Stimuli-Sensitive Nanosystems: For Drug and Gene Delivery

  • Han Chang Kang
  • Eun Seong Lee
  • Kun Na
  • You Han Bae
Part of the Fundamental Biomedical Technologies book series (FBMT, volume 4)

Apart from its previous history in pharmaceutics, nanotechnology has recently become a major paradigm for the delivery of anticancer drugs, imaging agents, and genetic material. Pharmaceutical nanosystems have shown beneficial therapeutic efficacy with reduced side effects in treating diseases when compared to traditional dosage forms. For example, delivery of high doses of therapeutic and/or diagnostic agents to target cancer sites has been achieved using nano-sized carrier systems. This effect is primarily attributed to passive accumulation in solid tumors and inflamed regions by the EPR effect and the size (20–200 nm) of the carriers, followed by passive diffusional release of the drug in the extracellular space and/or active internalization into the cells via various entry mechanisms.


Drug Release Block Copolymer Gene Delivery Lower Critical Solution Temperature Vinyl Ether 
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.


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  1. Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., and Walter, P. 2002. Molecular Biology of the Cell. 4th Edition. New York: Garland Science.Google Scholar
  2. Alexiou, C., Jurgons, R., Seliger, C., and Iro, H. 2006. Medical applications of magnetic nanoparticles. J. Nanosci. Nanotechnol. 6:2762–2768.PubMedCrossRefGoogle Scholar
  3. Bae, Y., Fukyshima, S., Harada, A., and Kataoka, K. 2003. Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. Angew. Chem. Int. Ed. Engl. 42:4640–4643.PubMedCrossRefGoogle Scholar
  4. Bae, Y., Jang, W. D., Nishiyama, N., Fukushima, S., and Kataoka, K. 2005a. Multifunctional polymeric micelles with folate-mediated cancer cell targeting and pH-triggered drug releasing properties for active intracellular drug delivery. Mol. BioSyst. 1:242–250.PubMedCrossRefGoogle Scholar
  5. Bae, Y., Nishiyama, N., Fukushima, S., Koyama, H., Yasuhiro, M., and Kataoka, K. 2005b. Preparation and biological characterization of polymeric micelle drug carriers with intracellular pH-triggered drug release property: tumor permeability, controlled subcellular drug distribution, and enhanced in vivo antitumor efficacy. Bioconjug. Chem. 16:122–130.PubMedCrossRefGoogle Scholar
  6. Balakirev, M., Schoehn, G., and Chroboczek, J. 2000. Lipoic acid-derived amphiphiles for redox-controlled DNA delivery. Chem. Biol. 7:813–819.PubMedCrossRefGoogle Scholar
  7. Bisht, H. S., Manickam, D. S., You, Y., and Oupicky, D. 2006. Temperature-controlled properties of DNA complexes with poly(ethyleneimine)-graft-poly(N-isopropylacrylamide). Biomacromolecules 7:1169–1178.PubMedCrossRefGoogle Scholar
  8. Blessing, T., Remy, J. S., and Behr, J. P. 1998. Template oligomerization of DNA-bound cations produces calibrated nanometric particles J. Am. Chem. Soc. 120:8519–8520.CrossRefGoogle Scholar
  9. Boesch, D., Gaveriaux, C., Jachez, B., Pourtier-Manzanedo, A., Bollinger, P., and Loor, F. 1991. In vivo circumvention of P-glycoprotein-mediated multidrug resistance of tumor cells with SDZ PSC 833. Cancer Res. 51:4226–4233.PubMedGoogle Scholar
  10. Boussif, O., Lezoualc’h, F., Zanta, M. A., Mergny, M. D., Scherman, D., Demeneix, B., and Behr, J. P. 1995. A versatile vector for gene and oligonucleotides transfer into cells in culture and in vivo: polyethyleneimine. Proc. Natl. Acad. Sci. USA. 92:7297–7301.PubMedADSCrossRefGoogle Scholar
  11. Brannon-Peppas, L. and Blanchette, J. O. 2004. Nanoparticle and targeted systems for cancer therapy. Adv. Drug Deliv. Rev. 56:1649–1659.PubMedCrossRefGoogle Scholar
  12. Cammas, S., Suzuki, K., Sone, C., Sakuri, Y., Kataoka, K., and Okano, T. 1997. Thermo-responsive polymer nanoparticles with a core-shell micelle structure as site-specific drug carriers. J. Control. Release 48:157–164.CrossRefGoogle Scholar
  13. Cataldo, A. M., Petanceska, S., Peterhoff, C. M., Terio, N. B., Epstein, C. J., Villar, A., Carlson, E. J., Staufenbiel, M., and Nixon, R. A. 2003. App gene dosage modulates endosomal abnormalities of Alzheimer’s disease in a segmental trisomy 16 mouse model of Down syndrome. J. Neurosci. 23:6788–6792.PubMedGoogle Scholar
  14. Cho, Y. W., Kim, J. D., and Park, K. 2003. Polycation gene delivery systems: escape from endosomes to cytosol. J. Pharm. Pharmacol. 55:721–734.PubMedCrossRefGoogle Scholar
  15. Chung, J. E., Yokoyama, M., Aoyagi, Y., Sakurai, Y., and Okano, T. 1998. Effect of molecular architecture of hydrophobically modified poly(N-isopropylacrylamide) on the formation of thermoresponsive core-shell micellar drug carriers. J. Control. Release 53:119–130.PubMedCrossRefGoogle Scholar
  16. Chung, J. E., Yokoyama, M., Yamato, T., Aoyagi, Y., Sakurai, Y., and Okano, T. 1999. Thermo-responsive drug delivery from polymeric micelles constructed using block copolymers of poly(N-isopropylacrylamide) and poly(butylmethacrylate). J. Control. Release 62:115–127.PubMedCrossRefGoogle Scholar
  17. Chung, J. E., Yokoyama, M., and Okano, T. 2000. Inner core segment design for drug delivery control of thermo-responsive polymeric micelles. J. Control. Release 65:93–103.PubMedCrossRefGoogle Scholar
  18. Dauty, E., Remy, J. S., Blessing, T., and Behr, J. P. 2001. Dimerizable cationic detergents with a low cmc condense plasmid DNA into nanometric particles and transfect cells in culture. J. Am. Chem. Soc. 123:9227–9234.PubMedCrossRefGoogle Scholar
  19. Dewhirst, M. W. 1995. Thermal dosimetry. In Principles and Practice of Thermoradiotherapy and Thermochemotherapy, ed. M. H. Seegenschmiedt, P. Fessenden, and C. C. Vernon, pp. 123–136. Berlin: Springer.Google Scholar
  20. Diessemond, J., Witthoff, M., Brauns, T. C., Harberer, D., and Gros, M. 2003. pH Values on chronic wounds: evaluation during modern wound therapy. Hautarzt 54:959–965.CrossRefGoogle Scholar
  21. Dreher, M. R., Raucher, D., Balu, N., Colvin, O. M., Ludeman, S. M., and Chilkoti, A. 2003. Evaluation of an elastin-like polypeptide-doxorubicin conjugate for cancer therapy. J. Control. Release 91:31–43.PubMedCrossRefGoogle Scholar
  22. Drummond, D. C., Zignani, M., and Leroux, J. C. 2000. Current status of pH-sensitive liposomes in drug delivery. Prog. Lipid Res. 39:409–460.PubMedCrossRefGoogle Scholar
  23. Engin, K., Leeper, D. B., Cater, J. R., Thistlethwaite, A. J. Tupchong, L., and McFarlane, J. D. 1995. Extracellular pH distribution in human tumors. Int. J. Hyperthermia 11:211–216.PubMedCrossRefGoogle Scholar
  24. Eum, K. M., Langley, K. H., and Tirrell, D. A. 1989. Quasi-elastic and electrophoretic light-scattering studies of the reorganization of dioleoylphosphatidylcholine vesicle membrane by poly(2-ethylacrylic acid). Macromolecules 22:2755–2760.ADSCrossRefGoogle Scholar
  25. Evans, W. H. and Hardison, W. G. 1985. Phospholipid, cholesterol, polypeptide and glycoprotein composition of hepatic endosome subfractions. Biochem. J. 232:33–36.PubMedGoogle Scholar
  26. Funhoff, A. M., van Nostrum, C. F., Koning, G. A., Schuurmans-Nieuwenbroek, N. M., Crommelin, D. J., and Hennink, W. E. 2004. Endosomal escape of polymeric gene delivery complexes is not always enhanced by polymers buffering at low pH. Biomacromolecules 5:32–39.PubMedCrossRefGoogle Scholar
  27. Furgeson, D. Y., Dreher, M. R., and Chilkoti, A. 2006. Structural optimization of a “smart” doxorubicin-polypeptide conjugate for thermally targeted delivery to solid tumors. J. Control. Release 110:362–369.PubMedCrossRefGoogle Scholar
  28. Gardner, S. N. 2000. A mechanistic, predictive model of dose-response curves for cell cycle phase-specific and -nonspecific drugs. Cancer Res. 60:1417–1425.PubMedGoogle Scholar
  29. Gaucher, G., Dufresne, M. H., Sant, V. P., Kang, N., Maysinger, D., and Leroux, J. C. 2005. Block copolymer micelles: preparation, characterization and application in drug delivery. J. Control. Release 109:169–188.PubMedCrossRefGoogle Scholar
  30. Gerasimov, O. V., Boomer, J. A., Qualls, M. M., and Thompson, D. H. 1999. Cytosolic drug delivery using pH- and light-sensitive liposomes. Adv. Drug Deliv. Rev. 38:317–338.PubMedCrossRefGoogle Scholar
  31. Gerlowski, L. E. and Jain, R. K. 1985. Effect of hyperthermia on microvascular permeability to macromolecules in normal and tumor tissues. Int. J. Microcirc. Clin. Exp. 4:363–372.PubMedGoogle Scholar
  32. Gillies, E. R. and Fréchet, J. M. 2005. pH-Responsive copolymer assemblies for controlled release of doxorubicin. Bioconjug. Chem. 16:361–368.PubMedCrossRefGoogle Scholar
  33. Gillies, E. R., Goodwin, A. P., and Fréchet, M. J. 2004a. Acetals as pH-sensitve linkages for drug delivery. Bioconjug. Chem. 15:1254–1263.PubMedCrossRefGoogle Scholar
  34. Gillies, E. R., Jonsson, T. B., and Fréchet, M. J. 2004b. Stimuli-responsive supramolecular assemblies of linear-dendritic copolymers. J. Am. Chem. Soc. 126:11936–11943.PubMedCrossRefGoogle Scholar
  35. Gottesman, M. M., Pastan, I., and Ambudkar, S. V. 1996. P-glycoprotein and multi drug resistance. Curr. Opin. Genet. Dev. 6:610–617.PubMedCrossRefGoogle Scholar
  36. Hager, A., Debus, G., Edel, H. G., Stransky, H., and Serrano, R. 1991. Auxin induces exocytosis and the rapid synthesis of a high-turnover pool of plasma-membrane H+ ATPase. Planta 185:527–537.CrossRefGoogle Scholar
  37. Hansen, J. M., Go, Y. M., and Jones, D. P. 2006. Nuclear and mitochondrial compartmentation of oxidative stress and redox signaling. Annu. Rev. Pharmacol. Toxicol. 46:215–234.PubMedCrossRefGoogle Scholar
  38. Heskins, M. and Guillet, J. E. 1968. Solution properties of poly(N-isopropylacrylamide). J. Macromol. Sci. Chem. A. 2:1441–1455.CrossRefGoogle Scholar
  39. Hobbs, S. K., Monsky, W. L., Yuan, F., Roberts, W. G., Griffith, L., Torchilin, V. P., and Jain, R. K., 1998. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl. Acad. Sci. USA. 95:4607–4612.PubMedADSCrossRefGoogle Scholar
  40. Hooijberg, J. H., Peters, G. J., Assaraf, Y. G., Kathmann, I., Priest, D. G., Bunni, M. A., Veerman, A. J., Scheffer, G. L., Kaspers, G. J., and Jansen, G. 2003.The role of multidrug resistance proteins MRP1, MRP2 and MRP3 in cellular folate homeostasis. Biochem. Pharmacol. 65:765–771.PubMedCrossRefGoogle Scholar
  41. Hruby, M., Konak, C., and Ulbrich, K. 2005. Polymeric micellar pH-sensitive drug delivery system for doxorubicin. J. Control. Release 103:137–148.PubMedCrossRefGoogle Scholar
  42. Jain, R. K. 1987. Transport of molecules across tumor vasculature. Cancer Metastasis Rev. 6:559–593.PubMedCrossRefGoogle Scholar
  43. Jeong, B., Bae, Y. H., and Kim, S. W. 1999. Biodegradable thermosensitive micelles of PEG–PLGA–PEG triblock copolymers. Colloids Surf. B. Biointerfaces 16:185–193.CrossRefGoogle Scholar
  44. Jones, R. A., Cheung, C. Y., Black, F. E., Zia, J. K., Stayton, P. S., Hoffman, A. S., and Wilson., M. R. 2003. Poly(2-alkylacrylic acid) polymers deliver molecules to the cytosol by pH-sensitive disruption of endosomal vesicles. Biochem. J. 372:65–75.PubMedCrossRefGoogle Scholar
  45. Kaneko, T., Willner, D., Monkovic, I., Knipe, J. O., Braslawsky, G. R., Greenfield, R. S., and Vyas, D. M. 1991. New hydrazone derivatives of adriamycin and their immunoconjugates: a correlation between acid stability and cytotoxicity. Bioconjug. Chem. 2:133–141.PubMedCrossRefGoogle Scholar
  46. Kang, H. C. and Bae, Y. H. 2007. pH-Tunable endosomolytic oligomers for enhanced nucleic acid delivery. Adv. Funct. Mater. 17:1263–1272.CrossRefGoogle Scholar
  47. Kang, H. C., Lee, M., and Bae, Y. H. 2005. Polymeric gene carriers. Crit. Rev. Eukaryot. Gene Expr. 15:317–342.PubMedGoogle Scholar
  48. Kang, H. C., Lee, M., and Bae, Y. H. 2007. Polymeric gene delivery vectors. In Nanotechnology in Therapeutics: Current Technology and Application, ed. N. A. Peppas, J. Z. Hilt, and J. B. Thomas, pp. 131–161. Wymondham: Horizon Bioscience.Google Scholar
  49. Kiang, T., Bright, C., Cheung, C. Y., Stayton, P. S., Hoffman, A. S., and Leong, K. W. 2004. Formulation of chitosan-DNA nanoparticles with poly(propyl acrylic acid) enhances gene expression. J. Biomater. Sci. Polym. Ed. 15:1405–1421.PubMedCrossRefGoogle Scholar
  50. Kikuchi, A. and Okano, T. 2002. Intelligent thermoresponsive polymeric stationary phases for aqueous chromatography of biological compounds. Prog. Polym. Sci. 27:1165–1193.CrossRefGoogle Scholar
  51. Kim, G. M., Bae, Y. H., and Jo, W. H. 2005a. pH-Induced micelle formation of poly(histidine-cophenylalanine)-block-poly(ethylene glycol) in aqueous media. Macromol. Biosci. 5:1118–1124.PubMedCrossRefGoogle Scholar
  52. Kim, Y. H., Park, J. H., Lee, M., Kim, Y. H., Park, T. G., and Kim, S. W. 2005b. Polyethylenimine with acid-labile linkages as a biodegradable gene carrier. J. Control. Release 103:209–219.PubMedCrossRefGoogle Scholar
  53. Kong, G. H. and Dewhirst, M. W. 1999. Hyperthermia and liposomes. Int. J. Hyperthermia 15:345–370.PubMedCrossRefGoogle Scholar
  54. Kunath, K., von Harpe, A., Fischer, D., Petersen, H., Bickel, U., Voigt, K., and Kissel, T. 2003. Low-molecular-weight polyethylenimine as a non-viral vector for DNA delivery: comparison of physicochemical properties, transfection efficiency and in vivo distribution with high-molecular-weight polyethylenimine. J. Control. Release 89:113–125.PubMedCrossRefGoogle Scholar
  55. Kurisawa, M., Yokoyama, M., and Okano, T. 2000. Gene expression control by temperature with thermo-responsive polymeric gene carriers. J. Control. Release 69:127–137.PubMedCrossRefGoogle Scholar
  56. Lavigne, M. D., Pennadam, S. S., Ellis, J., Yates, L. L., Alexander, C., and Górecki, D. C. 2007. Enhanced gene expression through temperature profile-induced variations in molecular architecture of thermoresponsive polymer vectors. J. Gene Med. 9:44–54.PubMedCrossRefGoogle Scholar
  57. Lazzarino, D. A., Blier, P., and Mellman, I. 1998. The monomeric guanosine triphosphatase rab4 controls an essential step on the pathway of receptor-mediated antigen processing in B cells. J. Exp. Med. 188:1769–1774.PubMedCrossRefGoogle Scholar
  58. Lee, E. S., Shin, H. J., Na, K., and Bae, Y. H. 2003a. Poly(L-histidine)-PEG block copolymer micelles and pH-induced destabilization. J. Control. Release 90:363–374.PubMedCrossRefGoogle Scholar
  59. Lee, E. S., Na, K., and Bae, Y. H. 2003b. Polymeric micelle for tumor pH and folate-mediated targeting. J. Control. Release 91:103–113.PubMedCrossRefGoogle Scholar
  60. Lee, E. S., Na, K., and Bae, Y. H. 2005a. Doxorubicin loaded pH-sensitive polymeric micelles for reversal of resistant MCF-7 tumor. J. Control. Release 103:405–418.PubMedCrossRefGoogle Scholar
  61. Lee, E. S., Na, K., and Bae, Y. H. 2005b. Super pH-sensitive multifunctional polymeric micelle. Nano Lett. 5:325–329.PubMedADSCrossRefGoogle Scholar
  62. Leeper, D. B., Engin, K., Thistlethwaite, A. J., Hitchon, H. D., Dover, J. D., Li, D. J., and Tupchong, L. 1994. Human tumor extracellular pH as a function of blood glucose concentration. Int. J. Radiat. Oncol. Biol. Phys. 28:935–943.PubMedGoogle Scholar
  63. Leroux, J., Roux, E., Le Garrec, D., Hong, K., and Drummond, D. C. 2001. N-isopropylacrylamide copolymers for the preparation of pH-sensitive liposomes and polymeric micelles. J. Control. Release 72:71–84.PubMedCrossRefGoogle Scholar
  64. Licciardi, M., Giammona, G., Du, J., Armes, S. P., Tang, Y., and Lewis, A. L. 2006. New folate-functionalized biocompatible block copolymer micelles as potential anti-cancer drug delivery systems. Polymer 47:2946–2955.CrossRefGoogle Scholar
  65. Liu, S. Q., Tong, Y. W., and Yang, Y. Y. 2005. Incorporation and in vitro release of doxorubicin in thermally sensitive micelles made from poly(N-isopropylacrylamide-co-N, N-dimethylacrylamide)-b-poly(D, L-lactide-co-glycolide) with varying compositions. Biomaterials 26:5064–5074.PubMedCrossRefGoogle Scholar
  66. Liu, S. Q., Wiradharma, N., Gao, S. J., Tong, Y. W., and Yang, Y. Y. 2007. Bio-functional micelles self-assembled from a folate-conjugated block copolymer for targeted intracellular delivery of anticancer drugs. Biomaterials 28:1423–1433.PubMedCrossRefGoogle Scholar
  67. Makhaeva, E. E., Tenhu, H., and Khokhlov, A. R. 1998. Conformational changes of poly(vinylcaprolactam) macromolecules and their complexes with ionic surfactants in aqueous solution. Macromolecules 31:6112–6118.ADSCrossRefGoogle Scholar
  68. Manickam, D. S. and Oupicky, D. 2006. Multiblock reducible copolypeptides containing histidine-rich and nuclear localization sequences for gene delivery. Bioconjug. Chem. 17:1395–1403.PubMedCrossRefGoogle Scholar
  69. Manickam, D. S., Bisht, H. S., Wan, L., Mao, G., and Oupicky, D. 2005. Influence of TAT-peptide polymerization on properties and transfection activity of TAT/DNA polyplexes. J. Control. Release 102:293–306.CrossRefGoogle Scholar
  70. Matsumura, Y. and Maeda, H. 1986. A new concept for macromolecular therapeutics in cancer-chemotherapy—mechanism of tumoritropic accumulation of proteins and the antitumor agent SMANCS. Cancer Res. 46:6387–6392.PubMedGoogle Scholar
  71. Meyer, D. E., Shin, B. C., Kong, G. A., Dewhirst, M. W., and Chilkoti, A. 2001. Drug targeting using thermally responsive polymers and local hyperthermia. J. Control. Release 74:213–224.PubMedCrossRefGoogle Scholar
  72. Midoux, P. and Monsigny, M. 1999. Efficient gene transfer by histidylated polylysine/pDNA complexes. Bioconjug. Chem. 10:406–411.PubMedCrossRefGoogle Scholar
  73. Miyata, K., Kakizawa, Y., Nishiyama, N., Harada, A., Yamasaki, Y., Koyama, H., and Kataoka, K. 2004. Block catiomer polyplexes with regulated densities of charge and disulfide cross-linking directed to enhance gene expression. J. Am. Chem. Soc. 126:2355–2361.PubMedCrossRefGoogle Scholar
  74. Mohajer, G., Lee, E. S., and Bae, Y. H. 2007. Enhanced intercellular retention activity of novel pH-sensitive polymeric micelles in wild and multidrug resistant MCF-7 Cells. Pharm. Res. 24:1618–1627.PubMedCrossRefGoogle Scholar
  75. Murthy, N., Campbell, J., Fausto, N., Hoffman, A. S., and Stayton, P. S. 2003. Bioinspired pH-responsive polymers for the intracellular delivery of biomolecular drugs. Bioconjug. Chem. 14:412–419.PubMedCrossRefGoogle Scholar
  76. Murata, M., Kaku, W., Anada, T., Sato, Y., Kano, T., Maeda, M., and Katayama, Y. 2003a. Novel DNA/polymer conjugate for intelligent antisense reagent with improved nuclease resistance. Bioorg. Med. Chem. Lett. 13:3967–3970.PubMedCrossRefGoogle Scholar
  77. Murata, M., Kaku, W., Anada, T., Sato, Y., Maeda, M., and Katayama, Y. 2003b. Temperature-dependent regulation of antisense activity using a DNA/poly(N-isopropylacrylamide) conjugate. Chem. Lett. 32:986–987.CrossRefGoogle Scholar
  78. Na, K. and Bae, Y. H. 2005. pH-Sensitive polymers for drug delivery. In Polymeric Drug Delivery Systems, ed. G. S. Kwon, pp. 129–194. Boca Raton: Taylor & Francis Group.Google Scholar
  79. Na, K., Lee, E. S., and Bae, Y. H. 2003. Adriamycin loaded pullulan acetate/sulfonamide conjugate nanoparticles responding to tumor pH: pH-dependent cell interaction, internalization and cytotoxicity in vitro. J. Control. Release 87:3–13.PubMedCrossRefGoogle Scholar
  80. Na, K., Lee, K. H., and Bae, Y. H. 2004. pH-Sensitivity and pH-dependent interior structural change of self-assembled hydrogel nanoparticles of pullulan acetate/oligo-sulfonamide conjugate. J. Control. Release 97:513–525.PubMedGoogle Scholar
  81. Na, K., Lee, K. H., Lee, D. H., and Bae, Y. H. 2006. Biodegradable thermo-sensitive nanoparticles from poly(L-lactic acid)/poly(ethylene glycol) alternating multi-block copolymer for potential anti-cancer drug carrier. Eur. J. Pharm. Sci. 27:115–122.PubMedCrossRefGoogle Scholar
  82. Ojugo, A. S. E., Mcsheehy, P. M. J., Mcintyre, D. J. O., Mccoy, C., Stubbs, M., Leach, M. O., Judson, I. R., and Griffiths, J. R. 1999. Measurement of the extraceullar pH of solid tumours in mice by magnetic resonance spectroscopy: a comparison of exogenous 19F and 31P probes. NMR Biomed. 12:495–504.PubMedCrossRefGoogle Scholar
  83. Okada, H. and Hillery, A. M. 2001. Vaginal Drug Delivery. New York: Taylor and Francis.Google Scholar
  84. Oupicky, D., Carlisle, R. C., and Seymour, L. W. 2001. Triggered intracellular activation of disulfide crosslinked polyelectrolyte gene delivery complexes with extended systemic circulation in vivo. Gene Ther. 8:713–724.PubMedCrossRefGoogle Scholar
  85. Oupicky, D., Parker, A. L., and. Seymour, L. W. 2002. Laterally stabilized complexes of DNA with linear reducible polycations: strategy for triggered intracellular activation of DNA delivery vectors. J. Am. Chem. Soc. 124:8–9.PubMedCrossRefGoogle Scholar
  86. Oupicky, D., Reschel, T., Konak, C., and Oupicka, L. 2003. Temperature-controlled behavior of self-assembly gene delivery vectors based on complexes of DNA with poly(L-lysine)-graft-poly(N-isopropylacrylamide). Macromolecules 36:6863–6872.ADSCrossRefGoogle Scholar
  87. Owen, D. H. and Katz, D. F. 2005. A review of the physical and chemical properties of human semen and the formulation of a semen stimulant. J. Androl. 26:459–469.PubMedCrossRefGoogle Scholar
  88. Pack, D. W., Hoffman, A. S., Pun, S., and Stayton, P. S. 2005. Design and development of polymers for gene delivery. Nat. Rev. Drug Discov. 4:581–593.PubMedCrossRefGoogle Scholar
  89. Park, J. S., Han, T. H., Lee, K. Y., Han, S. S., Hwang, J. J., Moon, D. H., Kim, S. Y., and Cho, Y. W. 2006. N-acetyl histidine-conjugated glycol chitosan self-assembled nanoparticles for intracytoplasmic delivery of drugs: endocytosis, exocytosis and drug release. J. Control. Release 115:37–45.PubMedCrossRefGoogle Scholar
  90. Pichon, C., Goncalves, C., and Midoux, P. 2001. Histidine-rich peptides and polymers for nucleic acids delivery. Adv. Drug Deliv. Rev. 53:75–94.PubMedCrossRefGoogle Scholar
  91. Ponce, A. M., Vujaskovic, Z., Yuan, F., Needham, D., and Dewhirst, M. W. 2006. Hyperthermia mediated liposomal drug delivery. Int. J. Hyperthermia 22:205–213.PubMedCrossRefGoogle Scholar
  92. Read, M. L., Singh, S., Ahmed, Z., Stevenson, M., Briggs, S. S., Oupicky, D., Barrett, L. B., Spice, R., Kendall, M., Berry, M., Preece, J. A., Logan, A., and Seymour, L. W. 2005. A versatile reducible polycation-based system for efficient delivery of a broad range of nucleic acids. Nucleic Acids Res. 33:e86.PubMedCrossRefGoogle Scholar
  93. Rodriguez-Cabello, J. C., Reguera, J., Girotti, A., Arias, F. J., and Alonso, M. 2006. Genetic engineering of protein-based polymers: the example of elastin like polymers. Adv. Polym. Sci. 200:119–167.CrossRefGoogle Scholar
  94. Rybak, S. L. and Murphy, R. F. 1998. Primary cell cultures from murine kidney and heart differ in endosomal pH. J. Cell. Physiol. 176:216–222.PubMedCrossRefGoogle Scholar
  95. Rybak, S. L., Lanni, F., and Murphy, R. F. 1997. Theoretical considerations on the role of membrane potential in the regulation of endosomal pH. Biophys. J. 73:674–687.PubMedCrossRefGoogle Scholar
  96. Sawant, R. M., Hurley, J. P., Salmaso, S., Kale, A., Tolcheva, E., Levchenko, T. S., and Torchilin, V. P. 2006. “Smart” drug delivery systems: double-targeting pH-responsive pharmaceutical nanocarriers. Bioconjug. Chem. 17:943–949.PubMedCrossRefGoogle Scholar
  97. Schaffer, D. V., Fidelman, N. A., Dan, N., and Lauffenburger, D. A. 2000. Vector unpacking as a potential barrier for receptor-mediated polyplex gene delivery. Biotechnol. Bioeng. 67:598–606.PubMedCrossRefGoogle Scholar
  98. Schmaljohann, D. 2006. Thermo- and pH-responsive polymers in drug delivery. Adv. Drug Deliv. Rev. 58:1655–1670.PubMedCrossRefGoogle Scholar
  99. Sehested, M., Skovsgarrd, T., van Deurs, B., and Winther-Nielsen, H. 1987. Increase in nonspecific adsorptive endocytosis in anthracycline- and vinca alkaloid-resistant Ehrlich ascites tumor cell lines. J. Natl. Cancer Inst. 78:171–179.PubMedGoogle Scholar
  100. Sethuraman, V. A. and Bae, Y. H. 2007. TAT peptide-based micelle system for potential active targeting of anti-cancer agents to acidic solid tumors. J. Control. Release 118:216–224.PubMedCrossRefGoogle Scholar
  101. Sethuraman, V. A., Na, K., and Bae, Y. H. 2006. pH-Responsive sulfonamide/PEI system for tumor specific gene delivery: in vitro study. Biomacromolecules 7:64–70.PubMedCrossRefGoogle Scholar
  102. Shin, J., Shum, P., and Thompson, D. H. 2003. Acid-triggered release via dePEGylation of DOPE liposomes containing acid-labile vinyl ether PEG-lipids. J. Control. Release 91:187–200.PubMedCrossRefGoogle Scholar
  103. Simon, S. M. and Schindler, M. 1994. Cell biological mechanisms of multidrug resistance in tumors. Proc. Natl. Acad. Sci. USA. 91:3497–3504.PubMedADSCrossRefGoogle Scholar
  104. Sonawane, N. D., Szoka, F. C., Jr., and Verkman, A. S. 2003. Chloride accumulation and swelling in endosomes enhances DNA transfer by polyamine-DNA polyplexes. J. Biol. Chem. 278:44826–44831.PubMedCrossRefGoogle Scholar
  105. Song, C. W. 1978. Effect of hyperthermia on vascular functions of normal tissues and experimental tumors: brief communication. J. Natl. Cancer Inst. 60:711–713.PubMedGoogle Scholar
  106. Stubbs, M., Mcsheehy, R. M. J., Griffiths, J. R., and Bashford, L. 2000. Causes and consequences of tumour acidity and implications for treatment. Opinion 6:15–19.Google Scholar
  107. Szakacs, G., Paterson, J. K., Ludwig, J. A., Booth-Genthe, C., and Gottesman, M. M. 2006. Targeting multidrug resistance in cancer. Nat. Rev. Drug Discov. 5:219–234.PubMedCrossRefGoogle Scholar
  108. Tacker, J. R. and Anderson, R. U. 1982. Delivery of antitumor drug to bladder cancer by use of phase transition liposomes and hyperthermia. J. Urology 127:1211–1214.Google Scholar
  109. Takeda, N., Nakamura, E., Yokoyama, M., and Okano, T. 2004. Temperature-responsive polymeric carriers incorporating hydrophobic monomers for effective transfection in small doses. J. Control. Release 95:343–355.PubMedCrossRefGoogle Scholar
  110. Tannock, I. F. and Rotin, D. 1989. Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res. 49:4373–4384.PubMedGoogle Scholar
  111. Thomas, J. L. and Tirrell, D. A. 2000. Polymer-induced leakage of cations from dioleoyl phosphatidylcholine and phosphatidylglycerol liposomes. J. Control. Release 67:203–209.PubMedCrossRefGoogle Scholar
  112. Tirrell, D. A., Takigawa, D. Y., and Seki, K. 1985. pH Sensitization of phospholipid vesicles via complexation with synthetic poly(carboxylic acid) s. Ann. N. Y. Acad. Sci. 446:237–248.PubMedADSCrossRefGoogle Scholar
  113. Türk, M., Dinçer, S., Yulu˘g, I. G., and Piskin, E. 2004. In vitro transfection of HeLa cells with temperature sensitive polycationic copolymers. J. Control. Release 96:325–340.PubMedCrossRefGoogle Scholar
  114. Urry, D. W. 1997. Physical chemistry of biological free energy transduction as demonstrated by elastic protein-based polymers. J. Phys. Chem. B 101:11007–11028.CrossRefGoogle Scholar
  115. Urry, D. W., Luan, C. H., Parker, T. M., Gowda, D. C., Prasad, K. U., Reid, M. C., and Safavy, A. 1991. Temperature of polypeptide inverse temperature transition depends on mean residue hydrophobicity. J. Am. Chem. Soc. 113:4346–4348.CrossRefGoogle Scholar
  116. van Adelsberg, J. and Al-Awqati, Q. 1998. Regulation of cell pH by Ca2+ -mediated exocytotic insertion of H-ATPase. J. Cell Biol. 102:1638–1645.CrossRefGoogle Scholar
  117. van Sluis, R., Bhujwalla, Z. M., Raghunand, N., Ballesteros, P., Alvarez, J. Cerdán, S. Galons, J. P., and Gillies, R.J. 1999. In vivo imaging of extracellular pH using 1H MRSI. Magn. Reson. Med. 41:743–750.PubMedCrossRefGoogle Scholar
  118. Wagner, E. 2004. Strategies to improve DNA polyplexes for in vivo gene transfer: will “artificial viruses” be the answer? Pharm. Res. 21:8–14.PubMedADSCrossRefGoogle Scholar
  119. Walker, G. F., Fella, C., Pelisek, J., Fahrmeir, J., Boeckle, S., Ogris, M., and Wagner, E. 2005. Toward synthetic viruses: endosomal pH-triggered deshielding of targeted polyplexes greatly enhances gene transfer in vitro and in vivo. Mol. Ther. 11:418–425.PubMedCrossRefGoogle Scholar
  120. Warren, L., Jardillier, J. C., and Ordentlich, P. 1991. Secretion of lysosomal enzymes by drug-sensitive and multiple drug-resistant cells. Cancer Res. 51:1996–2001.PubMedGoogle Scholar
  121. Wu, G., Fang, Y. Z., Yang, S., Lupton, J. R., and Turner, N. D. 2004. Glutathione metabolism and its implications for health. J. Nutr. 134:489–492.PubMedGoogle Scholar
  122. Xie, A. F. and Granick, S. 2002. Phospholipid membranes as substrates for polymer adsorption. Nat. Mater. 1:129–133.PubMedADSCrossRefGoogle Scholar
  123. Yamagata, M., Hasuda, K., Stamato, T., and Tannock, I. F. 1998. The contribution of lactic acid to acidification of tumours: studies of variant cells lacking lactate dehydrogenase. Br. J. Cancer 77:1726–1731.PubMedGoogle Scholar
  124. Yang, S. R., Lee, H. J., and Kim, J. D. 2006. Histidine-conjugated poly(amino acid) derivatives for the novel endosomolytic delivery carrier of doxorubicin. J. Control. Release 114:60–68.PubMedCrossRefGoogle Scholar
  125. Yessine, M. A. and Leroux, J. C. 2004. Membrane-destabilizing polyanions: interaction with lipid bilayers and endosomal escape of biomacromolecules. Adv. Drug Deliv. Rev. 56:999–1021.PubMedCrossRefGoogle Scholar
  126. Yessine, M. A., Lafleur, M., Meier, C., Petereit, H. U., and Leroux, J. C. 2003. Characterization of the membrane-destabilizing properties of different pH-sensitive methacrylic acid copolymers. Biochim. Biophys. Acta 1613:28–38.PubMedCrossRefGoogle Scholar
  127. Yokoyama, M. 2002. Gene delivery using temperature-responsive polymeric carriers. Drug Discov. Today 7:426–432.PubMedCrossRefGoogle Scholar
  128. Yuk, S. H. and Bae, Y. H. 1999. Phase-transition polymers for drug delivery. Crit. Rev. Ther. Drug Carrier Syst. 16:385–423.PubMedGoogle Scholar
  129. Zignani, M., Drummond, D. C., Meyer, O., Hong, K., and Leroux, J. C. 2000. In vitro characterization of a novel polymeric-based pH-sensitive liposome system. Biochim. Biophys. Acta 1463:383–394.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Han Chang Kang
    • 1
  • Eun Seong Lee
    • 1
  • Kun Na
    • 2
  • You Han Bae
    • 1
  1. 1.Department of Pharmaceutics and Pharmaceutical ChemistryUniversity of UtahSalt Lake CityUSA
  2. 2.Division of BiotechnologyThe Catholic University of KoreaKorea

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