Stimuli-Responsive PEGylated Nanogels for Smart Nanomedicine



PEGylated nanogels are composed of cross-linked polyamine gels core with tethered PEG chains. The stimuli-responsive PEGylated nanogels have significant volume phase transitions in response to the extracellular pH (7–6.5) of a tumor environment as well as endosomal/lysosomal pH (6.5–5.5). The pH-responsive PEGylated nanogels containing 19F compounds in the polyamine gels core have remarkable on–off 19FMR signals (T 2 values of 19F) and signal-to-noise (S/N) ratio in response to the extracellular of tumor environment, making these nanogels effective as tumor-specific smart 19F MRI (magnetic resonance imaging) nanoprobes. The doxorubicin (DOX)-loaded pH-responsive PEGylated nanogels release DOX intracellular in response to endosomal/lysosomal pH, thereby conferring more antitumor activity than free DOX against naturally drug-resistant human hepatoma cells. The PEGylated nanogel with gold nanoparticles as the fluorescence quencher in the core and fluorescence dye-labeled DEVD (Asp-Glu-Val-Asp) peptide at the tethered PEG chain end provide pronounced fluorescence signals in response to apoptotic cells. Thus, stimuli-responsive PEGylated nanogels can be utilized as smart nanomedicines for cancer diagnosis and therapy.


Fluorescence Resonance Energy Transfer Volume Phase Transition Fluorescence Resonance Energy Transfer Efficiency Cancer Response Fluorescence Positive Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Yallapu MM, Reddy MK, Labhasetwar V (2007) Nanogels: chemistry to drug delivery. In: Biomedical Applications Nanotechnology. Wiley, NY, pp 131–171CrossRefGoogle Scholar
  2. 2.
    Morimoto N, Hasegawa U, Sugawara A, Yamane S, Akiyoshi K (2007) Polysaccharide nanogel engineering: Design of nano-structured hydrogel materials and application to biotechnology and medicine. In: Nanotechnology Carbohyrate Chemistry. Transworld Research Network, Trivandrum, India, pp 67–85Google Scholar
  3. 3.
    Vinogradov SV, Bronich TK, Kabanov AV (2002) Adv Drug Deliv Rev 54:135–147CrossRefGoogle Scholar
  4. 4.
    Bronich TK, Bontha S, Shlyakhtenko LS, Bromberg L, Hatton TA, Kabanov AV (2006) J Drug Target 14:357–366CrossRefGoogle Scholar
  5. 5.
    Bontha S, Kabanov AV, Bronich TK (2006) J Control Release 114:163–174CrossRefGoogle Scholar
  6. 6.
    Vinogradov SV, Zeman AD, Batrakova EV, Kabanov AV (2005) J Control Release 107:143–157CrossRefGoogle Scholar
  7. 7.
    Bronich TK, Keifer PA, Shlyakhtenko LS, Kabanov AV (2005) J Am Chem Soc 127:8236–8237CrossRefGoogle Scholar
  8. 8.
    Matsumura Y, Maeda H (1986) Cancer Res 46:6387–6392Google Scholar
  9. 9.
    Oishi M, Nagasaki Y (2007) React Funct Polym 67:1311–1329CrossRefGoogle Scholar
  10. 10.
    Oishi M, Hayashi H, Itaka K, Kataoka K, Nagasaki Y (2007) Colloid Polym Sci 285:1055–1060CrossRefGoogle Scholar
  11. 11.
    Oishi M, Miyagawa N, Sakura T, Nagasaki Y (2007) React Funct Polym 67:662–668CrossRefGoogle Scholar
  12. 12.
    Hayashi H, Iijima M, Kataoka K, Nagasaki Y (2004) Macromolecules 37:5389–5396CrossRefGoogle Scholar
  13. 13.
    Gerweck LE, Seetharaman K (1996) Cancer Res 56:1194–1198Google Scholar
  14. 14.
    Wike-Hooley JL, Haveman J, Reinhold HS (1984) Radiother Oncol 2:343–366CrossRefGoogle Scholar
  15. 15.
    Gruenberg J (2001) Nat Rev Mol Cell Biol 2:721–730CrossRefGoogle Scholar
  16. 16.
    Clague MJ (1998) Biochem J 336:271–282Google Scholar
  17. 17.
    Mukherjee S, Ghosh RN, Maxfield FR (1997) Physiol Rev 77:759–803Google Scholar
  18. 18.
    Oishi M, Sumitani S, Nagasaki Y (2007) Bioconjugate Chem 18:1379–1382CrossRefGoogle Scholar
  19. 19.
    Oishi M, Hayashi H, Iijima M, Nagasaki Y (2007) J Mater Chem 17:3720–3725CrossRefGoogle Scholar
  20. 20.
    Oishi M, Tamura A, Nakamura T, Nagasaki Y (2009) Adv Funct Mater 19:827–834CrossRefGoogle Scholar
  21. 21.
    Poehlein GW (1986) Emulsion polymerization. In: Mark HF, Bikales NM, Overberger CG, Menges G, Kroschwitz JI (eds) Encyclopedia of polymer science and engineering, vol 6.1, 2nd edn. Wiley, New York, p 1986Google Scholar
  22. 22.
    Westby MJ (1988) Colloid Polym Sci 266:46–51CrossRefGoogle Scholar
  23. 23.
    Hoshino F, Sasaki M, Kawaguchi H, Ohtsuka Y (1987) Polym J 19:383–389CrossRefGoogle Scholar
  24. 24.
    Lee AS, Gast AP, Bütün V, Armes SP (1999) Macromolecules 32:4302–4310CrossRefGoogle Scholar
  25. 25.
    Wetering VP, Moret EE, Schuurmans-Nieuwenbroek MME, Steenbergen VMJ, Hennink WE (1999) Bioconjug Chem 10:589–597CrossRefGoogle Scholar
  26. 26.
    Kobayashi H, Brechbiel MW (2005) Adv Drug Deliv Rev 57:2271–2286CrossRefGoogle Scholar
  27. 27.
    Caravan P, Ellison JJ, McMurry TJ, Lauffer RB (1999) Chem Rev 99:2293–2352CrossRefGoogle Scholar
  28. 28.
    Yu J-X, Kodibagkar VD, Cui W, Mason RP (2005) Curr Med Chem 12:819–848CrossRefGoogle Scholar
  29. 29.
    Butun V, Billingham NC, Armes SPJ (1998) Am Chem Soc 120:11818–11819CrossRefGoogle Scholar
  30. 30.
    Duncan R (2003) Nat Rev Drug Discov 2:347–360CrossRefGoogle Scholar
  31. 31.
    Jain RK (2003) Eur J Pharm Sci 20:1–16CrossRefGoogle Scholar
  32. 32.
    Maeda H (2001) Adv Drug Delivery Rev 46:149–168CrossRefGoogle Scholar
  33. 33.
    Avichechter D, Schechter B, Arnon R (1998) React Funct Polym 36:59–69CrossRefGoogle Scholar
  34. 34.
    Bogdanov A Jr, Wright SC, Marecos EM, Bogdabova A, Martin C, Petherick P, Weissleder R (1997) J Drug Target 4:321–330CrossRefGoogle Scholar
  35. 35.
    Lee CM, Tanaka T, Murai T, Kondo M, Kimura J, Su W, Kitagawa T, Ito T, Matsuda H, Miyasaka M (2002) Cancer Res 62:4282–4288Google Scholar
  36. 36.
    Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave A (2001) J Clin Oncol 19:3312–3322Google Scholar
  37. 37.
    Newman MS, Colbern GT, Working PK, Engbers C, Amntea MA (1999) Cancer Chemother Pharmacol 43:1–7CrossRefGoogle Scholar
  38. 38.
    Nakanishi T, Fukushima S, Okano K, Suzuki M, Matsumura Y, Yokoyama M, Okano T, Sakurai Y, Kataoka K (2001) J Control Release 74:295–302CrossRefGoogle Scholar
  39. 39.
    Yokoyama M, Okano T, Sakurai Y, Suwa S, Kataoka K (1996) J Control Release 39:351–356CrossRefGoogle Scholar
  40. 40.
    Maeda H, Sawa T, Konno T (2001) J Control Release 74:47–61CrossRefGoogle Scholar
  41. 41.
    Tsukioka Y, Matsumura Y, Hamaguchi T, Koike H, Moriyasu F, Kakizone T (2002) Jpn J Cancer Res 93:1145–1153CrossRefGoogle Scholar
  42. 42.
    Kwon G, Naito M, Yokoyama M, Okano T, Sakurai Y, Kataoka K (1997) J Control Release 48:195–201CrossRefGoogle Scholar
  43. 43.
    Gillies ER, Frechet JM (2005) Bioconjug Chem 16:361–368CrossRefGoogle Scholar
  44. 44.
    Bae Y, Fukushima S, Harada A, Kataoka K (2003) Angew Chem Int Ed Engl 42:4640–4643CrossRefGoogle Scholar
  45. 45.
    Wirth T, Kuhnel F, Fleischmann-Mundt B, Woller N, Djojosubroto M, Rudolph KL, Manns M, Zender L, Kubuka S (2005) Cancer Res 65:7393–7402CrossRefGoogle Scholar
  46. 46.
    Huesker M, Folmer Y, Schneider M, Fulda C, Blum HE, Hafkemeyer P (2002) Hepatology 36:874–884Google Scholar
  47. 47.
    Omelyanenko V, Kopečková P, Kopeček J (1998) J Control Release 53:25–37CrossRefGoogle Scholar
  48. 48.
    Schoenberger J, Bauer J, Moosbauer J, Eilles C, Grimm D (2008) Curr Med Chem 15:187–194CrossRefGoogle Scholar
  49. 49.
    Thornberry NA, Lazebnik Y (1998) Science 281:1312–1316CrossRefGoogle Scholar
  50. 50.
    Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG, Earnshaw WC (1994) Nature 371:346–347CrossRefGoogle Scholar
  51. 51.
    Wyllie AH (1980) Nature 284:555–556CrossRefGoogle Scholar
  52. 52.
    Stefflova K, Chen J, Marotta D, Li H, Zheng G (2006) J Med Chem 49:3850–3856CrossRefGoogle Scholar
  53. 53.
    Wu Y, Xing D, Luo S, Tang Y, Chen Q (2006) Cancer Lett 235:239–247CrossRefGoogle Scholar
  54. 54.
    Harada A, Kataoka K (1998) Macromolecules 31:288–294CrossRefGoogle Scholar
  55. 55.
    Kenworthy AK, Hristova K, Needham D, Mclntosh TJ (1995) Biophys J 68:1921–1936CrossRefGoogle Scholar
  56. 56.
    Tanford C, Nozaki Y, Rohde MF (1977) J Phys Chem 81:1555–1560CrossRefGoogle Scholar
  57. 57.
    Gueroui Z, Libchaber A (2004) Phys Rev Lett 93:166108/1–166108/4CrossRefGoogle Scholar
  58. 58.
    Zhang L, Torgerson TR, Liu X-Y, Timmons S, Colosia AD, Hawiger J, Tam JP (1998) Proc Natl Acad Sci USA 95:9184–9189CrossRefGoogle Scholar
  59. 59.
    Oishi M, Hayashi H, Uno T, Ishii T, Iijima M, Nagasaki Y (2007) Macromol Chem Phys 208:1176–1182CrossRefGoogle Scholar
  60. 60.
    Agasti SS, You C-C, Arumugam P, Rotello VM (2008) J Mater Chem 18:70–73CrossRefGoogle Scholar
  61. 61.
    Isaacs SR, Cutler EC, Park JS, Lee TR, Shon Y-S (2005) Langmuir 21:5689–5692CrossRefGoogle Scholar
  62. 62.
    Templeton AC, Hostetler MJ, Kraft CT, Murray RW (1998) J Am Chem Soc 120:1906–1911CrossRefGoogle Scholar
  63. 63.
    Falcieri E, Matelli AM, Bareggi R, Cataldi A, Cocco L (1993) Biochem Biophys Res Commun 193:19–25CrossRefGoogle Scholar
  64. 64.
    Santini MT, Rainaldi G, Indovina PL (1999) Int J Radiat Biol 75:787–799CrossRefGoogle Scholar
  65. 65.
    Sutherland RM (1998) Science 240:177–184CrossRefGoogle Scholar
  66. 66.
    Moscona A (1957) Proc Natl Acad Sci USA 43:184–194CrossRefGoogle Scholar
  67. 67.
    Konerding MA, Fait E, Gaumann A (2001) Br J Cancer 84:1354–1362CrossRefGoogle Scholar
  68. 68.
    Lian T, Ho RJY (2001) J Pharm Sci 90:667–680CrossRefGoogle Scholar
  69. 69.
    Vasey PA, Kaye SB, Morrison R, Twelves C, Wilson P, Duncan R, Thoson AH, Murray LS, Hilditch TE, Murray T, Burtles S, Fraier D, Frigerio E, Cassidy J (1999) Clin Cancer Res 5:83–94Google Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Tsukuba Interdisciplinary Materials Science (TIMS)University of TsukubaTsukubaJapan

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