in CML cells. Cell biology and toxicology.Google Scholar
  107. Nativo, P., Prior, I. A., & Brust, M. (2008). Uptake and intracellular fate of surface-modified gold nanoparticles. ACS Nano, 2, 1639–1644.PubMedCrossRefPubMedCentralGoogle Scholar
  108. Negi, S., Terada, Y., Suzuyama, M., Matsumoto, H., Honbo, A., Amagase, Y., et al. (2015). Intrinsic cell permeability of the GAGA zinc finger protein into HeLa cells. Biochemical and Biophysical Research Communications, 464, 1034–1039.PubMedCrossRefPubMedCentralGoogle Scholar
  109. O’brien, H, C. & Mckinley, G. M. (1943). New microtome and sectioning method for electron microscopy. Science, 98, 455–456.Google Scholar
  110. Oehlke, J., Scheller, A., Wiesner, B., Krause, E., Beyermann, M., Klauschenz, E., et al. (1998). Cellular uptake of an alpha-helical amphipathic model peptide with the potential to deliver polar compounds into the cell interior non-endocytically. Biochimica et Biophysica Acta, 1414, 127–139.PubMedPubMedCentralCrossRefGoogle Scholar
  111. Orosco, R. K., Savariar, E. N., Weissbrod, P. A., Diaz-Perez, J. A., Bouvet, M., Tsien, R. Y., et al. (2016). Molecular targeting of papillary thyroid carcinoma with fluorescently labeled ratiometric activatable cell penetrating peptides in a transgenic murine model. Journal of Surgical Oncology, 113, 138–143.PubMedPubMedCentralCrossRefGoogle Scholar
  112. Oskolkov, N., Arukuusk, P., Copolovici, D. M., Lindberg, S., Margus, H., Padari, K., et al. (2011). NickFects, Phosphorylated Derivatives of Transportan 10 for Cellular Delivery of Oligonucleotides. International Journal of Peptide Research and Therapeutics, 17, 147–157.CrossRefGoogle Scholar
  113. Padari, K., Säälik, P., Hansen, M., Koppel, K., Raid, R., Langel, Ü., et al. (2005). Cell transduction pathways of transportans. Bioconjugate Chemistry, 16, 1399–1410.PubMedCrossRefGoogle Scholar
  114. Paddock, S. W. (2000). Principles and practices of laser scanning confocal microscopy. Molecular Biotechnology, 16, 127–149.PubMedCrossRefPubMedCentralGoogle Scholar
  115. Palm, C., Jayamanne, M., Kjellander, M., & Hallbrink, M. (2007). Peptide degradation is a critical determinant for cell-penetrating peptide uptake. Biochimica et Biophysica Acta, 1768, 1769–1776.PubMedPubMedCentralCrossRefGoogle Scholar
  116. Palm-Apergi, C., Lorents, A., Padari, K., Pooga, M., & Hällbrink, M. (2009). The membrane repair response masks membrane disturbances caused by cell-penetrating peptide uptake. The FASEB Journal, 23, 214–223.PubMedPubMedCentralCrossRefGoogle Scholar
  117. Pärnaste, L., Arukuusk, P., Zagato, E., Braeckmans, K., & Langel, Ü. (2016). Methods to follow intracellular trafficking of cell-penetrating peptides. Journal of Drug Targeting, 24, 508–519.PubMedPubMedCentralCrossRefGoogle Scholar
  118. Peraro, L., Deprey, K. L., Moser, M. K., Zou, Z., Ball, H. L., Levine, B. & Kritzer, J. A. (2018). Cell penetration profiling using the chloroalkane penetration assay. Journal of the American Chemical Society.Google Scholar
  119. Pilo, A. L., Bu, J., & McLuckey, S. A. (2016). Gas-phase oxidation of neutral basic residues in polypeptide cations by periodate. Journal of the American Society for Mass Spectrometry, 27, 1979–1988.PubMedPubMedCentralCrossRefGoogle Scholar
  120. Pitard, B., Oudrhiri, N., Vigneron, J. P., Hauchecorne, M., Aguerre, O., Toury, R., et al. (1999). Structural characteristics of supramolecular assemblies formed by guanidinium-cholesterol reagents for gene transfection. Proceedings of the National Academy of Sciences of the United States of America, 96, 2621–2626.PubMedPubMedCentralCrossRefGoogle Scholar
  121. Pooga, M., Hällbrink, M., Zorko, M., & Langel, Ü. (1998). Cell penetration by transportan. FASEB Journal, 12, 67–77.PubMedPubMedCentralCrossRefGoogle Scholar
  122. Pujals, S., Bastus, N. G., Pereiro, E., Lopez-Iglesias, C., Puntes, V. F., Kogan, M. J., et al. (2009). Shuttling gold nanoparticles into tumoral cells with an amphipathic proline-rich peptide. ChemBioChem, 10, 1025–1031.PubMedCrossRefPubMedCentralGoogle Scholar
  123. Pujals, S., Fernandez-Carneado, J., Lopez-Iglesias, C., Kogan, M. J., & Giralt, E. (2006). Mechanistic aspects of CPP-mediated intracellular drug delivery: Relevance of CPP self-assembly. Biochimica et Biophysica Acta, 1758, 264–279.PubMedCrossRefPubMedCentralGoogle Scholar
  124. Pushpanathan, M., Gunasekaran, P. & Rajendhran, J. (2013). Mechanisms of the antifungal action of marine metagenome-derived peptide, MMGP1, against Candida albicans. PLoS One, 8.Google Scholar
  125. Rakowska, P. D., Lamarre, B., & Ryadnov, M. G. (2014). Probing label-free intracellular quantification of free peptide by MALDI-ToF mass spectrometry. Methods, 68, 331–337.PubMedCrossRefPubMedCentralGoogle Scholar
  126. Rennert, R., Wespe, C., Beck-Sickinger, A. G., & Neundorf, I. (2006). Developing novel hCT derived cell-penetrating peptides with improved metabolic stability. Biochimica et Biophysica Acta, 1758, 347–354.PubMedCrossRefPubMedCentralGoogle Scholar
  127. Rezgui, R., Blumer, K., Yeoh-Tan, G., Trexler, A. J., & Magzoub, M. (2016). Precise quantification of cellular uptake of cell-penetrating peptides using fluorescence-activated cell sorting and fluorescence correlation spectroscopy. Biochimica et Biophysica Acta, 1858, 1499–1506.PubMedCrossRefPubMedCentralGoogle Scholar
  128. Richard, J. P., Melikov, K., Vives, E., Ramos, C., Verbeure, B., Gait, M. J., et al. (2003). Cell-penetrating peptides. A reevaluation of the mechanism of cellular uptake. Journal of Biological Chemistry, 278, 585–590.CrossRefGoogle Scholar
  129. Rigler, R., & Ehrenberg, M. (1973). Molecular interactions and structure as analysed by fluorescence relaxation spectroscopy. Quarterly Reviews of Biophysics, 6, 139–199.PubMedCrossRefPubMedCentralGoogle Scholar
  130. Rodrigues, M., Santos, A., de la Torre, B. G., Radis-Baptista, G., Andreu, D., & Santos, N. C. (2012). Molecular characterization of the interaction of crotamine-derived nucleolar targeting peptides with lipid membranes. Biochimica et Biophysica Acta, 1818, 2707–2717.PubMedPubMedCentralCrossRefGoogle Scholar
  131. Ruttekolk, I. R., Duchardt, F., Fischer, R., Wiesmuller, K. H., Rademann, J., & Brock, R. (2008). HPMA as a scaffold for the modular assembly of functional peptide polymers by native chemical ligation. Bioconjugate Chemistry, 19, 2081–2087.PubMedCrossRefPubMedCentralGoogle Scholar
  132. Ruttekolk, I. R., Verdurmen, W. P., Chung, Y. D., & Brock, R. (2011). Measurements of the intracellular stability of CPPs. Methods in Molecular Biology, 683, 69–80.PubMedCrossRefPubMedCentralGoogle Scholar
  133. Rydstrom, A., Deshayes, S., Konate, K., Crombez, L., Padari, K., Boukhaddaoui, H., et al. (2011). Direct translocation as major cellular uptake for CADY self-assembling peptide-based nanoparticles. PLoS ONE, 6, e25924.PubMedPubMedCentralCrossRefGoogle Scholar
  134. Säälik, P., Elmquist, A., Hansen, M., Padari, K., Saar, K., Viht, K., et al. (2004). Protein cargo delivery properties of cell-penetrating peptides. A comparative study. Bioconjug Chem, 15, 1246–1253.PubMedCrossRefPubMedCentralGoogle Scholar
  135. Säälik, P., Padari, K., Niinep, A., Lorents, A., Hansen, M., Jokitalo, E., et al. (2009). Protein delivery with transportans is mediated by caveolae rather than flotillin-dependent pathways. Bioconjugate Chemistry, 20, 877–887.PubMedCrossRefGoogle Scholar
  136. Sagan, S., Bechara, C. & Burlina, F. (2015). Study of CPP mechanisms by mass spectrometry. Methods in Molecular Biology, 2806-4_7.Google Scholar
  137. Scott, G. H., & Packer, D. M. (1939). The localization of minerals in animal tissues by the electron microscope. Science, 89, 227–228.PubMedCrossRefPubMedCentralGoogle Scholar
  138. Sharma, A., Singla, D., Rashid, M., & Raghava, G. P. (2014). Designing of peptides with desired half-life in intestine-like environment. BMC Bioinformatics, 15, 282.PubMedPubMedCentralCrossRefGoogle Scholar
  139. Silhol, M., Tyagi, M., Giacca, M., Lebleu, B., & Vives, E. (2002). Different mechanisms for cellular internalization of the HIV-1 Tat-derived cell penetrating peptide and recombinant proteins fused to Tat. European Journal of Biochemistry, 269, 494–501.PubMedCrossRefPubMedCentralGoogle Scholar
  140. Sousa, A. A., Morgan, J. T., Brown, P. H., Adams, A., Jayasekara, M. P., Zhang, G., et al. (2012). Synthesis, characterization, and direct intracellular imaging of ultrasmall and uniform glutathione-coated gold nanoparticles. Small (Weinheim an der Bergstrasse, Germany), 8, 2277–2286.CrossRefGoogle Scholar
  141. Stalmans, S., Gevaert, B., Verbeke, F., D’Hondt, M., Bracke, N., Wynendaele, E., et al. (2016). Quality control of cationic cell-penetrating peptides. Journal of Pharmaceutical and Biomedical Analysis, 117, 289–297.PubMedCrossRefPubMedCentralGoogle Scholar
  142. Stangl, S., Varga, J., Freysoldt, B., Trajkovic-Arsic, M., Siveke, J. T., Greten, F. R., et al. (2014). Selective in vivo imaging of syngeneic, spontaneous, and xenograft tumors using a novel tumor cell-specific hsp70 peptide-based probe. Cancer Research, 74, 6903–6912.PubMedCrossRefPubMedCentralGoogle Scholar
  143. Sun, Y., Wallrabe, H., Seo, S. A., & Periasamy, A. (2011). FRET microscopy in 2010: The legacy of theodor forster on the 100th anniversary of his birth. ChemPhysChem, 12, 462–474.PubMedCrossRefPubMedCentralGoogle Scholar
  144. Suzuki, T., Futaki, S., Niwa, M., Tanaka, S., Ueda, K., & Sugiura, Y. (2002). Possible existence of common internalization mechanisms among arginine-rich peptides. Journal of Biological Chemistry, 277, 2437–2443.PubMedPubMedCentralCrossRefGoogle Scholar
  145. Swiecicki, J. M., di Pisa, M., Burlina, F., Lecorche, P., Mansuy, C., Chassaing, G., et al. (2015). Accumulation of cell-penetrating peptides in large unilamellar vesicles: A straightforward screening assay for investigating the internalization mechanism. Biopolymers, 104, 533–543.CrossRefGoogle Scholar
  146. Swiecicki, J. M., Thiebaut, F., Di Pisa, M., Gourdin-Bertin, S., Tailhades, J., Mansuy, C., et al. (2016). How to unveil self-quenched fluorophores and subsequently map the subcellular distribution of exogenous peptides. Sci Rep, 6.Google Scholar
  147. Taheri, M. L., Stach, E. A., Arslan, I., Crozier, P. A., Kabius, B. C., Lagrange, T., et al. (2016). Current status and future directions for in situ transmission electron microscopy. Ultramicroscopy, 170, 86–95.PubMedPubMedCentralCrossRefGoogle Scholar
  148. Tang, J., Yin, R., Tian, Y., Huang, Z., Shi, J., Fu, X., et al. (2012). A novel self-assembled nanoparticle vaccine with HIV-1 Tat(4)(9)(-)(5)(7)/HPV16 E7(4)(9)(-)(5)(7) fusion peptide and GM-CSF DNA elicits potent and prolonged CD8(+) T cell-dependent anti-tumor immunity in mice. Vaccine, 30, 1071–1082.PubMedPubMedCentralCrossRefGoogle Scholar
  149. Thoren, P. E., Persson, D., Esbjorner, E. K., Goksor, M., Lincoln, P., & Norden, B. (2004). Membrane binding and translocation of cell-penetrating peptides. Biochemistry, 43, 3471–3489.CrossRefGoogle Scholar
  150. Thoren, P. E., Persson, D., Isakson, P., Goksor, M., Onfelt, A., & Norden, B. (2003). Uptake of analogs of penetratin, Tat(48-60) and oligoarginine in live cells. Biochemical and Biophysical Research Communications, 307, 100–107.PubMedCrossRefPubMedCentralGoogle Scholar
  151. Titze, B., & Genoud, C. (2016). Volume scanning electron microscopy for imaging biological ultrastructure. Biology of the Cell, 108, 307–323.PubMedCrossRefPubMedCentralGoogle Scholar
  152. Tiwari, P. M., Eroglu, E., Bawage, S. S., Vig, K., Miller, M. E., Pillai, S., et al. (2014). Enhanced intracellular translocation and biodistribution of gold nanoparticles functionalized with a cell-penetrating peptide (VG-21) from vesicular stomatitis virus. Biomaterials, 35, 9484–9494.PubMedCrossRefPubMedCentralGoogle Scholar
  153. Trehin, R., Nielsen, H. M., Jahnke, H. G., Krauss, U., Beck-Sickinger, A. G., & Merkle, H. P. (2004). Metabolic cleavage of cell-penetrating peptides in contact with epithelial models: Human calcitonin (hCT)-derived peptides, Tat(47–57) and penetratin(43–58). Biochemical Journal, 382, 945–956.PubMedPubMedCentralCrossRefGoogle Scholar
  154. Tremmel, R., Uhl, P., Helm, F., Wupperfeld, D., Sauter, M., Mier, W., et al. (2016). Delivery of Copper-chelating Trientine (TETA) to the central nervous system by surface modified liposomes. International Journal of Pharmaceutics, 512, 87–95.PubMedPubMedCentralCrossRefGoogle Scholar
  155. Tünnemann, G., Martin, R. M., Haupt, S., Patsch, C., Edenhofer, F., & Cardoso, M. C. (2006). Cargo-dependent mode of uptake and bioavailability of TAT-containing proteins and peptides in living cells. The FASEB Journal, 20, 1775–1784.PubMedPubMedCentralCrossRefGoogle Scholar
  156. Uusna, J., Langel, K., & Langel, Ü. (2015). Toxicity, immunogenicity, uptake, and kinetics methods for CPPs. Methods in Molecular Biology, 1324, 133–148.CrossRefGoogle Scholar
  157. van Bracht, E., Versteegden, L. R., Stolle, S., Verdurmen, W. P., Woestenenk, R., Raave, R., et al. (2014). Enhanced cellular uptake of albumin-based lyophilisomes when functionalized with cell-penetrating peptide TAT in HeLa cells. PLoS ONE, 9, e110813.PubMedPubMedCentralCrossRefGoogle Scholar
  158. Vasconcelos, D., Madani, F., Lehto, T., Radoi, V., Hällbrink, M., Vukojević, V. & Langel, Ü. (2017). Simultaneous membrane interaction of amphipathic peptide monomers, self-aggregates and cargo complexes detected by Fluorescence Correlation Spectroscopy. submitted.Google Scholar
  159. Veiman, K. L., Mäger, I., Ezzat, K., Margus, H., Lehto, T., Langel, K., et al. (2013). PepFect14 peptide vector for efficient gene delivery in cell cultures. Molecular Pharmaceutics, 10, 199–210.CrossRefGoogle Scholar
  160. Vives, E., Brodin, P., & Lebleu, B. (1997). A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. Journal of Biological Chemistry, 272, 16010–16017.PubMedPubMedCentralCrossRefGoogle Scholar
  161. Vukojevic, V., Gräslund, A., & Bakalkin, G. (2011). Fluorescence imaging with single-molecule sensitivity and fluorescence correlation spectroscopy of cell-penetrating neuropeptides. Methods in Molecular Biology, 789, 147–170.CrossRefGoogle Scholar
  162. Waizenegger, T., Fischer, R., & Brock, R. (2002). Intracellular concentration measurements in adherent cells: A comparison of import efficiencies of cell-permeable peptides. Biological Chemistry, 383, 291–299.PubMedCrossRefPubMedCentralGoogle Scholar
  163. Webb, D. J., & Brown, C. M. (2013). Epi-fluorescence microscopy. Methods in Molecular Biology, 931, 29–59.PubMedCrossRefPubMedCentralGoogle Scholar
  164. Wender, P. A., Mitchell, D. J., Pattabiraman, K., Pelkey, E. T., Steinman, L., & Rothbard, J. B. (2000). The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: Peptoid molecular transporters. Proceedings of the National Academy of Sciences, 97, 13003–13008.CrossRefGoogle Scholar
  165. Wimley, W. C. (2015). Determining the Effects of Membrane-Interacting Peptides on Membrane Integrity. Methods in Molecular Biology, 1324, 89–106.PubMedCrossRefPubMedCentralGoogle Scholar
  166. Xue, G., Liu, Z., Wang, L., & Zu, L. (2015). The role of basic residues in the fragmentation process of the lysine rich cell-penetrating peptide TP10. Journal of Mass Spectrometry, 50, 220–227.PubMedCrossRefPubMedCentralGoogle Scholar
  167. Yamamoto, S., Fukui, Y., Kaihara, S., & Fujimoto, K. (2011). Preparation and assembly of poly(arginine)-coated liposomes to create a free-standing bioscaffold. Langmuir, 27, 9576–9582.PubMedCrossRefPubMedCentralGoogle Scholar
  168. Yang, C., Uertz, J., Yohan, D., & Chithrani, B. D. (2014). Peptide modified gold nanoparticles for improved cellular uptake, nuclear transport, and intracellular retention. Nanoscale, 6, 12026–12033.PubMedCrossRefPubMedCentralGoogle Scholar
  169. Youngblood, D. S., Hatlevig, S. A., Hassinger, J. N., Iversen, P. L., & Moulton, H. M. (2007). Stability of cell-penetrating peptide-morpholino oligomer conjugates in human serum and in cells. Bioconjugate Chemistry, 18, 50–60.PubMedCrossRefPubMedCentralGoogle Scholar
  170. Yuste, R. (2005). Fluorescence microscopy today. Nature Methods, 2, 902–904.PubMedCrossRefPubMedCentralGoogle Scholar
  171. Zhai, X. H., Liu, M., Guo, X. J., Wang, S. C., Zhang, H. X., & Guo, Y. M. (2011). SKOV-3 cell imaging by paramagnetic particles labeled with hairpin cell-penetrating peptides. Chinese Medical Journal (Engl), 124, 111–117.Google Scholar
  172. Zhang, P., Cheetham, A. G., Lin, Y. A., & Cui, H. (2013). Self-assembled Tat nanofibers as effective drug carrier and transporter. ACS Nano, 7, 5965–5977.PubMedPubMedCentralCrossRefGoogle Scholar
  173. Zhang, Z., Lv, H., & Zhou, J. (2009). Novel solid lipid nanoparticles as carriers for oral administration of insulin. Pharmazie, 64, 574–578.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Biochemistry and BiophysicsStockholm UniversityStockholmSweden
  2. 2.Institute of TechnologyUniversity of TartuTartuEstonia

Personalised recommendations