Site Specific Drug-Carriers : Polymeric Micelles as High Potential Vehicles for Biologically Active Molecules

  • Sandrine Cammas
  • Kazunori Kataoka
Part of the NATO ASI Series book series (NSSE, volume 327)


For centuries, men try to overcome the problems of low efficiency of therapeutic molecules by tremendously increasing the amount of administrated drug. However, since nothing is totally inert with regard to living matter, compromises between side effects, such as toxicity, unwanted disposition and degradation, and therapeutic doses have to be found in order to achieve satisfactorily the treatment of a given disease. Unfortunately, such compromises are not always very easy to obtain mainly due to the excessive toxicity of the drug and/or because of its insufficient solubility [1,2].


Block Copolymer Polymeric Micelle Thermosensitive Liposome Macromolecular Prodrug Polyion Complex Micelle 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Vert, M. (1985) Polyvalent polymeric drug carriers, In S.D. Bruck (ed.), Critical Reviews in Therapeutic Drug Carrier Systems, CRC Press Inc., Florida, 2(3), pp. 291–327.Google Scholar
  2. 2.
    Tomlinson, E. (1986) (Patho)physiology and the temporal and spatial aspects of drug delivery, In E. Tomlinson and S.S. Davis (eds.), Site-Specific Drug Delivery, Cell Biology, Medical and Pharmaceutical Aspects, John Wiley &Sons Ltd., 1–26.Google Scholar
  3. 3.
    Ehrlich, P. (1906) Collected Study on Immunology, John Wiley & Sons,New York, 11, 442.Google Scholar
  4. 4.
    Trail, P.A., Willner, D., Lasch, S.J., Henderson, A.J., Hofstead, S., Casazza, A.M., Firestone, R.A., Hellstrom, I. and Hellstrom, K.E. (1993) Cure of xenografted human carcinomas by BR96-Doxorubicin immunoconjugates, Science 261, 212–215.CrossRefGoogle Scholar
  5. 5.
    Uckun, F.M., Evans, W.E., Forsyth, C.J., Waddick, K.G., Ahlgren, L.T., Chelstrom, L.M., Burkhardt, A., Bolen, J. and Myer, D.E. (1995) Biotherapy of B-cell precursor leukemia by targeting genistein to CD19-associated tyrosine kinases, Science 267, 886–891.CrossRefGoogle Scholar
  6. 6.
    Okano, T., Yui, N., Yokoyama and M., Yoshida, R. (1994) Advances in Polymeric Systems for Drug Delivery, T. Ikoma, I. Karube and R. Kuroda (eds.), Japanese Technology Reviews (section E : Biotechnology), Gordon and Breach Science Publishers, 4(1).Google Scholar
  7. 7.
    Maeda, H., Seymour, L.W. and Miyamoto, Y. (1992) Conjugates of anticancer agents and polymers: advantages of macromolecular therapeutic in vivo, Bioconj. Chem. 3(5), 128–139.CrossRefGoogle Scholar
  8. 8.
    Takakura, Y., Takagi, A., Hashida, M. and Sezaki, H. (1987) Disposition and tumor localization of Mitocyn C-dextran conjugates in mice, Pharm. Res. 4(4), 293–300.CrossRefGoogle Scholar
  9. 9.
    Ringsdorf, H. (1975) Structure and properties of pharmacologically active polymers, J. Polym. Sci. : Symposium 51, 135.CrossRefGoogle Scholar
  10. 10.
    Firestone, R.A. (1994) Low-density lipoprotein as a vehicle for targeting antitumor compounds to cancer cells, Bioconj. Chem. 5, 105–113.CrossRefGoogle Scholar
  11. 11.
    Ulbrich, K. (1991) Water-soluble polymeric carriers of drugs, J. Bioactive and Compatible Polymers 6, 348–357.Google Scholar
  12. 12.
    Koch, M. ( December 7–10, 1994) France-Japan DDS Symposium, Advances in Novel science and Technology of Drug Delivery and Targeting.Google Scholar
  13. 13.
    Sezaki, H. and Hashida, M. (1984) Macromolecule-drug conjugates in targeted cancer chemotherapy in CRC Critical Reviews in Therapeutic Drug Carrier Systems, CRC press, Inc., 1(1), 1–38.Google Scholar
  14. 14.
    Bader, H., Ringsdorf, H. and Schmidt, B. (1984) Water-soluble polymers in medicine, Angew. Makromol. Chem. 123/124, 457–485.Google Scholar
  15. 15.
    Hoes, C.J.T. and Feijen, J. (1989) The application of drug-polymer conjugates in chemotherapy, In F.H.D. Roerdink and A.M. Kroon (eds.), Drug Carrier Systems, John Wiley &Sons Ldt., 57–109.Google Scholar
  16. 16.
    Kopecek, J. (1982) Biodegradation of Polymers for Biomedical Use in H Benoit and P. Rempp (eds.), IUPAC Macromolecules , Pergamon, Oxford, 305–320.Google Scholar
  17. 17.
    Kopecek, J. and Duncan, R. (1987) Poly[N-(2-hydroxypropyl)methacrylamide] macromolecules as drug carrier systems in I. Ilium, S.S. Davies and A. Hilger (eds.), Controlled Release of Drugs from Polymer Particles and Macromolecules, Bristol.Google Scholar
  18. 18.
    Kopecek, J. and Duncan, R. (1987) Targetable polymeric prodrugs J. Control. Rel, 5, 315–327.CrossRefGoogle Scholar
  19. 19.
    Rihova, B., Kopecek, J., Ulbrich, K. and Chytry, V. (1985) Makromol. Chem., Supply 9, 13.CrossRefGoogle Scholar
  20. 20.
    Duncan,R. (1985)CRC Critical Reviews in Therapeutic Drug Carrier Systems,., 4, 281.Google Scholar
  21. 21.
    Rihova, B., Strohalm, J., Plocova, D. and Ulbrich, K. (1990) Selectivity of antibodytargeted anthracycline antibiotics on T lymphocytes, J. Bioactive and Compatible Polymers,5, 249–266.CrossRefGoogle Scholar
  22. 22.
    Seymour, L.W., Ulbrich, K., Wedge, S.R., Hume, I.C., Strohalm, J. and Duncan, R. (1991) N-(2-hydroxypropyl)methacrylamide copolymers targeted to the hepatocyte galactose-receptor: pharmacokinetics in DBA2 mice, Br. J. Cancer, 63, 859–866.CrossRefGoogle Scholar
  23. 23.
    Subr, V., Strohalm, J., Ulbrich, K., Duncan, R. and Hume, I.C. (1992) Polymers containing enzymatically degradable bonds, XII. Effect of spacer structure on the rate of release of daunomycin and adriamycin from poly [N-(2-hydroxypropyl)methacrylamide] copolymer drug carriers in vitro and antitumour activity measured in vivo, J. Control. Rel., 8, 123–132.CrossRefGoogle Scholar
  24. 24.
    O’Hare, K.B., Duncan, R., Strohalm, J., Ulbrich, K. and Kopeckova, P. (1993) Polymeric drug-carriers containing Doxorubicin and melanocyte-stimulating hormone: in vitro and in vivo evaluation against murine melanoma, J. Drug Targeting, 1, 217–229.CrossRefGoogle Scholar
  25. 25.
    Krinick, N.L., Sun, Y., Joyner, D., Spikes, J.D., Straight, R.C. and Kopecek, J. (1994) A polymeric drug delivery system for simultaneous delivery of drugs activatable by enzymes and/or light, J. Biomater. Sci. Polymer Edn., 5(4), 303–324.CrossRefGoogle Scholar
  26. 26.
    Rihova, B., Jegorov, A., Strohalm, J., Matha, V., Rossmann, P., Fornusek, L. and Ulbrich, K. (1990) Antibody-targeted cyclosporin A, J. Control. Rel., 19, 25–40.CrossRefGoogle Scholar
  27. 27.
    Rihova, B., Veres, K., Fornusek, L., Ulbrich, K., Strohalm, J., Vetvicka, V., Bilej, M. and Kopecek, J. (1989) Action of polymeric prodrugs based on N-(2-hydroxypropyl)methacrylamide copolymers. II. Body distribution and T-cell accumulation of 1 free and polymer-bound daunomycin, J. Control. Rel., 10, 37–49.CrossRefGoogle Scholar
  28. 28.
    Flanagan, P.A., Duncan, R., Subr, V., Ulbrich, K., Kopeckova, P. and Kopecek, J. (1992) Evaluation of protein-N-(2-hydroxypropyl)-methacrylamide copolymer conjugates as targetable drug-carriers. 2. Body distribution of conjugates containing transferrin, antitransferrin receptor antibody or anti-Thy 1.2 antibody and effectiveness of transferrincontaining daunomycin conjugates against mouse L1210 leukaemia in vivo, J. Control. Rel., 18, 25–38.CrossRefGoogle Scholar
  29. 29.
    Krinick, N.L., Rihova, B., Ulbrich, K., Strohalm, J. and Kopecek, J. (1990) Targetable photoactivable drugs, 2a ) Synthesis of N-(2-hydroxypropyl)methacrylamide copolymeranti- Thy 1.2 antibody-chlorine eft conjugates and a preliminary study of their photodynamic effect on mouse splenocytes in vitro, Makromol Chem, 191, 839–856.CrossRefGoogle Scholar
  30. 30.
    Rihova, B., Krinick, N.L. and Kopecek, J. (1993) Targetable photoactivatable drugs. 3. In vitro efficacy of polymer bound chlorin e£ toward human hepatocarcinoma cell line (PLC/PRF/5) targeted with galactosamine and to mouse splenocytes targeted with anti-Thy 1.2 antibodies, J. Control. Rel., 25, 71–87.CrossRefGoogle Scholar
  31. 31.
    Seymour, L.W., Duncan, R., Chytry, V., Strohalm, J., Ulbrich, K. and Kopecek, J. (1991) Intraperitoneal and subcutaneous retention of a soluble polymeric drug-carrier bearing galactose, J. Control. Rel., 16, 255–262.CrossRefGoogle Scholar
  32. 32.
    Duncan, R., Seymour, L.W., O’Hare, K.B., Flanagan, P.A., Wedge, S., Hume, I.C., Ulbrich, K., Strohalm, J., Subr, V., Spreafico, F, Grandi, M., Ripamonti, M., Farao, M. and Suarato, A. (1992) Preclinical evaluation of polymer-bound doxorubicin, J. Control. Rel., 19, 331–346.CrossRefGoogle Scholar
  33. 33.
    van Heeswijk, W.A.R., Brinks, G.J. and J. Feijen, (1984) Synthesis and characterization of covalently bound polymer-hormone conjugates for the controlled release of hormones, In E. Chiellini and P. Giusti (eds.), Polymers in Medecine, Plenun Publishing Corporation, 147–156.Google Scholar
  34. 34.
    Hoes, C.J.T., Potman, W., de Grooth, B.G., Greve, J. and Feijen, J. (1986) Chemical control of drug delivery in A.F. Harms (ed.), Innovative Approaches in Drug Research, Elsevier Science Publishers B.V., Amsterdam, 267–283.Google Scholar
  35. 35.
    van Heeswijk, W.A.R., Stoffer, T., Eenink, M.J.D., Potman, W., van der Vijgh, W.J.F., Poort, J.V.D., Pinedo, H.M., Lelieveld, P. and Feijen, J. (1984) Synthesis, characterization and antitumour activity of macromolecular prodrugs of adriamycin J.M. Anderson and S.W. Kim (eds.), Recent Advances in Drug Delivery Systems, Plenum Publishing Corporation, 77–100.Google Scholar
  36. 36.
    van Heewijk, W.A.R., Hoes, C.J.T., Stoffer, T., Eenink, M.J.D., Potman, W. and Feijen, J. (1985) The synthesis and characterization of polypeptide-adriamycin conjugates and its complexes with adriamycin. Part I, J. Control. Rel., 1, 301–315.Google Scholar
  37. 37.
    Hoes, C.J.T., Boon, P.J., Kaspersen, F., Bos, E.S. and Feijen, J. (1993) Design of soluble conjugate of biodegradable polymeric carriers and adriamycin, Makromol. Chem, Macromol. Symp., 70/71, 119–136.CrossRefGoogle Scholar
  38. 38.
    Hoes, C.J.T., Grootoonk, J., Duncan, R., Hume, I.C., Bhakoo, M., Bouma, J.M.W. and Feijen, J. (1993) Biological properties of adriamycin bound to biodegradable polymeric carriers, J. Control Rel., 23, 37–54.CrossRefGoogle Scholar
  39. 39.
    Hoes, C.J.T., Grootoonk, J., Feijen, J., Boon, P.J., Kaspersen, F., Loeffen, P., Schlachter, I., Winters, M. and Bos, E.S. (1992) Synthesis and biodistribution of immunoconjugates of a human IgM and polymeric drug carriers, J. Control. Rel., 19, 59–76.CrossRefGoogle Scholar
  40. 40.
    Nukui, M., Hoes, K., van den Berg, H. and Feijen, J. (1991) Association of macromolecular prodrugs consisting of adriamycin bound to poly(L-glutamic acid), Makromol. Chem., 192, 2925–2942.CrossRefGoogle Scholar
  41. 41.
    Chen, G.C. and Hoffman, A.S. (1994) Synthesis of carboxylated poly(NIPAAm) oligomers and their application to form thermo‐reversible polymer‐enzyme conjugates, J. Biomater. Sci. Polymer Edn., 5(4), 371–382.CrossRefGoogle Scholar
  42. 42.
    Heskins, M. and Guillet, J.E. (1968) J. Macromol. Sci., A2, 1441.CrossRefGoogle Scholar
  43. 43.
    Y. Takei, (1994) Temperature‐responsive polymers for biomedical modulation systems, pH.D. Thesis, Sophia University, Tokyo (Japan).Google Scholar
  44. 44.
    Valuev, L.I., Zefirova, O.N., Obydennova, I.V. and Plate, N.A. (1994) Targeted delivery of drugs provided by water-soluble polymeric systems with low critical solution temperature (LCST), J. Bioactive and Compatible Polymers, 9, 55–65.CrossRefGoogle Scholar
  45. 45.
    Takakura, Y., Matsumoto, S., Hashida, M. and Sezaki, H. (1984) Enhanced lymphatic delivery of mitomycin C conjugated with dextran, Cancer Res., 44, 2505–2510.Google Scholar
  46. 46.
    Takakura, Y., Fujita, T., Hashida, M. and Sezaki, H. (1990) Disposition characteristics of macromolecules in tumour-bearing mice, Pharm. Res., 7(4), 339–346.CrossRefGoogle Scholar
  47. 47.
    Fujita, T., Yasuda, Y., Takakura, T., Hashida, M. and Sezaki, H. (1991) Tissue distribution of 111 In-labeled uricase conjugated with charged dextrans and polyethylene glycol, J. Pharmacobio-Dyn., 14, 623–629.Google Scholar
  48. 48.
    Fujita, T., Nishikawa, M., Tamaki, C., Takakura, Y., Hashida, M. and Sezaki, H. (1992) Targeted delivery of human recombinant superoxide dismutase by chemical modification with mono-and polysaccharide derivatives, J. Pharm. Exp. Therap., 263(3) 971–978.Google Scholar
  49. 49.
    Nishikawa, M., Kamijo, A., Fujita, T., Takakura, Y., Sezaki, H. and Hashida, M. (1993) Synthesis and pharmacokinetics of a new liver-specific carrier, glycosylated carboxymethyldextran, and its application to drug targeting, Pharm. Res., 10(9), 1253–1261.CrossRefGoogle Scholar
  50. 50.
    Takakura, Y., Fujita, T., Furitsu, H., Nishikawa, M., Sezaki, H. and Hashida, M. (1994) Pharmacokinetics of succinylated proteins and dextran sulfate in mice: Implications for hepatic targeting of protein drugs by direct succinylation via scavenger receptors, Int. J. Pharm., 105, 19–29.CrossRefGoogle Scholar
  51. 51.
    Kojima, T., Hashida, M., Muranishi, S. and Sezaki, H. (1980) Mitomycin C-dextran conjugate: a novel high molecular weight pro-drug of mitomycin C, J. Pharm. Pharmacol., 32, 30–34.CrossRefGoogle Scholar
  52. 52.
    Malek, P., Kolc, J., Hero Id, M. and Hoffman, J. (1958) Lymphotropic antibiotics- "Antibiolymphins", Antibiotics Annual, New York, Medical Encyclopedia Inc., 546–556.Google Scholar
  53. 53.
    Hashida, M., Nishikawa, M., Yamashita, F. and Takakura, T. (1994) Targeting delivery of protein drugs by chemical modification, Drug Develop. Indust. Pharm., 20(4) 581–590.CrossRefGoogle Scholar
  54. 54.
    Takakura, Y., Masuda, S., Tokuda, H. and Nishikawa, M. (1994) Targeted delivery of superoxide dismutase to macrophages via mannose receptor-mediated mechanism, Biochem. Pharm., 47(5) 853–858.CrossRefGoogle Scholar
  55. 55.
    Fujita, T., Nishikawa, M., Ohtsubo, Y., Onho, J., Takakura, Y., Sezaki, H. and Hashida, M. (1994) Control of in vivo fate of albumin derivatives utilizing combined chemical modification, J. Drug Targ., 2, 157–165.CrossRefGoogle Scholar
  56. 56.
    Nishikawa, M., Ohtsubo, Y., Ohno, J., Fujita, T., Koyama, Y., Yamashita, F., Hashida, M. and Sezaki, H. (1992) Pharmacokinetics of receptor-mediated hepatic uptake of glycosylated albumine in mice, Int. J. Pharm., 85, 75–85.CrossRefGoogle Scholar
  57. 57.
    Leamon, C.P. and Low, P.S. (1992) Cytotoxicity of momordin-folate conjugates in cultured human cells, J. Biol. Chem., 267(35) 24966–24971.Google Scholar
  58. 58.
    Leamon, C.P., Pastan, I. and Low, P.S. (1993) Cytotoxicity of iolate-Pseudomonasexotoxin conjugates toward tumor cells. Contribution of translocation domain,J. Biol. Chem., 268(33) 24847–24854.Google Scholar
  59. 59.
    Leamon, C.P. and Low, P.S. (1993) Membrane folate-binding proteins are responsible for folate-protein conjugate endocytosis into cultured cells, Biochem. J., 291, 855–860.Google Scholar
  60. 60.
    Leamon, C.P. and Low, P.S. (1994) Selective targeting of malignant cells with cytotoxin-folate conjugates, J. Drug Targeting,2, 101–112.CrossRefGoogle Scholar
  61. 61.
    Dougherty, T.J. (1985) Photodynamic Therapy in D. Kessel (ed.), Methods in Porphirin Photosensitization, Plenum press, New York, 313–323.Google Scholar
  62. 62.
    Flynn, G., Hackett, T.J., McHale, L. and McHale, A.P. (1994) Magnetically responsive photosensitizing reagents for possible use in photoradiation therapy, Cancer Letters, 78, 109–114.CrossRefGoogle Scholar
  63. 63.
    Ulbrich, K., Surb, V., Seymour, L.W. and Duncan, R. (1993) Novel biodegradable hydrogels prepared using the divinylic crosslinking agent N,0- dimethacryloylhydroxylamine. 1. Synthesis and characterization of rates of gel degradation, and rate of release of model drugs, in vitro and in vivo, J. Control. Rel., 24, 181–190.CrossRefGoogle Scholar
  64. 64.
    Scholes, P.D., Coombes, A.G.A., Ilium, L., Davis, S.S., Vert, M. and Davies, M.C. (1993) The preparation of sub-200 nm poly(lactide-co-glycolide) microspheres for site specific drug delivery, J. Control. Rel., 25, 145–153.CrossRefGoogle Scholar
  65. 65.
    Davis, S.S., Ilium, L., Moghimi, S.M., Davies, M.C., Porter, C.J.H., Muir, I.S., Brindley, A., Christy, N.M., Norman, M.E., Williams, P. and Dunn, S.E. (1993) Microspheres for targeting drugs to specific body sites, J. Control. Rel., 24, 157–163.CrossRefGoogle Scholar
  66. 66.
    Le Ray, A.M., Vert, M., Gautier, J.C. and Benoît, J.P. (1994) Fate of [14C]poly(DL-lactide- co-glycolide) nanoparticles after intravenous and oral administration to mice, Int. J. Pharm., 106, 201–211.CrossRefGoogle Scholar
  67. 67.
    Mehta, R.C., Jeyanthi, R., Calis, S., Thanoo, B.C., Burton, K.W. and DeLuca, P.P. (1994) Biodegradable microspheres as depot system for parenteral delivery of peptide drugs, J. Control. Rel, 29, 375–384.CrossRefGoogle Scholar
  68. 68.
    Kreuter, J. (1994) Nanoparticles in J. Swarbrich (ed.), Colloidal Drug Delivery Systems in Drugs and Pharmaceutical Sciences, Marcel Dekker, Inc., 219–342.Google Scholar
  69. 69.
    Wu, X.Y. and Lee, P.I. (1993) Preparation and characterization of thermal- and pHsensitive nanospheres, Pharm. Res., 10(10) 1544–1547.CrossRefGoogle Scholar
  70. 70.
    Moghimi, S.M., Hawley, A.E., Christy, N.M., Gray, T., Ilium, L. and Davis, S.S. (1994) Surface engineered nanospheres with enhanced drainage into lymphatics and uptake by macrophages of the regional lymph nodes, FEBS Let., 344, 25–30.CrossRefGoogle Scholar
  71. 71.
    Couvreur, P., Fattal, E. and Andremont, A. (1991) Liposomes and nanoparticles in the treatment of intracellular bacterial infections, Pharm. Res., 8(9) 1079–1086.CrossRefGoogle Scholar
  72. 72.
    Couvreur, P. and Vauthier, C. (1991) Polyalkylcyanoacrylate nanoparticles as drug carrier: present state and persectives, J. Control. Rel., 17, 187–198.CrossRefGoogle Scholar
  73. 73.
    Maincent, P., Thouvenot, P., Amicabile, C., Hoffman, M., Kreuter, J., Couvreur, P. and Devissaguet, J.P. (1992) Lymphatic targeting of polymeric nanoparticles after intraperitoneal administration in rats, Pharm. Res., 9(12) 1534–1539.CrossRefGoogle Scholar
  74. 74.
    Balland, O., Pinto-Alphandary, H., Pecquet, S., Andremont, A. and Couvreur, P. (1994) The uptake of ampicillin-loaded nanoparticles by murine macrophages infected with Salmonella typhimurium, J. Antimicrobial Chemotherapy, 33, 509–522.CrossRefGoogle Scholar
  75. 75.
    Pinto-Alphandary, H., Ballant, O., Laurent, M., Andremont, A., Puisieux, F. and Couvreur, P. (1994) Intracellular visualization of ampicillin-loaded nanoparticles in peritoneal macrophages infected in vitro with Salmonella typhimurium, Pharm. Res.,11(1), 38–46.CrossRefGoogle Scholar
  76. 76.
    Némati, F., Dubernet, C., Colin de Verdiere, A., Poupon, M.F., Trepeul-Acar, L., Puisieux, F. and Couvreur, P. (1994) Some parameters influencing cytotoxicity of free doxorubicin and doxorubicin-loaded nanoparticles in sensitive and multidrug resistant leucemic murine cells: incubation time, number of nanoparticles per cell, Int. J. Pharm., 102, 55–62.CrossRefGoogle Scholar
  77. 77.
    Bennis, S., Chapey, C., Couvreur, P. and Robert, J. (1994) Enhanced cytotoxicity of doxorubicin encapsulated in poly isohexyl-cyano aery late nanospheres against multidrugresistant tumour cells in culture, European J. Cancer, 30 A(l), 89–93.CrossRefGoogle Scholar
  78. 78.
    Poste, G. (1983) Drug targeting in cancer therapy in G. Gregoriadis, G. Poste, J. Senior and A. Trouet (eds.), Receptor-Mediated Targeting of Drugs, Published in cooperation with NATO Scientific Affairs Division, 427–474.Google Scholar
  79. 79.
    Crommelin, D.J.A. and Schreier, H. (1994) Liposomes in J. Swarbrick (ed.), Colloidal Drug Delivery Systems in Drugs and Pharmaceutical Sciences, Marcel Dekker, Inc., 73–190.Google Scholar
  80. 80.
    Ahmad, I., Longenecker, M., Samuel, J. and Allen, T.M. (1993) Antibody-targeted delivery of doxorubicin entrapped in sterically stabilized liposomes can eradicate lung cancer in mice, Cancer Res., 53,1484–1488.Google Scholar
  81. 81.
    Seki, K. and Tirrell, D.A. (1984) pH-dependent complexation of poly(acrylic acid) derivatives with phospholipid vesicles membranes, Macromolecules, 17, 1692–1698.CrossRefGoogle Scholar
  82. 82.
    Thomas, J.L. and Tirrell, D.A. (1992) Polyelectrolyte-sensitized phospholipids vesicles, Acc. Chem. Res., 25(8) 336–342.CrossRefGoogle Scholar
  83. 83.
    Tirrell, D.A., Takigawa, D.Y. and Seki, K. (1985) pH sensitization of phospholipids vesicles via complexation with synthetic poly(carboxylie acid)s, in Macromolecules as Drugs and as Carriers for Biologically Active Materials Vol. 446, Annals of the New York Academy of Sciences, 237–247.Google Scholar
  84. 84.
    Ropert, C., Lavignon, M., Dubernet, C., Couvreur, P. and Malvy, C. (1992) Oligonucleotides encapsulated in pH sensitive liposomes are efficient toward friend retrovirus, Biochem. Biophys. Res. Comm., 183(2) 879–885.CrossRefGoogle Scholar
  85. 85.
    Ropert, C., Malvy, C. and Couvreur, P. (1993) Inhibition of the friend retrovirus by antisense oligonucleotides encapsulated in liposomes: mechanism of action, Pharm. Res., 10(10) 1427–1433.CrossRefGoogle Scholar
  86. 86.
    Magin, R.L. and Weinstein, J.N. (1983) Delivery of drugs in temperature-sensitive liposomes, In G. Gregoriadis, J. Senior and A. Trouet (eds.), Targeting of drugs, Plenun Press New York and London, Published in Cooperation with NATO Scientific Affairs Division, 203–221.Google Scholar
  87. 87.
    Oku, N., Naruse, R., Doi, K. and Okada, S. (1994) Potential usage of thermosensitive liposomes for macromolecule delivery, Biochem. Biophys. Act., 1191, 389–391.CrossRefGoogle Scholar
  88. 88.
    Merlin, J.M., Marechal, S., Ramacci, C., Notter, D. and Vigneron, C. (1993) Antiproliferative activity of thermosensitive liposome-encaspulated doxorubicin combined with 43 °C hyperthermia in sensitive and multi drug-resistant MCF-7 cells, European J. cancer, 29 A(16) 2264–2268.CrossRefGoogle Scholar
  89. 89.
    Lee, R.J. and Low, P.S. (1994) Delivery of liposomes into cultured KB cells via folate receptor-mediated endocytosis, J. Biol. Chem., 269(5) 3198–3204.Google Scholar
  90. 90.
    Wang, S., Lee, R.J., Cauchon, G., Gorenstein, D.G. and Low, P.S. (in press) Delivery of antisense oligodeoxyribonucleotides against the human epidermal growth factor receptor into cultured KB cells using folate-PEG-liposomes, J. Biol. Chem.Google Scholar
  91. 91.
    Lee, R.J. and Low, P.S. (in press) Folate-mediated tumor cell targeting of liposomeentrapped doxorubicin in vitro, Biochem. Biophys. Act.Google Scholar
  92. 92.
    Loughrey, H.C., Ferraretto, A., Cannon, A.M., Masserini, G. and Soria, M.R. (1993) Characterization of biotinylated liposomes for in vivo targeting applications, FEBS Let., 332()2), 183–188.CrossRefGoogle Scholar
  93. 93.
    Tomalia, D.A. (1993) StarburstTM/casdade dendrimers: fundamental building blocks for new nanoscopic chemistry set, Aldrichimica Acta, 26(4) 91–101.Google Scholar
  94. 94.
    Fréchet, J.M.J. (1994) Functional polymers and dendrimers: reactivity, molecular architecture, and interfacial energy, Science, 263, 1710–1715.CrossRefGoogle Scholar
  95. 95.
    Peppas, N.A., Nagai, N. and Miyajima, M. (1994) Prospects of using star polymers and dendrimers in drug delivery and pharmaceutical application, Pharm. Tech. Japan, 10(6) 611–617.Google Scholar
  96. 96.
    Peppas, N.A. and Langer, R. (1994) New challenges in biomaterials, Science, 263, 1715–1720.CrossRefGoogle Scholar
  97. 97.
    Barth, R.F., Adams, D.M., Soloway, A.H., Alam, F. and Darby, M.V. (1994) Boronated starburst dendrimer-monoclonal antibody immunoconjugates: evaluation as a potential delivery system for neutron capture therapy, Bioconj. Chem., 5, 58–66.CrossRefGoogle Scholar
  98. 98.
    Jansen, J.F.G.A., de Bradander-van der Berg, E.M.M. and Meijer, E.W. (1994) Encapsulation of guest molecules into dentritic box, Science, 266, 1226–1229.CrossRefGoogle Scholar
  99. 99.
    Kataoka, K. (1994) Design of nanoscopic vehicles for drug targeting based on micellization of amphiphilic block copolymers, in R.A. Guadiana (ed.), J.M.S. -Pure Appl. Chem.,A31 (ll) 1759–1769.CrossRefGoogle Scholar
  100. 100.
    Bader, J.H., Ringsdorf, H. and Schmidt, B. (1984) Watersoluble polymers in medicine, Angew. Makromol. Chem., 123, 457–485.CrossRefGoogle Scholar
  101. 101.
    Pratten, M.K., Lloyd, J.B., Hurpel, G. and Ringsdorf, H. (1985) Makromol. Chem., 186, 725.CrossRefGoogle Scholar
  102. 102.
    Yokoyama, M., Inoue, S., Kataoka, K., Yui, N. and Sakurai, Y. (1987) Preparation of adriamycin-conjugated poly(ethylene glycol)-poly(aspartic acid) block copolymer, Makromol. Chem., Rapid Commun., 8, 431–435.CrossRefGoogle Scholar
  103. 103.
    Yokoyama, M., Inoue, S., Kataoka, K., Yui, N., Okano, T. and Sakurai, Y., (1989) Molecular design for missile drug: synthesis of adriamycin conjugated with IgG using poly(ethylene glycol)-poly(aspartic acid) block copolymer as intermediate carrier, Makromol. Chem., 190, 2041–2054.CrossRefGoogle Scholar
  104. 104.
    Yokoyama, M., Miyauchi, M., Yamada, N., Okano, T., Sakurai, Y., Kataoka, K. and Inoue, S. (1990)Characterization and anticancer activity of the micelle-forming polymeric anticancer drug adriamycin-conjugated poly (ethylene glycol)-poly (aspar tic acid) block copolymer,Cancer Res., 50, 1693–1700.Google Scholar
  105. 105.
    Yokoyama, M., Miyauchi, M., Yamada, N., Okano, T., Sakurai, Y., Kataoka, K. and Inoue, S. (1990) Polymer micelles as novel drug carrier: adriamycin-conjugated poly(ethylene glycol)-poly(aspartic acid) block copolymer, J. Control. Rel., 11, 269–278.CrossRefGoogle Scholar
  106. 106.
    Yokoyama, M., Okano, T., Sakurai, Y., Ekimoto, H., Shibazaki, C. and Kataoka, K. (1991) Toxicity and antitumor activity against solid tumors of micelle-forming polymeric anticancer drug and its extremely long circulation in blood, Cancer Res., 51, 3229–3236.Google Scholar
  107. 107.
    Yokoyama, M., Kwon, G.S., Okano, T., Sakurai, Y., Seto, T. and Kataoka, K. (1992) Preparation of micelle-forming polymer-drug conjugates, Bioconj. Chem., 3, 295–301.CrossRefGoogle Scholar
  108. 108.
    Yokoyama, M., Kwon, G.S., Okano, T., Sakurai, Y., Ekimoto, H., Okamoto, K., Seto, T. and Kataoka, K. (1993) Optimization of in vivo antitumor activity of micelle-forming polymeric drug against murine colon adenocarcinoma 26, Drug Deliv., 1, 11.CrossRefGoogle Scholar
  109. 109.
    Kataoka, K., Kwon, G.S., Yokoyama, M., Okano, T. and Sakurai, Y. (1993) Block copolymer micelles as vehicles for drug delivery, J. Control. Rel., 24, 119–132.CrossRefGoogle Scholar
  110. 110.
    Kataoka, K., Kwon, G.S., Yokoyama, M., Okano, T. and Sakurai, Y. (1992) Polymeric micelles as novel drug carriers and virus mimicking vehicles in J. Kahovec (ed.), Macromolecules, 267–276.Google Scholar
  111. 111.
    Yokoyama, M., Sugiyama, T., Okano, T., Sakurai, Y., Naito, M. and Kataoka, K. (1993) Analysis of micelle formation of an adriamycin-conjugated poly(ethylene glycol)- poly(aspartic acid) block copolymer by gel permeation chromatography, Pharm. Res., 10(6) 895–899.CrossRefGoogle Scholar
  112. 112.
    Kwon, G.S., Yokoyama, M., Okano, T., Sakurai, Y. and Kataoka, K. (1993) Biodistribution of micelle-forming polymer-drug conjugates, Pharm. Res., 10(7) 970–974.CrossRefGoogle Scholar
  113. 113.
    Kwon, G., Suwa, S., Yokoyama, M., Okano, T., Sakurai, Y. and Kataoka, K. (1994) Enhanced tumor accumulation and prolonged circulation times of micelle-forming poly(ethylene oxide-aspartate) block copolymer-adriamycin conjugates, J. Control. Rel., 29, 17–23.CrossRefGoogle Scholar
  114. 114.
    Kwon, G., Naito, M., Yokoyama, M., Okano, T., Sakurai, Y. and Kataoka, K.(1993)Micelles based on AB block copolymers of poly (ethylene oxide) and poly ((3-benzyl Laspartate), Langmuir, 9, 945–949.CrossRefGoogle Scholar
  115. 115.
    Kwon, G.S., Naito, M., Kataoka, K., Yokoyama, M., Sakurai, Y. and Okano, T. (1994) Block copolymer micelles for hydrophobic drugs, Colloids Surf. B : Biointerfaces, 2, 429–434.CrossRefGoogle Scholar
  116. 116.
    Kwon, G.S., Naito, M., Yokoyama, M., Okano, T., Sakurai, Y. and Kataoka, K. (1995) Physical entrapment of adriamycin in AB block copolymer micelles, Pharm. Res., 12(2) 192–195.CrossRefGoogle Scholar
  117. 117.
    Cammas, S., Nagasaki, N. and Kataoka, K. (1995) Heterobifunctional Poly(ethylene oxide) : Synthesis of a-methoxy-co-amino and a-hydroxy-co-amino PEOs with the same molecular weights Bioconj. Chem., 6(2) 226–230.CrossRefGoogle Scholar
  118. 118.
    Cammas, S. XANDXKataoka, K. (in press) Functional poly(ethylene oxide)-co-poly(pbenzyl- L-aspartate) polymeric micelles : block-copolymer synthesis and micelles formation, Macromol. Phys. Chem Google Scholar
  119. 119.
    Harada, A., Kataoka, K. (in press) Formation of polyion complex micelles in an aqueous milieu from a pair of oppositely-charged block copolymers with poly(ethylene glycol) segments, Macromolecules.Google Scholar

Copyright information

© Springer Science+Business Media B.V. 1996

Authors and Affiliations

  • Sandrine Cammas
    • 1
  • Kazunori Kataoka
    • 2
  1. 1.International Center for Biomaterials Science and Department of Materials ScienceScience University of TokyoNoda-shi, ChibaJapan
  2. 2.Institute for Biomedical EngineeringTokyo Women’s Medical CollegeShinjuku-Ku TokyoJapan

Personalised recommendations