Pharmaceutical Research

, 24:1 | Cite as

Micellar Nanocarriers: Pharmaceutical Perspectives

  • V. P. Torchilin
Review Article


Micelles, self-assembling nanosized colloidal particles with a hydrophobic core and hydrophilic shell are currently successfully used as pharmaceutical carriers for water-insoluble drugs and demonstrate a series of attractive properties as drug carriers. Among the micelle-forming compounds, amphiphilic copolymers, i.e., polymers consisting of hydrophobic block and hydrophilic block, are gaining an increasing attention. Polymeric micelles possess high stability both in vitro and in vivo and good biocompatibility, and can solubilize a broad variety of poorly soluble pharmaceuticals many of these drug-loaded micelles are currently at different stages of preclinical and clinical trials. Among polymeric micelles, a special group is formed by lipid-core micelles, i.e., micelles formed by conjugates of soluble copolymers with lipids (such as polyethylene glycol–phosphatidyl ethanolamine conjugate, PEG–PE). Polymeric micelles, including lipid-core micelles, carrying various reporter (contrast) groups may become the imaging agents of choice in different imaging modalities. All these micelles can also be used as targeted drug delivery systems. The targeting can be achieved via the enhanced permeability and retention (EPR) effect (into the areas with the compromised vasculature), by making micelles of stimuli-responsive amphiphilic block-copolymers, or by attaching specific targeting ligand molecules to the micelle surface. Immunomicelles prepared by coupling monoclonal antibody molecules to p-nitrophenylcarbonyl groups on the water-exposed termini of the micelle corona-forming blocks demonstrate high binding specificity and targetability. This review will discuss some recent trends in using micelles as pharmaceutical carriers.

Key words

anti-cancer drugs diagnostic agents drug-carriers micelles polymeric micelles poorly soluble drugs 


  1. 1.
    H. Müller. Colloidal Carriers for Controlled Drug Delivery and Targeting: Modification, Characterization, and In Vivo Distribution, Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1991.Google Scholar
  2. 2.
    S. Cohen and H. Bernstein. Microparticulate Systems for the Delivery of Proteins and Vaccines, Marcel Dekker, New York, 1996.Google Scholar
  3. 3.
    D. D. Lasic and F. J. Martin. Stealth Liposomes, CRC, Boca Raton, Florida, 1995.Google Scholar
  4. 4.
    V. P. Torchilin and V. S. Trubetskoy. Which polymers can make nanoparticulate drug carriers long-circulating? Adv. Drug Deliv. Rev. 16:141–155 (1995).CrossRefGoogle Scholar
  5. 5.
    T. N. Palmer, V. J. Caride, M. A. Caldecourt, J. Twickler, and V. Abdullah. The mechanism of liposome accumulation in infarction. Biochim. Biophys. Acta 797:363–368 (1984).PubMedGoogle Scholar
  6. 6.
    H. Maeda, J. Wu, T. Sawa, Y. Matsumura, and K. Hori. Tumor vascular permeability and the epr effect in macromolecular therapeutics: a review. J. Control. Release 65:271–284 (2000).PubMedCrossRefGoogle Scholar
  7. 7.
    V. P. Torchilin. Polymer-coated long-circulating microparticulate pharmaceuticals. J. Microencapsul. 15:1–19 (1998).PubMedCrossRefGoogle Scholar
  8. 8.
    C. A. Lipinski, F. Lombardo, B. W. Dominy, and P. J. Feeney. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 46:3–36 (2000).CrossRefGoogle Scholar
  9. 9.
    B. A. Teicher. Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, Humana, Totowa, New Jersey, 1997.Google Scholar
  10. 10.
    A. M. Fernandez, K. Van Derpoorten, L. Dasnois, K. Lebtahi, V. Dubois, T. J. Lobl, S. Gangwar, C. Oliyai, E. R. Lewis, D. Shochat, and A. Trouet. N-succinyl-(beta-alanyl-l-leucyl-l-alanyl-l-leucyl)doxorubicin: an extracellularly tumor-activated prodrug devoid of intravenous acute toxicity. J. Med. Chem. 44:3750–3753 (2001).PubMedCrossRefGoogle Scholar
  11. 11.
    S. H. Yalkowsky. Techniques of Solubilization of Drugs, Marcel Dekker, New York, 1981.Google Scholar
  12. 12.
    C. A. Lipinski. Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods 44:235–249 (2000).PubMedCrossRefGoogle Scholar
  13. 13.
    B. A. Shabner and G. M. Collings (eds.), Cancer Chemotherapy: Principles and Practice, J.B. Lippincott, Philadelphia, 1990.Google Scholar
  14. 14.
    K. Yokogawa, E. Nakashima, J. Ishizaki, H. Maeda, T. Nagano, and F. Ichimura. Relationships in the structure-tissue distribution of basic drugs in the rabbit. Pharm. Res. 7:691–696 (1990).PubMedCrossRefGoogle Scholar
  15. 15.
    A. Hageluken, L. Grunbaum, B. Nurnberg, R. Harhammer, W. Schunack, and R. Seifert. Lipophilic beta-adrenoceptor antagonists and local anesthetics are effective direct activators of g-proteins. Biochem. Pharmacol. 47:1789–1795 (1994).PubMedCrossRefGoogle Scholar
  16. 16.
    D. Thompson and M. V. Chaubal. Cyclodextrins (CDS)—excipients by definition, drug delivery systems by function (part I: injectable applications). Drug Deliv. Technol. 2:34–38 (2000).Google Scholar
  17. 17.
    H. C. Ansel, L. V. Allen, and N. G. Popovich. Pharmaceutical Dosage Forms and Drug Delivery Systems, Kluwer, Norwell, Massachusetts, 1999.Google Scholar
  18. 18.
    D. D. Lasic and D. Papahadjopoulos. Medical Applications of Liposomes, Elsevier, New York, 1998.Google Scholar
  19. 19.
    P. P. Constantinides, K. J. Lambert, A. K. Tustian, B. Schneider, S. Lalji, W. Ma, B. Wentzel, D. Kessler, D. Worah, and S. C. Quay. Formulation development and antitumor activity of a filter-sterilizable emulsion of paclitaxel. Pharm. Res. 17:175–182 (2000).PubMedCrossRefGoogle Scholar
  20. 20.
    R. Ray, A. H. Kibbe, R. Rowe, P. Shleskey, and P. Weller. Handbook of Pharmaceutical Excipients, APhA, Washington, District of Columbia, 2003.Google Scholar
  21. 21.
    M. J. Rosen (ed.), Surfactants and Interfacial Phenomena, Wiley, New York, 1989.Google Scholar
  22. 22.
    K. L. Mittal and B. Lindman (eds.), Surfactants in Solution (vols. 1–3), Plenum, New York, 1991.Google Scholar
  23. 23.
    M. Jones and J. Leroux. Polymeric micelles—a new generation of colloidal drug carriers. Eur. J. Pharm. Biopharm. 48:101–111 (1999).PubMedCrossRefGoogle Scholar
  24. 24.
    A. Martin (ed.), Physical Pharmacy. Lippinkott, Williams and Wilkins, Philadelphia, 1993.Google Scholar
  25. 25.
    D. D. Lasic. Mixed micelles in drug delivery. Nature 355: 279–280 (1992).PubMedCrossRefGoogle Scholar
  26. 26.
    P. H. Elworthy, A. T. Florence, and C. B. Macfarlane (eds.), Solubilization by Surface Active Agents, Chapman & Hall, London, UK, 1968.Google Scholar
  27. 27.
    D. Attwood and A. T. Florence (eds.), Surfactant Systems, Chapman & Hall, London, UK, 1983.Google Scholar
  28. 28.
    A. V. Kabanov, E. V. Batrakova, and N. S. Melik-Nubarov et al. A new class of drug carriers; micells poly(oxyethylene)–poly(oxypropylene) block copolymers as microcontainers for drug targeting from blood to brain. J. Control. Release 22:141–158 (1992).CrossRefGoogle Scholar
  29. 29.
    G. S. Kwon. Diblock copolymer nanoparticles for drug delivery. Crit. Rev. Ther. Drug Carr. Syst. 15:481–512 (1998).Google Scholar
  30. 30.
    M. Jones and J. Leroux. Polymeric micelles—a new generation of colloidal drug carriers. Eur. J. Pharm. Biopharm. 48:101–111 (1999).PubMedCrossRefGoogle Scholar
  31. 31.
    V. P. Torchilin. Structure and design of polymeric surfactant-based drug delivery systems. J. Control. Release 73:137–172 (2001).PubMedCrossRefGoogle Scholar
  32. 32.
    A. A. Gabizon. Liposome circulation time and tumor targeting: implications for cancer chemotherapy. Adv. Drug Deliv. Rev. 16:285–294 (1995).CrossRefGoogle Scholar
  33. 33.
    G. S. Kwon and K. Kataoka. Block copolymer micelles as long-circulating drug vehicles. Adv. Drug Deliv. Rev. 16:295–309 (1995).CrossRefGoogle Scholar
  34. 34.
    R. K. Jain. Transport of molecules, particles, and cells in solid tumors. Ann. Rev. Biomed. Eng. 1:241–263 (1999).CrossRefGoogle Scholar
  35. 35.
    F. Yuan, M. Dellian, M. Fukumura, M. Leunig, D. A. Berk, V. P. Torchilin, and R. K. Jain. Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res. 55:3752–3756 (1995).PubMedGoogle Scholar
  36. 36.
    V. Weissig, K. R. Whiteman, and V. P. Torchilin. Accumulation of protein-loaded long-circulating micelles and liposomes in subcutaneous Lewis lung carcinoma in mice. Pharm. Res. 15:1552–1556 (1998).PubMedCrossRefGoogle Scholar
  37. 37.
    V. S. Trubetskoy and V. P. Torchilin. Use of polyoxyethylene–lipid conjugates as long-circulating carriers for delivery of therapeutic and diagnostic agents. Adv. Drug Deliv. Rev. 16:311–320 (1995).CrossRefGoogle Scholar
  38. 38.
    O. Soga, C. F. van Nostrum, M. Fens, C. J. Rijcken, R. M. Schiffelers, G. Storm, and W. E. Hennink. Thermosensitive and biodegradable polymeric micelles for paclitaxel delivery. J. Control. Release 103:341–353 (2005).PubMedCrossRefGoogle Scholar
  39. 39.
    D. Le Garrec, S. Gori, L. Luo, D. Lessard, D. C. Smith, M. A. Yessine, M. Ranger, and J. C. Leroux. Poly(N-vinylpyrrolidone)-block-poly(d,l-lactide) as a new polymeric solubilizer hydrophobic anticancer drugs: in vitro and in vivo evaluation. J. Control. Release 99:83–101 (2004).PubMedCrossRefGoogle Scholar
  40. 40.
    X. Shuai, T. Merdan, A. K. Schaper, F. Xi, and T. Kissel. Core-cross-linked polymeric micelles as paclitaxel carriers. Bioconjug. Chem. 15:441–448 (2004).PubMedCrossRefGoogle Scholar
  41. 41.
    F. Mathot, L. van Beijsterveldt, V. Preat, M. Brewster, and A. Arien. Intestinal uptake and biodistribution of novel polymeric micelles after oral administration. J. Control. Release 111:47–55 (2006).PubMedCrossRefGoogle Scholar
  42. 42.
    E. K. Park, S. Y. Kim, S. B. Lee, and Y. M. Lee. Folate-conjugated methoxy poly(ethylene glycol)/poly(epsilon-caprolactone) amphiphilic block copolymeric micelles for tumor-targeted drug delivery. J. Control. Release 109:158–168 (2005).PubMedCrossRefGoogle Scholar
  43. 43.
    H. Gao, Y. W. Yang, Y. G. Fan, and J. B. Ma. Conjugates of poly(dl-lactic acid) with ethylenediamino or diethylenetriamino bridged bis(beta-cyclodextrin)s and their nanoparticles as protein delivery systems. J. Control. Release 112:301–311 (2006).PubMedCrossRefGoogle Scholar
  44. 44.
    D. J. Pillion, J. A. Amsden, C. R. Kensil, and J. Recchia. Structure–function relationship among quillaja saponins serving as excipients for nasal and ocular delivery of insulin. J. Pharm. Sci. 85:518–524 (1996).PubMedCrossRefGoogle Scholar
  45. 45.
    F. Lallemand, O. Felt-Baeyens, K. Besseghir, F. Behar-Cohen, and R. Gurny. Cyclosporine a delivery to the eye: a pharmaceutical challenge. Eur. J. Pharm. Biopharm. 56:307–318 (2003).PubMedCrossRefGoogle Scholar
  46. 46.
    J. Liaw, S. F. Chang, and F. C. Hsiao. In vivo gene delivery into ocular tissues by eye drops of poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) (peo–ppo–peo) polymeric micelles. Gene Ther. 8:999–1004 (2001).PubMedCrossRefGoogle Scholar
  47. 47.
    G. S. Kwon and K. Kataoka. Block copolymer micelles as long-circulating drug vehicles. Adv. Drug Deliv. Rev. 16:295–309 (1995).CrossRefGoogle Scholar
  48. 48.
    G. Gaucher, M. H. Dufresne, V. P. Sant, N. Kang, D. Maysinger, and J. C. Leroux. Block copolymer micelles: preparation, characterization and application in drug delivery. J. Control. Release 109:169–188 (2005).PubMedCrossRefGoogle Scholar
  49. 49.
    H. M. Aliabadi and A. Lavasanifar. Polymeric micelles for drug delivery. Expert Opin. Drug Deliv. 3:139–162 (2006).PubMedCrossRefGoogle Scholar
  50. 50.
    L. Zhang and A. Eisenberg. Multiple morphologies of “crew-cut” aggregates of polystyrene-b-poly(acrylic acid) block copolymers. Science 268:1728–1731 (1995).CrossRefPubMedGoogle Scholar
  51. 51.
    G. S. Kwon and T. Okano. Soluble self-assembled block copolymers for drug delivery. Pharm. Res. 16:597–600 (1999).PubMedCrossRefGoogle Scholar
  52. 52.
    A. V. Kabanov, E. V. Batrakova, and V. Y Alakhov. Pluronic block copolymers as novel polymer therapeutics for drug and gene delivery. J. Control. Release 82:189–212 (2002).PubMedCrossRefGoogle Scholar
  53. 53.
    S. B. La, T. Okano, and K. Kataoka. Preparation and characterization of the micelle-forming polymeric drug indomethacin-incorporated poly(ethylene oxide)-poly(beta-benzyl L-aspartate) block copolymer micelles. J. Pharm. Sci. 85:85–90 (1996).PubMedCrossRefGoogle Scholar
  54. 54.
    R. Gref, A. Domb, P. Quellec, T. Blunk, R. H. Muller, J. M. Verbavatz, and R. Langer. The controlled intravenous delivery of drugs using peg-coated sterically stabilized nanospheres. Adv. Drug Deliv. Rev. 16:215–233 (1995).CrossRefGoogle Scholar
  55. 55.
    S. A. Hagan, A. G. A. Coombes, and M. C. Garnett, et al. Polylactide-poly(ethelene glycol) copolymers as drug delivery systems. 1. Characterization of water dispersible micelle-forming systems. Langmuir 12:2153–2161 (1996).CrossRefGoogle Scholar
  56. 56.
    T. Inoue, G. Chen, K. Nakamae, and A. S. Hoffman. An AB block copolymers of oligo(methyl methacrylate) and poly(acrylic acid) for micellar delivery of hydrophobic drugs. J. Control. Release 51:221–229 (1998).PubMedCrossRefGoogle Scholar
  57. 57.
    R. J. Hunter. In Foundations of Colloid Science, Vol. 1, Oxford University Press, New York, 1991.Google Scholar
  58. 58.
    Z. Gao and A. A. Eisenberg. A model of micellization for block copolymers in solutions. Macromolecules 26:7353–7360 (1993).CrossRefGoogle Scholar
  59. 59.
    C. M. Marques. Bunchy Micelles. Langmuir 13:1430–1433 (1997).CrossRefGoogle Scholar
  60. 60.
    G. S. Kwon. Polymeric micelles for delivery of poorly water-soluble compounds. Crit. Rev. Ther. Drug Carr. Syst. 20: 357–403 (2003).CrossRefGoogle Scholar
  61. 61.
    H. Otsuka, Y. Nagasaki, and K. Kataoka. PEGylated nanoparticles for biological and harmaceutical applications. Adv. Drug Deliv. Rev. 55:403–419 (2003).PubMedCrossRefGoogle Scholar
  62. 62.
    M. L. Adams, A. Lavasanifar, and G. S. Kwon. Amphiphilic block copolymers for drug delivery. J. Pharm. Sci. 92: 1343–1355 (2003).PubMedCrossRefGoogle Scholar
  63. 63.
    A. N. Lukyanov and V. P. Torchilin. Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs. Adv. Drug Deliv. Rev. 56:1273–1289 (2004).PubMedCrossRefGoogle Scholar
  64. 64.
    A. V. Kabanov, P. Lemieux, S. Vinogradov, and V. Alakhov. Pluronic block copolymers: novel functional molecules for gene therapy. Adv. Drug Deliv. Rev. 54:223–233 (2002).PubMedCrossRefGoogle Scholar
  65. 65.
    Y. Kakizawa and K. Kataoka. Block copolymer micelles for delivery of gene and related compounds. Adv. Drug Deliv. Rev. 54:203–222 (2002).PubMedCrossRefGoogle Scholar
  66. 66.
    T. Morcol, P. Nagappan, L. Nerenbaum, A. Mitchell, and S. J. Bell. Calcium phosphate–PEG–insulin–casein (CAPIC) particles as oral delivery systems for insulin. Int. J. Pharm. 277: 91–97 (2004).PubMedCrossRefGoogle Scholar
  67. 67.
    A. Abuchowski, T. van Es, N. C. Palczuk, J. R. McCoy, and F. F. Davis. Treatment of l5178y tumor-bearing bdf1 mice with a nonimmunogenic l-glutaminase-l-asparaginase. Cancer Treat. Rep. 63:1127–1132 (1979).PubMedGoogle Scholar
  68. 68.
    J. M. Harris, N. E. Martin, and M. Modi. Pegylation: a novel process for modifying pharmacokinetics. Clin. Pharmacokinet. 40:539–551 (2001).PubMedCrossRefGoogle Scholar
  69. 69.
    M. J. Roberts, M. D. Bentley, and J. M. Harris. Chemistry for peptide and protein pegylation. Adv. Drug Deliv. Rev. 54: 459–476 (2002).PubMedCrossRefGoogle Scholar
  70. 70.
    F. M. Veronese and J. M. Harris. Introduction and overview of peptide and protein pegylation. Adv. Drug Deliv. Rev. 54: 453–456 (2002).PubMedCrossRefGoogle Scholar
  71. 71.
    A. L. Klibanov, K. Maruyama, V. P. Torchilin, and L. Huang. Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett. 268:235–237 (1990).PubMedCrossRefGoogle Scholar
  72. 72.
    P. Calvo, B. Gouritin, I. Brigger, C. Lasmezas, J. Deslys, A. Williams, J. P. Andreux, D. Dormont, and P. Couvreur. Pegylated polycyanoacrylate nanoparticles as vector for drug delivery in prion diseases. J. Neurosci. Methods 111:151–155 (2001).PubMedCrossRefGoogle Scholar
  73. 73.
    S. M. Moghimi. Chemical camouflage of nanospheres with a poorly reactive surface: towards development of stealth and target-specific nanocarriers. Biochim. Biophys. Acta 1590: 131–139 (2002).PubMedCrossRefGoogle Scholar
  74. 74.
    R. Smith and C. Tanford. The critical micelle concentration of dipalmitoylphosphatidylcholine in water and water–methanol solutions. J. Mol. Biol. 67:75–83 (1972).PubMedCrossRefGoogle Scholar
  75. 75.
    V. P. Torchilin, V. S. Trubetskoy, K. R. Whiteman, P. Caliceti, P. Ferruti, and F. M. Veronese. New synthetic amphiphilic polymers for steric protection of liposomes in vivo. J. Pharm. Sci. 84:1049–1053 (1995).PubMedCrossRefGoogle Scholar
  76. 76.
    V. P. Torchilin, T. S. Levchenko, K. R. Whiteman, A. A. Yaroslavov, A. M. Tsatsakis, A. K. Rizos, E. V. Michailova, and M. I. Shtilman. Amphiphilic poly-n-vinylpyrrolidones: synthesis, properties and liposome surface modification. Biomaterials 22:3035–3044 (2001).PubMedCrossRefGoogle Scholar
  77. 77.
    D. Le Garrec, J. Taillefer, J. E. Van Lier, V. Lenaerts, and J. C. Leroux. Optimizing pH-responsive polymeric micelles for drug delivery in a cancer photodynamic therapy model. J. Drug Target. 10:429–437 (2002).PubMedCrossRefGoogle Scholar
  78. 78.
    S. D. Johnson, J. M. Anderson, and R. E. Marchant. Biocompatibility studies on plasma polymerized interface materials encompassing both hydrophobic and hydrophilic surfaces. J. Biomed. Mater. Res. 26:915–35 (1992).PubMedCrossRefGoogle Scholar
  79. 79.
    V. P. Torchilin, M. I. Shtilman, V. S. Trubetskoy, K. R. Whiteman, and A. M. Milstein. Amphiphilic vinyl polymers effectively prolong liposome circulation time in vivo. Biochim. Biophys. Acta 1195:181–184 (1994).PubMedCrossRefGoogle Scholar
  80. 80.
    D. Sharma, T. P. Chelvi, J. Kaur, K. Chakravorty, T. K. De, A. Maitra, and R. Ralhan. Novel Taxol formulation: polyvinylpyrrolidone nanoparticle-encapsulated Taxol for drug delivery in cancer therapy. Oncol. Res. 8:281–286 (1996).PubMedGoogle Scholar
  81. 81.
    M. Moneghini, D. Voinovich, F. Princivalle, and L. Magarotto. Formulation and evaluation of vinylpyrrolidone/vinylacetate copolymer microspheres with carbamazepine. Pharm. Dev. Technol. 5:347–353 (2000).PubMedCrossRefGoogle Scholar
  82. 82.
    A. Benahmed, M. Ranger, and J. C. Leroux. Novel polymeric micelles based on the amphiphilic diblock copolymer poly(N-vinyl-2-pyrrolidone)-block-poly(d,l-lactide). Pharm. Res. 18: 323–328 (2001).PubMedCrossRefGoogle Scholar
  83. 83.
    B. Luppi, I. Orienti, F. Bigucci, T. Cerchiara, G. Zuccari, S. Fazzi, and V. Zecchi. Poly(vinylalcohol-co-vinyloleate) for the preparation of micelles enhancing retinyl palmitate transcutaneous permeation. Drug Deliv. 9:147–152 (2002).PubMedCrossRefGoogle Scholar
  84. 84.
    B. Luppi, F. Bigucci, T. Cerchiara, V. Andrisano, V. Pucci, R. Mandrioli, and V. Zecchi. Micelles based on polyvinyl alcohol substituted with oleic acid for targeting of lipophilic drugs. Drug Deliv. 12:21–26 (2005).PubMedCrossRefGoogle Scholar
  85. 85.
    Y. S. Nam, H. S. Kang, J. Y. Park, T. G. Park, S. H. Han, and I. S. Chang. New micelle-like polymer aggregates made from PEI-PLGA diblock copolymers: micellar characteristics and cellular uptake. Biomaterials 24:2053–2059 (2003).PubMedCrossRefGoogle Scholar
  86. 86.
    A. V. Kabanov, V. P. Chekhonin, V. Alakhov, E. V. Batrakova, A. S. Lebedev, N. S. Melik-Nubarov, S. A. Arzhakov, A. V. Levashov, G. V. Morozov, and E. S. Severin et al. The neuroleptic activity of haloperidol increases after its solubilization in surfactant micelles. Micelles as microcontainers for drug targeting. FEBS Lett. 258:343–345 (1989).PubMedCrossRefGoogle Scholar
  87. 87.
    D. W. Miller, E. V. Batrakova, T. O. Waltner, V. Yu. Alakhov, and A. V. Kabanov. Interactions of pluronic block copolymers with brain microvessel endothelial cells: evidence of two potential pathways for drug absorption. Bioconjug. Chem. 8: 649–657 (1997).PubMedCrossRefGoogle Scholar
  88. 88.
    S. Katayose and K. Kataoka. Remarkable increase in nuclease resistance of plasmid DNA through supramolecular assembly with poly(ethylene glycol)-poly(L-lysine) block copolymer. J. Pharm. Sci. 87:160–163 (1998).PubMedCrossRefGoogle Scholar
  89. 89.
    V. S. Trubetskoy, G. S. Gazelle, G. L. Wolf, and V. P. Torchilin. Block-copolymer of polyethylene glycol and polylysine as a carrier of organic iodine: design of long-circulating particulate contrast medium for x-ray computed tomography. J. Drug Target. 4:381–388 (1997).PubMedGoogle Scholar
  90. 90.
    M. Yokoyama, M. Miyauchi, N. Yamada, T. Okano, Y. Sakurai, K. Kataoka, and S. Inoue. Characterization and anticancer activity of the micelle-forming polymeric anticancer drug adriamycin-conjugated poly(ethylene glycol)-poly(aspartic acid) block copolymer. Cancer Res. 50:1693–1700 (1990).PubMedGoogle Scholar
  91. 91.
    A. Harada and K. Kataoka. Novel polyion complex micelles entrapping enzyme molecules in the core. Preparation of narrowly-distributed micelles from lysozyme and poly(ethylene glycol)-poly(aspartic acid) block copolymer in aqueous medium. Macromolecules 31:288–294 (1998).CrossRefGoogle Scholar
  92. 92.
    G. S. Kwon, M. Naito, M. Yokoyama, T. Okano, Y. Sakurai, and K. Kataoka. Physical entrapment of adriamycin in AB block copolymer micelles. Pharm. Res. 12:192–195 (1995).PubMedCrossRefGoogle Scholar
  93. 93.
    G. S. Kwon, M. Naito, M. Yokoyama, T. Okano, Y. Sakurai, and K. Kataoka. Block copolymer micelles for drug delivery: loading and release of doxorubicin. J. Control. Release 48: 195–201 (1997).CrossRefGoogle Scholar
  94. 94.
    Y. I. Jeong, J. B. Cheon, S. H. Kim, J. W. Nah, Y. M. Lee, and Y. K. Sung et al. Clonazepam release from core-shell type nanoparticles in vitro. J. Control. Release 51:169–178 (1998).PubMedCrossRefGoogle Scholar
  95. 95.
    S. Y. Kim, I. G. Shin, Y. M. Lee, C. G. Cho, and Y. K. Sung. Metoxy poly(ethylene glucol) and ɛ-caprolactone amphiphilic block copolymeric micelle containing indomethacin. II. Micelle formation and drug release behaviors. J. Control. Release 51:13–22 (1998).PubMedCrossRefGoogle Scholar
  96. 96.
    C. Allen, Y. Yu, D. Maysinger, and A. Eisenberg. Polycaprolactone-b-poly(ethylene oxide) block copolymer micelles as a novel drug delivery vehicle for neurotrophic agents FK506 and L-685,818. Bioconjug. Chem. 9:564–572 (1998).PubMedCrossRefGoogle Scholar
  97. 97.
    M. Ramaswamy, X. Zhang, H. Burt, and K. M. Wasan. Human plasma distribution of free paclitaxel and paclitaxel associated with diblock copolymers. J. Pharm. Sci. 86:460–464 (1997).PubMedCrossRefGoogle Scholar
  98. 98.
    A. V. Kabanov and V. A. Kabanov. Interpolyelectrolyte and block ionomer complexes for gene delivery: physico-chemical aspects. Adv. Drug Deliv. Rev. 30:49–60 (1990).CrossRefGoogle Scholar
  99. 99.
    V. Toncheva, E. Schacht, S. Y. Ng, J. Barr, and J. Heller. Use of block copolymers of poly(ortho esters) and poly (ethylene glycol) micellar carriers as potential tumour targeting systems. J. Drug Target. 11:345–353 (2003).PubMedCrossRefGoogle Scholar
  100. 100.
    Y. Tang, S. Y. Liu, S. P. Armes, and N. C. Billingham. Solubilization and controlled release of a hydrophobic drug using novel micelle-forming ABC triblock copolymers. Biomacromolecules 4:1636–1645 (2003).PubMedCrossRefGoogle Scholar
  101. 101.
    W. J. Lin, L. W. Juang, and C. C. Lin. Stability and release performance of a series of pegylated copolymeric micelles. Pharm. Res. 20:668–673 (2003).PubMedCrossRefGoogle Scholar
  102. 102.
    S. C. Lee, C. Kim, I. Chan Kwon, H. Chung, and S. Young Jeong. Polymeric micelles of poly(2-ethyl-2-oxazoline)-block-poly(epsilon-caprolactone) copolymer as a carrier for paclitaxel. J. Control. Release 89:437–446. (2003).CrossRefGoogle Scholar
  103. 103.
    G. B. Jiang, D. Quan, K. Liao, and H. Wang. Novel polymer micelles prepared from chitosan grafted hydrophobic palmitoyl groups for drug delivery. Mol. Pharmacol. 3:152–160 (2006).CrossRefGoogle Scholar
  104. 104.
    S. Weiping, Y. Changqing, C. Yanjing, Z. Zhiguo, and K. Xiangzheng. Self-assembly of an amphiphilic derivative of chitosan and micellar solubilization of puerarin. Colloids Surf., B Biointerfaces 48:13–16 (2006).CrossRefGoogle Scholar
  105. 105.
    A. V. Ambade, E. N. Savariar, and S. Thayumanavan. Dendrimeric micelles for controlled drug release and targeted delivery. Mol. Pharmacol. 2:264–272 (2005).CrossRefGoogle Scholar
  106. 106.
    D. Bhadra, S. Bhadra, and N. K. Jain. Pegylated lysine based copolymeric dendritic micelles for solubilization and delivery of artemether. J. Pharm. Pharm. Sci. 8:467–482 (2005).PubMedGoogle Scholar
  107. 107.
    K. Prompruk, T. Govender, S. Zhang, C. D. Xiong, and S. Stolnik. Synthesis of a novel peg-block-poly(aspartic acid-stat-phenylalanine) copolymer shows potential for formation of a micellar drug carrier. Int. J. Pharm. 297:242–253 (2005).PubMedGoogle Scholar
  108. 108.
    J. Djordjevic, M. Barch, and K. E. Uhrich. Polymeric micelles based on amphiphilic scorpion-like macromolecules: novel carriers for water-insoluble drugs. Pharm. Res. 22:24–32 (2005).PubMedCrossRefGoogle Scholar
  109. 109.
    L. Tao, and K. E. Uhrich. Novel amphiphilic macromolecules and their in vitro characterization as stabilized micellar drug delivery systems. J. Colloid Interface Sci. 298:102–110 (2006).PubMedCrossRefGoogle Scholar
  110. 110.
    F. Wang, T. K. Bronich, A. V. Kabanov, R. D. Rauh, and J. Roovers. Synthesis and evaluation of a star amphiphilic block copolymer from poly(epsilon-caprolactone) and poly(ethylene glycol) as a potential drug delivery carrier. Bioconjug. Chem. 16:397–405 (2005).PubMedCrossRefGoogle Scholar
  111. 111.
    H. Arimura, Y. Ohya, and T. Ouchi. Formation of core-shell type biodegradable polymeric micelles from amphiphilic poly(aspartic acid)-block-polylactide diblock copolymer. Biomacromolecules 6:720–725 (2005).PubMedCrossRefGoogle Scholar
  112. 112.
    D. D. Lasic, M. C. Woodle, F. J. Martin, and T. Valentincic. Phase behavior of “stealth-lipid” decithin mixtures. Period. Biol. 93:287–290 (1991).Google Scholar
  113. 113.
    S. J. Duquemin and J. R. Nixon. The effect of sodium lauryl sulphate, cetrimide and polysorbate 20 surfactants on complex coacervate volume and droplet size. J. Pharm. Pharmacol. 37: 698–702 (1985).PubMedGoogle Scholar
  114. 114.
    V. T. Torchilin, A. N. Lukyanov, Z. Gao, and B. Papahadjopoulos-Sternberg. Proc. Natl. Acad. Sci. USA 100:6039–6044. (2003).PubMedCrossRefGoogle Scholar
  115. 115.
    A. N. Lukyanov, Z. Gao, L. Mazzola, and V. P. Torchilin. Polyethylene glycol-diacyllipid micelles demonstrate increased acculumation in subcutaneous tumors in mice. Pharm. Res. 19: 1424–1429 (2002).PubMedCrossRefGoogle Scholar
  116. 116.
    A. N. Lukyanov, W. C. Hartner, and V. P. Torchilin. Increased accumulation of peg-pe micelles in the area of experimental myocardial infarction in rabbits. J. Control. Release 94:187–193 (2004).PubMedCrossRefGoogle Scholar
  117. 117.
    J. Wang, D. A. Mongayt, A. N. Lukyanov, T. S. Levchenko, and V. P. Torchilin. Preparation and in vitro synergistic anticancer effect of vitamin k3 and 1,8-diazabicyclo[5,4,0]undec-7-ene in poly(ethylene glycol)-diacyllipid micelles. Int. J. Pharm. 272:129–135 (2004).PubMedCrossRefGoogle Scholar
  118. 118.
    A. Krishnadas, I. Rubinstein, and H. Onyuksel. Sterically stabilized phospholipid mixed micelles: in vitro evaluation as a novel carrier for water-insoluble drugs. Pharm. Res. 20:297–302 (2003).PubMedCrossRefGoogle Scholar
  119. 119.
    Z. Gao, A. Lukyanov, A. Singhal, and V. Torchilin. Diacylipid-polymer micelles as nanocarriers for poorly soluble anticancer drugs. Nano Lett. 2:979–982 (2002).CrossRefGoogle Scholar
  120. 120.
    R. Nagarajan and K. Ganesh. Block copolymer self-assembly in selective solvents: theory of solubilization in spherical micelles. Macromolecules 22:4312–4325 (1989).CrossRefGoogle Scholar
  121. 121.
    L. Xing, and W. L. Mattice. Large internal structures of micelles of triblock copolymers with small insoluble molecules in their cores. Langmuir 14:4074–4080 (1998).CrossRefGoogle Scholar
  122. 122.
    C. Allen, D. Maysinger and A. Eisenberg. Nano-engineering block copolymer aggregates for drug delivery. Colloids Surf., B Biointerfaces 16:1–35 (1999).CrossRefGoogle Scholar
  123. 123.
    S. Y. Lin and Y. Kawashima. The influence of three poly(oxyethylene)poly(oxypropylene) surface-active block copolymers on the solubility behavior of indomethacin. Pharm. Acta Helv. 60:339–344 (1985)PubMedGoogle Scholar
  124. 124.
    S. Y. Lin and Y. Kawashima. Pluronic surfactants affecting diazepam solubility, compatibility, and adsorption from i.v. admixture solutions. J. Parenter. Sci. Technol. 41:83–87 (1987).PubMedGoogle Scholar
  125. 125.
    M. Yokoyama, T. Okano, and K. Kataoka. Improved synthesis of adriamycin-conjugated poly(ethylene oxide)-poly(aspartic acid) block copolymer and formation of unimodal micellar structure with controlled amount of physically entrapped adriamycin. J. Control. Release 32:269–277 (1994).CrossRefGoogle Scholar
  126. 126.
    M. Yokoyama, S. Fukushima, R. Uehara, K. Okamoto, K. Kataoka, and Y. Sakurai et al. Characterization of physical entrapment and chemical conjugation of adriamycin in polymeric micelles and their design for in vivo delivery to a solid tumor. J. Control. Release 50:79–92 (1998).PubMedCrossRefGoogle Scholar
  127. 127.
    M. Yokoyama, A. Satoh, Y. Sakurai, T. Okano, Y. Matsumura, and T. Kakizoe et al. Incorporation of water-insoluble anticancer drug into polymeric micelles and control of their particle size. J. Control. Release 55:219–229 (1998).PubMedCrossRefGoogle Scholar
  128. 128.
    E. V. Batrakova, T. Y. Dorodnych, E. Y. Klinskii, E. N. Kliushnenkova, O. Shemchukova, and O. N. Goncharova et al. Anthracycline antibiotics non-covalently incorporated into the block copolymer micelles: in vivo evaluation of anti-cancer activity. Brit. J. Cancer 74:1545–1552 (1996).PubMedGoogle Scholar
  129. 129.
    A. V. Kabanov, I. R. Nazarova, I. R. Astafieva, E. V. Batrakova V. Yu. Alakhov, and A. A. Yaroslavov et al. Micelle formation and solubilization of fluorescence probes in poly(oxyethylene-b-oxypropylene-b-oxyethylene) solutions. Macromolecules 28:2303–2314 (1995).CrossRefGoogle Scholar
  130. 130.
    A. V. Kabanov, S. V. Vinogradov, U. G. Suzdaltseva, and V. Yu. Alakhov. Water-soluble block polycations as carriers for oligonucleotide delivery. Bioconjug. Chem. 6:639–643 (1995).PubMedCrossRefGoogle Scholar
  131. 131.
    V. Yu. Alakhov and A. V. Kabanov. Block copolymeric biotransport carriers as versatile vehicles for drug delivery. Expert Opin. Investig. Drugs 7:1453–1473 (1998).PubMedCrossRefGoogle Scholar
  132. 132.
    Y. Matsumura, M. Yokoyama, K. Kataoka, T. Okano, Y. Sakurai and T. Kawaguchi et al. Reduction of the side effects of an antitumor agent, KRN5500, by incorporation of the drug into polymeric micelles. Jpn. J. Cancer Res. 90:122–128 (1999).PubMedGoogle Scholar
  133. 133.
    G. S. Kwon, M. Yokoyama, T. Okano, Y. Sakurai, and K. Kataoka. Biodistribution of micelle-forming polymer–drug conjugates. Pharm. Res. 10:970–974 (1993).PubMedCrossRefGoogle Scholar
  134. 134.
    G. S. Kwon, S. Suwa, M. Yokoyama, T. Okano, Y. Sakurai, and K. Kataoka. Enhanced tumor accumulation and prolonged circulation times of micelles-forming poly(ethylene oxide-aspartate) block copolymers-adriamycin conjugates. J. Control. Release 29:17–23 (1994).CrossRefGoogle Scholar
  135. 135.
    K. Kataoka, G. S. Kwon, M. Yokoyama, T. Okano, and Y. Sakurai. Block-copolymer micelles as vehicles for drug delivery. J. Control. Release 24:119–132 (1993).CrossRefGoogle Scholar
  136. 136.
    G. Kwon, M. Naito, M. Yokoyama, T. Okano, Y. Sakurai, and K. Kataoka. Micelles based on ab block copolymers of poly(ethylene oxide) and poly(benzyl-aspartat). Langmuir 9:945–949 (1993).CrossRefGoogle Scholar
  137. 137.
    G. S. Kwon and T. Okano. Polymeric micelles as new drug carriers. Adv. Drug Deliv. Rev. 21:107–116 (1996).CrossRefGoogle Scholar
  138. 138.
    C. Allen, J. Han, Y. Yu, D. Maysinger, and A. Eisenberg. Polycaprolactone-b-poly(ethylene oxide) copolymer micelles as a delivery vehicle for dihydrotestosterone. J. Control. Release 63:275–286 (2000).PubMedCrossRefGoogle Scholar
  139. 139.
    V. S. Trubetskoy and V. P. Torchilin. Polyethylene glycol based micelles as carriers of therapeutic and diagnostic agents. STP Pharma. Sci. 6:79–86 (1996).Google Scholar
  140. 140.
    J. Wang, D. Mongayt, and V. P. Torchilin. Polymeric micelles for delivery of poorly soluble drugs: preparation and anticancer activity in vitro of paclitaxel incorporated into mixed micelles based on poly(ethylene glycol)-lipid conjugate and positively charged lipids. J. Drug Target. 13:73–80 (2005).PubMedCrossRefGoogle Scholar
  141. 141.
    K. M. Huh, S. C. Lee, Y. W. Cho, J. Lee, J. H. Jeong, and K. Park. Hydrotropic polymer micelle system for delivery of paclitaxel. J. Control. Release 101:59–68 (2005).PubMedCrossRefGoogle Scholar
  142. 142.
    H. Lee, F. Zeng, M. Dunne, and C. Allen. Methoxy poly(ethylene glycol)-block-poly(delta-valerolactone) copolymer micelles for formulation of hydrophobic drugs. Biomacromolecules 6:3119–3128 (2005).PubMedCrossRefGoogle Scholar
  143. 143.
    M. Watanabe, K. Kawano, M. Yokoyama, P. Opanasopit, T. Okano, and Y. Maitani. Preparation of camptothecin-loaded polymeric micelles and evaluation of their incorporation and circulation stability. Int. J. Pharm. 308:183–189 (2006).PubMedCrossRefGoogle Scholar
  144. 144.
    L. Mu, T. A. Elbayoumi, and V. P. Torchilin. Mixed micelles made of poly(ethylene glycol)–phosphatidylethanolamine conjugate and d-alpha-tocopheryl polyethylene glycol 1000 succinate as pharmaceutical nanocarriers for camptothecin. Int. J. Pharm. 306:142–149 (2005).PubMedCrossRefGoogle Scholar
  145. 145.
    P. Opanasopit, M. Yokoyama, M. Watanabe, K. Kawano, Y. Maitani, and T. Okano. Block copolymer design for camptothecin incorporation into polymeric micelles for passive tumor targeting. Pharm. Res. 21:2001–2008 (2004).PubMedCrossRefGoogle Scholar
  146. 146.
    P. Xu, E. A. Van Kirk, S. Li, W. J. Murdoch, J. Ren, M. D. Hussain, M. Radosz, and Y. Shen. Highly stable core-surface-crosslinked nanoparticles as cisplatin carriers for cancer chemotherapy. Colloids Surf., B Biointerfaces 48:50–57 (2006).CrossRefGoogle Scholar
  147. 147.
    A. A. Exner, T. M. Krupka, K. Scherrer, and J. M. Teets. Enhancement of carboplatin toxicity by pluronic block copolymers. J. Control. Release 106:188–197 (2005).PubMedCrossRefGoogle Scholar
  148. 148.
    H. Cabral, N. Nishiyama, S. Okazaki, H. Koyama, and K. Kataoka. Preparation and biological properties of dichloro(1,2-diaminocyclohexane)platinum(ii) (dachpt)-loaded polymeric micelles. J. Control. Release 101:223–232 (2005).PubMedCrossRefGoogle Scholar
  149. 149.
    H. M. Aliabadi, A. Mahmud, A. D. Sharifabadi, and A. Lavasanifar. Micelles of methoxy poly(ethylene oxide)-b-poly(epsilon-caprolactone) as vehicles for the solubilization and controlled delivery of cyclosporine a. J. Control. Release 104: 301–311 (2005).PubMedGoogle Scholar
  150. 150.
    H. M. Aliabadi, D. R. Brocks, and A. Lavasanifar. Polymeric micelles for the solubilization and delivery of cyclosporine a: pharmacokinetics and biodistribution. Biomaterials 26:7251–7259 (2005).PubMedCrossRefGoogle Scholar
  151. 151.
    P. Lim Soo, J. Lovric, P. Davidson, D. Maysinger, and A. Eisenberg. Polycaprolactone-block-poly(ethylene oxide) micelles: a nanodelivery system for 17beta-estradiol. Mol. Pharmacol. 2:519–527 (2005).CrossRefGoogle Scholar
  152. 152.
    R. Vakil and G. S. Kwon. Peg-phospholipid micelles for the delivery of amphotericin b. J. Control. Release 101:386–389 (2005).PubMedGoogle Scholar
  153. 153.
    J. Liu, F. Zeng, and C. Allen. Influence of serum protein on polycarbonate-based copolymer micelles as a delivery system for a hydrophobic anti-cancer agent. J. Control. Release 103: 481–497 (2005).PubMedCrossRefGoogle Scholar
  154. 154.
    L. Ould-Ouali, M. Noppe, X. Langlois, B. Willems, P. Te Riele, P. Timmerman, M. E. Brewster, A. Arien, and V. Preat. Self-assembling peg-p(cl-co-tmc) copolymers for oral delivery of poorly water-soluble drugs: a case study with risperidone. J. Control. Release 102:657–668 (2005).PubMedCrossRefGoogle Scholar
  155. 155.
    S. V. Vinogradov, E. V. Batrakova, S. Li, and A. V. Kabanov. Mixed polymer micelles of amphiphilic and cationic copolymers for delivery of antisense oligonucleotides. J. Drug Target. 12:517–526 (2004).PubMedCrossRefGoogle Scholar
  156. 156.
    R. B. Greenwald, C. W. Gilbert, A. Pendri, C. D. Conover, J. Xia, and A. Martinez. Drug delivery systems: water soluble taxol 2′-poly(ethylene glycol) ester prodrugs-design and in vivo effectiveness. J. Med. Chem. 39:424–431 (1996).PubMedCrossRefGoogle Scholar
  157. 157.
    M. Hans, K. Shimoni, D. Danino, S. J. Siegel, and A. Lowman. Synthesis and characterization of mpeg-pla prodrug micelles. Biomacromolecules 6:2708–2717 (2005).PubMedCrossRefGoogle Scholar
  158. 158.
    Z. Gao, A. N. Lukyanov, A. R. Chakilam, and V. P. Torchilin. Peg-pe/phosphatidylcholine mixed immunomicelles specifically deliver encapsulated taxol to tumor cells of different origin and promote their efficient killing. J. Drug Target. 11:87–92 (2003).PubMedCrossRefGoogle Scholar
  159. 159.
    S. Alkan-Onyuksel, H. B. Ramakrishnan, and J. M. Chai. Pezzuto, a mixed micellar formulation suitable for the parenteral administration of taxol. Pharm. Res. 11:206–212 (1994).PubMedCrossRefGoogle Scholar
  160. 160.
    H. Maeda, T. Sawa, and T. Konno. Mechanism of tumor-targeted delivery of macromolecular drugs, including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug smancs. J. Control. Release 74:47–61 (2001).PubMedCrossRefGoogle Scholar
  161. 161.
    V. Weissig, K. R. Whiteman, and V. P. Torchilin. Accumulation of protein-loaded long-circulating micelles and liposomes in subcutaneous Lewis lung carcinoma in mice. Pharm. Res. 15:1552–1556 (1998).PubMedCrossRefGoogle Scholar
  162. 162.
    F. Yuan, M. Leunig, S. K. Huang, D. A. Berk, D. Papahadjopoulos, and R. K. Jain. Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft. Cancer Res. 54:3352–3356 (1994).PubMedGoogle Scholar
  163. 163.
    S. K. Hobbs, W. L. Monsky, F. Yuan, W. G. Roberts, L. Griffith, V. P. Torchilin, and R. K. Jain. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl. Acad. Sci. U. S. A. 95:4607–4612 (1998).PubMedCrossRefGoogle Scholar
  164. 164.
    W. L. Monsky, D. Fukumura, T. Gohongi, M. Ancukiewcz, H. A. Weich, and V. P. Torchilin et al. Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor. Cancer Res. 59:4129–4135 (1999).PubMedGoogle Scholar
  165. 165.
    M. Yokoyama, T. Okano, Y. Sakurai, S. Fukushima, K. Okamoto, and K. Kataoka. Selective delivery of adriamycin to a solid tumor using a polymeric micelle carrier system. J. Drug Target. 7:171–186 (1999).PubMedCrossRefGoogle Scholar
  166. 166.
    M. J. Parr, D. Masin, P. R. Cullis, and M. B. Bally. Accumulation of liposomal lipid and encapsulated doxorubicin in murine Lewis lung carcinoma: the lack of beneficial effects by coating liposomes with poly(ethylene glycol). J. Pharmacol. Exp. Ther. 280:1319–1327 (1997).PubMedGoogle Scholar
  167. 167.
    G. Helmlinger, F. Yuan, M. Dellian, and R. K. Jain. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat. Med. 3:177–182 (1997).PubMedCrossRefGoogle Scholar
  168. 168.
    I. F. Tannock and D. Rotin. Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res. 49:4373–4384 (1989).PubMedGoogle Scholar
  169. 169.
    F. Kohori, K. Sakai, T. Aoyagi, M. Yokoyama, Y. Sakurai, and T. Okano. Preparation an characterization of thermally responsive block copolymer micelles comprising poly(N-isopropylacrylamide-b-DL-lactide). J. Control. Release 55:87–98 (1998).PubMedCrossRefGoogle Scholar
  170. 170.
    O. Meyer, D. Papahadjopoulos, and J. C. Leroux. Copolymers of N-isopropylacrylamide can trigger pH sensitivity to stable liposomes. FEBS Lett. 41:61–64 (1998).CrossRefGoogle Scholar
  171. 171.
    S. Cammas, K. Suzuki, C. Sone, Y. Sakurai, K. Kataoka, and T. Okano. Thermorespensive polymer nanoparticles with a core-shell micelle structure as site specific drug carriers. J. Control. Release 48:157–164 (1997).CrossRefGoogle Scholar
  172. 172.
    V. P. Sant, D. Smith, and J. C. Leroux. Novel pH-sensitive supramolecular assemblies for oral delivery of poorly water soluble drugs: preparation and characterization. J. Control. Release 97:301–312 (2004).PubMedCrossRefGoogle Scholar
  173. 173.
    H. S. Yoo, E. A. Lee, and T. G. Park. Doxorubicin-conjugated biodegradable polymeric micelles having acid-cleavable linkages. J. Control. Release 82:17–27 (2002).PubMedCrossRefGoogle Scholar
  174. 174.
    M. C. Jones, M. Ranger, and J. C. Leroux. pH-sensitive unimolecular polymeric micelles: synthesis of a novel drug carrier. Bioconjug. Chem. 14:774–781 (2003).PubMedCrossRefGoogle Scholar
  175. 175.
    C. H. Wang, C. H. Wang, and G. H. Hsiue. Polymeric micelles with a ph-responsive structure as intracellular drug carriers. J. Control. Release 108:140–149 (2005).PubMedCrossRefGoogle Scholar
  176. 176.
    G. H. Hsiue, C. H. Wang, C. L. Lo, C. H. Wang, J. P. Li, and J. L. Yang. Environmental-sensitive micelles based on poly(2-ethyl-2-oxazoline)-b-poly(l-lactide) diblock copolymer for application in drug delivery. Int. J. Pharm. 317:69–75 (2006).PubMedCrossRefGoogle Scholar
  177. 177.
    C. Giacomelli, L. Le Men, R. Borsali, J. Lai-Kee-Him, A. Brisson, S. P. Armes, and A. L. Lewis. Phosphorylcholine-based ph-responsive diblock copolymer micelles as drug delivery vehicles: light scattering, electron microscopy, and fluorescence experiments. Biomacromolecules 7:817–828 (2006).PubMedCrossRefGoogle Scholar
  178. 178.
    W. S. Shim, S. W. Kim, E. K. Choi, H. J. Park, J. S. Kim, and D. S. Lee. Novel pH sensitive block copolymer micelles for solvent free drug loading. Macromol. Biosci. 6:179–186 (2006).PubMedCrossRefGoogle Scholar
  179. 179.
    M. Hruby, C. Konak, and K. Ulbrich. Polymeric micellar pH-sensitive drug delivery system for doxorubicin. J. Control. Release 103:137–148 (2005).PubMedCrossRefGoogle Scholar
  180. 180.
    Y. Bae, N. Nishiyama, S. Fukushima, H. Koyama, M. Yasuhiro, and K. Kataoka. 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 (2005).PubMedCrossRefGoogle Scholar
  181. 181.
    C. F. Van Norstrum, D. Naradovic, J. Barends, M. J. Van Steenbergen, and W. E. Hennink. Nanoparticles and hydrogels with transient stability from thermosensitive block copolymers. Proceedings of 30th CRS Meeting, UK (2003) #163.Google Scholar
  182. 182.
    H. Yan and K. Tsujii. Potential application of poly(n-isopropylacrylamide) gel containing polymeric micelles to drug delivery systems. Colloids Surf., B Biointerfaces 46:142–146 (2005).CrossRefGoogle Scholar
  183. 183.
    H. Wei, X. Z. Zhang, Y. Zhou, S. X. Cheng, and R. X. Zhuo. Self-assembled thermoresponsive micelles of poly(n-isopropylacrylamide-b-methyl methacrylate). Biomaterials 27:2028–2034 (2006).PubMedCrossRefGoogle Scholar
  184. 184.
    S. Q. Liu, Y. W. Tong, and Y. Y. Yang. 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-c o-glycolide) with varying compositions. Biomaterials 26:5064–5074 (2005).PubMedCrossRefGoogle Scholar
  185. 185.
    J. E. Chung, M. Yokoyama, M. Yamato, T. Aoyagi, Y. Sakurai, and T. Okano. Thermo-responsive drug delivery from polymeric micelles constructed using block copolymers of poly(N-isopropylacrylamide) and poly(butylmethacrylate). J. Control. Release 62:115–127 (1999).PubMedCrossRefGoogle Scholar
  186. 186.
    N. Rapoport, W. G. Pitt, H. Sun, and J. L. Nelson. Drug delivery in polymeric micelles: from in vitro to in vivo. J. Control. Release 91:85–95 (2003).PubMedCrossRefGoogle Scholar
  187. 187.
    Z. G. Gao, H. D. Fain, and N. Rapoport. Controlled and targeted tumor chemotherapy by micellar-encapsulated drug and ultrasound. J. Control. Release 102:203–222 (2005).PubMedCrossRefGoogle Scholar
  188. 188.
    V. P. Torchilin. Targeted polymeric micelles for delivery of poorly soluble drugs. Cell. Mol. Life Sci. 61:2549–2559 (2004).PubMedCrossRefGoogle Scholar
  189. 189.
    S. Vinogradov, E. Batrakova, S. Li, and A. Kabanov. Polyion complex micelles with protein-modified corona for receptor-mediated delivery of oligonucleotides into cells. Bioconjug. Chem. 10:851–860 (1999).PubMedCrossRefGoogle Scholar
  190. 190.
    V. P. Chekhonin, A. V. Kabanov, Y. A. Zhirkov, and G. V. Morozov. Fatty acid acylated Fab-fragments of antibodies to neurospecific proteins as carriers for neuroleptic targeted delivery in brain. FEBS Lett. 287:149–152 (1991).PubMedCrossRefGoogle Scholar
  191. 191.
    Y. Nagasaki, K. Yasugi, Y. Yamamoto, A. Harada, and K. Kataoka. Sugar-installed block copolymer micelles: their preparation and specific interaction with lectin molecules. Biomacromolecules 2:1067–1070 (2001).PubMedCrossRefGoogle Scholar
  192. 192.
    E. Jule, Y. Nagasaki, and K. Kataoka. Lactose-installed poly(ethylene glycol)-poly(d,l-lactide) block copolymer micelles exhibit fast-rate binding and high affinity toward a protein bed simulating a cell surface. A surface plasmon resonance study. Bioconjug. Chem. 14:177–186 (2003).PubMedCrossRefGoogle Scholar
  193. 193.
    M. Ogris, S. Brunner, S. Schuller, R. Kircheis, and E. Wagner. PEGylated DNA/transferrin-PEI complexes: reduced interaction with blood components, extended circulation in blood and potential for systemic gene delivery. Gene Ther. 6:595–605 (1999).PubMedCrossRefGoogle Scholar
  194. 194.
    P. R. Dash, M. L. Read, K. D. Fisher, K. A. Howard, M. Wolfert, D. Oupicky, V. Subr, J. Strohalm, K. Ulbrich, and L. W. Seymour. Decreased binding to proteins and cells of polymeric gene delivery vectors surface modified with a multivalent hydrophilic polymer and retargeting through attachment of transferrin. J. Biol. Chem. 275:3793–802 (2000).PubMedCrossRefGoogle Scholar
  195. 195.
    C. P. Leamon, D. Weigl, and R. W. Hendren. Folate copolymer-mediated transfection of cultured cells. Bioconjug. Chem. 10:947–957. (1999).PubMedCrossRefGoogle Scholar
  196. 196.
    C. P. Leamon and P. S. Low. Folate-mediated targeting: from diagnostics to drug and gene delivery. Drug Discov. Today 6:44–51 (2001).PubMedCrossRefGoogle Scholar
  197. 197.
    J. H. Jeong, S. H. Kim, S. W. Kim, and T. G. Park. In vivo tumor targeting of odn-peg-folic acid/pei polyelectrolyte complex micelles. J. Biomater. Sci., Polym. Ed. 16:1409–1419 (2005).CrossRefGoogle Scholar
  198. 198.
    E. S. Lee, K. Na, and Y. H. Bae. Polymeric micelle for tumor pH and folate-mediated targeting. J. Control. Release 91:103–113 (2003).PubMedCrossRefGoogle Scholar
  199. 199.
    E. S. Lee, K. Na, and Y. H. Bae. Doxorubicin loaded pH-sensitive polymeric micelles for reversal of resistant mcf-7 tumor. J. Control. Release 103:405–418 (2005).PubMedCrossRefGoogle Scholar
  200. 200.
    V. P. Torchilin, T. S. Levchenko, A. N. Lukyanov, B. A. Khaw, A. L. Klibanov, R. Rammohan, G. P. Samokhin, and K. R. Whiteman. p-Nitrophenylcarbonyl-PEG–PE-liposomes: fast and simple attachment of specific ligands, including monoclonal antibodies, to distal ends of PEG chains via p-nitrophenylcarbonyl groups. Biochim. Biophys. Acta 1511:397–411 (2001).PubMedCrossRefGoogle Scholar
  201. 201.
    L. Z. Iakoubov and V. P. Torchilin. A novel class of antitumor antibodies: nucleosome-restricted antinuclear autoantibodies (ANA) from healthy aged nonautoimmune mice. Oncol. Res. 9:439–446 (1997).PubMedGoogle Scholar
  202. 202.
    J. H. Felgner, R. Kumar, C. N. Sridhar, C. J. Wheeler, Y. J. Tsai, R. Border, P. Ramsey, M. Martin, and P. L. Felgner. Enhanced gene delivery and mechanism studies with a novel series of cationic lipid formulations. J. Biol. Chem. 269:2550–2561 (1994).PubMedGoogle Scholar
  203. 203.
    T. Ota, M. Maeda, and M. Tatsuka. Cationic liposomes with plasmid DNA influence cancer metastatic capability. Anticancer Res. 22:4049–4052 (2002).PubMedGoogle Scholar
  204. 204.
    S. Kaiser, and M. Toborek. Liposome-mediated high-efficiency transfection of human endothelial cells. J. Vasc. Res. 38: 133–143 (2001).PubMedCrossRefGoogle Scholar
  205. 205.
    M. R. Almofti, H. Harashima, Y. Shinohara, A. Almofti, Y. Baba, and H. Kiwada. Cationic liposome-mediated gene delivery: Biophysical study and mechanism of internalization. Arch. Biochem. Biophys. 410:246–253 (2003).PubMedCrossRefGoogle Scholar
  206. 206.
    I. M. Hafez, N. Maurer, and P. R. Cullis. On the mechanism whereby cationic lipids promote intracellular delivery of polynucleic acids. Gene Ther. 8:1188–1196 (2001).PubMedCrossRefGoogle Scholar
  207. 207.
    R. Ni, Y. Nishikawa, and B. I. Carr. Cell growth inhibition by a novel vitamin k is associated with induction of protein tyrosine phosphorylation. J. Biol. Chem. 273:9906–9911 (1998).PubMedCrossRefGoogle Scholar
  208. 208.
    V. P. Torchilin. Peg-based micelles as carriers of contrast agents for different imaging modalities. Adv. Drug Deliv. Rev. 54: 235–252 (2002).PubMedCrossRefGoogle Scholar
  209. 209.
    U. P. Schmiedl, J. A. Nelson, L. Teng, F. Starr, R. Malek, and R. J. Ho. Magnetic resonance imaging of the hepatobiliary system: intestinal absorption studies of manganese mesoporphyrin. Acad. Radiol. 2:994–1001 (1995).PubMedCrossRefGoogle Scholar
  210. 210.
    C. W. Grant, S. Karlik, and E. Florio. A liposomal MRI contrast agent: phosphatidylethanolamine-dtpa. Magn. Reson. Med. 11:236–243 (1989).PubMedGoogle Scholar
  211. 211.
    G. W. Kabalka, E. Buonocore, K. Hubner, M. Davis, and L. Huang. Gadolinium-labeled liposomes containing paramagnetic amphipathic agents: targeted MRI contrast agents for the liver. Magn. Reson. Med. 8:89–95 (1988).PubMedGoogle Scholar
  212. 212.
    E. Unger, T. Fritz, G. Wu, D. Shen, B. Kulik, T. New, M. Crowell, and N. Wilke. Liposomal MR contrast agents. J. Liposome Res. 4:811–834 (1994).Google Scholar
  213. 213.
    V. S. Trubetskoy, M. D. Frank-Kamenetsky, K. R. Whiteman, G. L. Wolf, and V. P. Torchilin. Stable polymeric micelles: lymphangiographic contrast media for gamma scintigraphy and magnetic resonance imaging. Acad. Radiol. 3:232–238 (1996).PubMedCrossRefGoogle Scholar
  214. 214.
    V. S. Trubetskoy, and V. P. Torchilin. New approaches in the chemical design of Gd-containing liposomes for use in magnetic resonance imaging of lymph nodes. J. Liposome Res. 4:961–980 (1994).Google Scholar
  215. 215.
    G. Wolf. Targeted delivery of imaging agents: an overview. In V. P. Torchilin (ed.), Handbook of Targeted Delivery of Imaging Agents. CRC, Boca Raton, Florida, 1995, pp. 3–22.Google Scholar
  216. 216.
    W. Krause, J. Leike, A. Sachse, and G. Schuhmann-Giampieri. Characterization of iopromide liposomes. Invest. Radiol. 28: 1028–1032 (1993).PubMedCrossRefGoogle Scholar
  217. 217.
    P. Leander. A new liposomal contrast medium for CT of the liver. An imaging study in a rabbit tumour model. Acta Radiol. 37:63–68 (1996).PubMedCrossRefGoogle Scholar
  218. 218.
    V. P. Torchilin, M. D. Frank-Kamenetsky, and G. L. Wolf. CT visualization of blood pool in rats by using long-circulating, iodine-containing micelles. Acad. Radiol. 6:61–65 (1999).PubMedCrossRefGoogle Scholar
  219. 219.
    V. I. Slepnev, L. E. Kuznetsova, A. N. Gubin, E. V. Batrakova, V. Alakhov, and A. V. Kabanov. Micelles of poly(oxyethylene)-poly(oxypropylene) block copolymer (pluronic) as a tool for low-molecular compound delivery into a cell: phosphorylation of intracellular proteins with micelle incorporated [gamma-32p]atp. Biochem. Int. 26:587–595 (1992).PubMedGoogle Scholar
  220. 220.
    T. Nakanishi, S. Fukushima, K. Okamoto, M. Suzuki, Y. Matsumura, M. Yokoyama, T. Okano, Y. Sakurai, and K. Kataoka. Development of the polymer micelle carrier system for doxorubicin. J. Control. Release 74:295–302 (2001).PubMedCrossRefGoogle Scholar
  221. 221.
    H. Uchino, Y. Matsumura, T. Negishi, F. Koizumi, T. Hayashi, T. Honda, N. Nishiyama, K. Kataoka, S. Naito, and T. Kakizoe. Cisplatin-incorporating polymeric micelles (NC-6004) can reduce nephrotoxicity and neurotoxicity of cisplatin in rats. Br. J. Cancer 93:678–687 (2005).PubMedCrossRefGoogle Scholar
  222. 222.
    T. Y. Kim, D. W. Kim, J. Y. Chung, S. G. Shin, S. C. Kim, D. S. Heo, N. K. Kim, and Y. J. Bang. Phase I and pharmacokinetic study of Genexol-PM, a cremophor-free, polymeric micelle-formulated paclitaxel, in patients with advanced malignancies. Clin. Cancer Res. 10:3708–3716 (2004).PubMedCrossRefGoogle Scholar
  223. 223.
    T. Trimaille, K. Mondon, R. Gurny, and M. Moller. Novel polymeric micelles for hydrophobic drug delivery based on biodegradable poly(hexyl-substituted lactides). Int. J. Pharm. 319:147–154 (2006).PubMedCrossRefGoogle Scholar
  224. 224.
    M. N. Sibata, A. C. Tedesco, and J. M. Marchetti. Photophysicals and photochemicals studies of zinc(ii) phthalocyanine in long time circulation micelles for photodynamic therapy use. Eur. J. Pharm. Sci. 23:131–138 (2004).PubMedCrossRefGoogle Scholar
  225. 225.
    A. K. Gupta, S. Madan, D. K. Majumdar, and A. Maitra. Ketorolac entrapped in polymeric micelles: preparation, characterisation and ocular anti-inflammatory studies. Int. J. Pharm. 209:1–14 (2000).PubMedCrossRefGoogle Scholar
  226. 226.
    M. H. Dufresne, D. L. Garrec, V. Sant, J. C. Leroux, and M. Ranger. Preparation and characterization of water-soluble ph-sensitive nanocarriers for drug delivery. Int. J. Pharm. 277: 81–90 (2004).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and NanomedicineNortheastern UniversityBostonUSA

Personalised recommendations