Advertisement

Drug Delivery with Protein and Peptide Carriers

  • John M. Whiteley

Abstract

Drugs or toxins such as methotrexate, adriamycin, daunomycin, fluorodeoxyuridine, neocarzinostatin, and ricin can be bound, either covalently or by occlusion, to proteins, synthetic polypeptides, and antibodies. Common reactions for coupling these drugs to carriers include the use of carbodiimides, the generation of Schiff bases followed by reduction, and the formation of disulfide linkages. Often a spacer group such as a dextran or polypeptide is included to facilitate the interaction. The resultant conjugates usually contain from approximately 5 to 25 mol of drug per mole of carrier and most retain attenuated antimetabolic properties typical of the free drug. The complexes, however, also possess the properties of the carrier, and in this way delivery and uptake of a bound drug by cells can be significantly different from that of the free drug. For example, in vivo, the higher molecular weight of the conjugate can lead to a larger retention time for the drug prior to excretion, with the attendant greater opportunity for interaction with target cells. Additionally, the mechanism by which the drug is taken up into a cellular target may be altered for the drug-carrier complex and, in the case of an antibody carrier, tissue specificity may also be added to the properties of the drug. These and other characteristics of the complexes are discussed in detail in the text and their possible relevance to chemotherapy is outlined.

Keywords

Free Drug Folinic Acid Dihydrofolate Reductase Diphtheria Toxin Divinyl 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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    P. Ehrlich, Collected Studies on Immunity, Vol. II, Wiley, New York (1906), pp. 442–447.Google Scholar
  2. 2.
    S. C. Silverstein, R. M. Steinman, and Z. A. Cohn, Endocytosis, Ann. Rev. Biochem. 46, 669–722 (1977).CrossRefGoogle Scholar
  3. 3.
    H. J.-P. Ryser, Uptake of protein by mammalian cells: An underdeveloped area, Science 159, 390–396 (1968).CrossRefGoogle Scholar
  4. 4.
    G. C. Easty, The uptake of fluorescent labelled proteins by normal and tumour cells, Brit. J. Cancer 18, 368–377 (1964).CrossRefGoogle Scholar
  5. 5.
    J. L. Mego and J. D. McQueen, The uptake of labeled proteins by particulate fractions of tumor and normal tissues after injection into mice, Cancer Res. 25, 865–869 (1965).Google Scholar
  6. 6.
    T. Ghose, R. C. Nairn, and J. E. Fothergill, Uptake of proteins by malignant cells, Nature 196, 1108–1109(1962).CrossRefGoogle Scholar
  7. 7.
    R. G. Long, J. G. McAfee, and J. Winkelman, Evaluation of radioactive compounds for the external detection of cerebral tumors, Cancer Res. 23, 98–108 (1963).Google Scholar
  8. 8.
    C. deDuve, in: Biological Approaches to Cancer Chemotherapy (R. J. C. Harris, ed.), p. 101, Academic Press, London (1961).Google Scholar
  9. 9.
    T. Ghose and A. H. Blair, Antibody-linked cytotoxic agents in the treatment of cancer: Current status and future prospects, J. Natl. Cancer Inst. 61, 657–676 (1978).Google Scholar
  10. 10.
    G. F. Rowland, G. J. O’Neill, and D. A. L. Davies, Suppression of tumour growth in mice by a drug-antibody conjugate using a novel approach to linkage, Nature 255, 487–488 (1975).CrossRefGoogle Scholar
  11. 11.
    D. G. Gilliland, Z. Steplewski, R.J. Collier, K.F. Mitchell, T.H. Chang, and H. Koprowski, Antibody-directed cytotoxic agents: Use of monoclonal antibody to direct the action of toxin A chains to colorectal carcinoma cells, Proc. Natl. Acad. Sci. U.S.A., 77, 4539–4543 (1980).CrossRefGoogle Scholar
  12. 12.
    A. Huang, L. Huang, and S. J. Kennel, Monoclonal antibody covalently coupled with fatty acid, J. Biol. Chem. 255, 8015–8018 (1980).Google Scholar
  13. 13.
    P. E. Thorpe, D. W. Mason, A. N. F. Brown, S. J. Simmonds, W. C. J. Ross, A. J. Cumber, and J. A. Forrester, Selective killing of malignant cells in a leukaemic rat bone marrow using an antibody-ricin conjugate, Nature 297, 594–596 (1982).CrossRefGoogle Scholar
  14. 14.
    B. C. F. Chu and J. M. Whiteley, High molecular weight derivatives of methotrexate as chemotherapeutic agents, Mol. Pharmacol. 13, 80–88 (1977).Google Scholar
  15. 15.
    G. Barbanti-Brodano and L. Fiume, In vitro effect of a 5-fluorodeoxyuridine albumin conjugate on tumour cells and on peritoneal macrophages, Experientia 30, 1180–1182 (1974).CrossRefGoogle Scholar
  16. 16.
    N. G. L. Harding, Amethopterin linked covalently to water-soluble macromolecules, Ann. N.Y. Acad. Sci. 186, 270–283 (1971).CrossRefGoogle Scholar
  17. 17.
    A. Trouet, D. D. Campeneere, and C. de Duve, Chemotherapy through lysosomes with a DNA-daunorubicin complex, Nature 239, 110–112 (1972).CrossRefGoogle Scholar
  18. 18.
    G. Atassi, M. Duarte-Karim, and H. J. Tagnan, Comparison of adriamycin with DNA-adriamycin complex in chemotherapy of experimental tumors and metastases, Eur. J.Cancer 11, 309–316 (1975).CrossRefGoogle Scholar
  19. 19.
    R. Green, J. Miller, and W. Crosby, Enhancement of iron chelation by desferoxamine entrapped in red blood cell ghosts, Blood 57, 866–872 (1981).Google Scholar
  20. 20.
    A. J. Matas, D. E. R. Sutherland, M. W. Steffes, S. M. Mauer, A. Lowe, R. L. Simmons, and J. S. Najarian, Hepatocellular transplantation for metabolic deficiencies: Decrease of plasma bilirubin in gunn rats, Science 192, 892–894 (1976).CrossRefGoogle Scholar
  21. 21.
    T. M. S. Chang, Artificial Cells, Charles C Thomas, Springfield, Ill. (1972).Google Scholar
  22. 22.
    J. C. Venter, B. R. Venter, J. E. Dixon, and N. O. Kaplan, A possible role for glass bead immobilized enzymes as therapeutic agents (immobilized uricase as enzyme therapy for hyperuricemia), Biochem. Med. 12, 79–91 (1975).CrossRefGoogle Scholar
  23. 23.
    A. Senyei, K. Widder, and G. Czerlinski, Magnetic guidance of drug-carrying microspheres, J. Appl. Phys. 49, 3578–3583 (1978).CrossRefGoogle Scholar
  24. 24.
    N. Mason, C. Thies, and T. J. Cicero, in vivo and in vitro evaluation of a microencapsulated narcotic antagonist, J. Pharm. Sci. 65, 847–850 (1976).CrossRefGoogle Scholar
  25. 25.
    G. Gregoriadis, The carrier potential of liposomes in biology and medicine, New Engl. J. Med. 295, 707–710 and 765–770 (1976).Google Scholar
  26. 26.
    H. K. Kimelberg, T. F. Tracy, S. M. Biddlecome, and R. S. Bourke, The effect of entrapment in liposomes on the in vivo distribution of [3H] methotrexate in a primate, Cancer Res. 36, 2949–2957 (1976).Google Scholar
  27. 27.
    W.-P. Fung, M. Przybylski, H. Ringsdorf, and D. S. Zaharko, in vitro inhibitory effects of polymer-linked methotrexate derivatives on tetrahydrofolate dehydrogenase and murine L5178Y cells, J. Natl. Cancer Inst. 62, 1261–1264 (1979).Google Scholar
  28. 28.
    S. Olsnes and A. Pihl, Different biological properties of the two constituent peptide chains of ricin. A toxic protein inhibiting protein synthesis, Biochemistry 12, 3121–3126 (1973).CrossRefGoogle Scholar
  29. 29.
    S. Olsnes, K. Refsnes, and A. Phil, Mechanism of action of the toxic lectins abrin and ricin, Nature 249, 627–631 (1974).CrossRefGoogle Scholar
  30. 30.
    J. W. Goding, Antibody production by hybridomas, J. Immunol. Meth. 39, 285–308 (1980).CrossRefGoogle Scholar
  31. 31.
    V. Raso and T. Griffin, Specific cytotoxicity of human immunoglobulin-directed Fab’-ricin A chain conjugate, J. Immunol. 125, 2610–2616 (1980).Google Scholar
  32. 32.
    J. M. Whiteley, Z. Nimec, and J. Galivan, Treatment of Reuber H35 hepatoma cells with carrier-bound methotrexate, Mol. Pharmacol. 19, 505–508 (1981).Google Scholar
  33. 33.
    H.J.-P. Ryser and W.-C. Shen, Conjugation of methotrexate to poly(L-lysine) increases drug transport and overcomes drug resistance in cultured cells, Proc. Natl. Acad. Sci. U.S.A. 75, 3867–3870 (1978).CrossRefGoogle Scholar
  34. 34.
    P. N. Kulkarni, A. H. Blair, and T. I. Ghose, Covalent-binding of methotrexate to immunoglobulins and the effect of antibody-linked drug on tumor growth in vivo, Cancer Res. 41, 2700–2706 (1981).Google Scholar
  35. 35.
    E. Calendi, G. Constanzi, F. Indiveri, G. Lotti, and C. Zini, Histoimmunologic specificity of an anti-lymphoid tissue sarcoma γ-globulin bound to methotrexate, Boll. Chim. Farm. 108, 25–28 (1969).Google Scholar
  36. 36.
    K. Prabhakaran, E. B. Harris, and W. F. Kirchheimer, A possible method for improving the efficacy of dapsone, Experientia 36, 1350–1351 (1980).CrossRefGoogle Scholar
  37. 37.
    T. Ghose and S. P. Nigam, Antibody as carrier of chlorambucil, Cancer 29, 1398–1400 (1972).CrossRefGoogle Scholar
  38. 38.
    D. A. Davies and G. J. O’Neill, In vivo and in vitro effects of tumor-specific antibodies with chlorambucil, Brit. J. Cancer 28 (Supp. 1), 285–298 (1973).Google Scholar
  39. 39.
    V. Raso, Antibody mediated delivery of toxic molecules to antigen bearing target cells, Immunolog. Rev. 62, 93–117 (1982).CrossRefGoogle Scholar
  40. 40.
    E. Hurwitz, R. Levy, R. Maron, M. Wilchek, R. Arnon, and M. Sela, The covalent binding of daunomycin and adriamycin to antibodies with retention of both drug and antibody activities, Cancer Res. 35, 1175–1181 (1975).Google Scholar
  41. 41.
    R. Arnon and M. Sela, In vitro and in vivo efficacy of conjugates of daunomycin with anti-tumor antibodies, Immunolog. Rev. 2, 5–27 (1982).CrossRefGoogle Scholar
  42. 42.
    G. P. Mell, J. M. Whiteley, and F. M. Huennekens, Purification of dihydrofolate reductase via amethopterin-aminoethyl starch, J. Biol. Chem. 243, 6074–6075 (1968).Google Scholar
  43. 43.
    R. B. Angier, J. H. Boothe, J. H. Mowat, C. W. Waller, and J. Semb, Pteridine chemistry. II. The action of excess nitrous acid upon pteroylglutamic acid and derivatives, J. Am. Chem. Soc. 74, 408–411 (1952).CrossRefGoogle Scholar
  44. 44.
    Y. Masuho, K. Kishida, M. Saito, N. Umemoto, and T. Hara, Importance of the antigen-binding valency and the nature of the cross-linking bond in ricin A chain conjugates with antibody, J. Biochem. 91, 1583–1591 (1982).Google Scholar
  45. 45.
    T. F. Bumol, Q. C. Wang, R. A. Reisfeld, and N. O. Kaplan, Monoclonal antibody and an antibody-toxin conjugate to a cell surface proteoglycan of melanoma cells suppress in vivo tumor growth, Proc. Natl. Acad. Sci. U.S.A. 80, 529–533 (1983).CrossRefGoogle Scholar
  46. 46.
    T. Lang, C. J. Suckling, and H. C. S. Wood, Affinity chromatography using agarose-triazine derivatives, J. Chem. Soc. 2189–2194 (1977).Google Scholar
  47. 47.
    M. Szekerke and J. S. Driscoll, The use of macromolecules as carriers of antitumor drugs, Eur. J. Cancer 13, 529–537 (1977).CrossRefGoogle Scholar
  48. 48.
    H. Sawada, K. Tatsumi, S. Masataka, T. Makumuka, and W. Gyoichi, Effects of neocarzinostatin on DNA synthesis in L1210 cells, Cancer Res. 34, 3341–3346 (1974).Google Scholar
  49. 49.
    T. A. Beerman and J. H. Goldberg, DNA strand scission by the antitumor protein neocarzinostatin, Biochem. Biophys. Res. Commun. 59, 1254–1261 (1974).CrossRefGoogle Scholar
  50. 50.
    T. S. A. Samy and V. Raso, Radioimmunoassay of neocarzinostatin, on antitumor protein, Cancer Res. 36, 4378–4381 (1976).Google Scholar
  51. 51.
    L. Chess, R. P. MacDermott, and S. F. Schlossman, Immunologic functions of isolated human lymphocyte subpopulations. I. Quantitative isolation of human T and B cells and response to mitogens, J. Immunol. 113, 1113–1121 (1974).Google Scholar
  52. 52.
    M. S. Verlander, J. C. Venter, M. Goodman, N. O. Kaplan, and B. Saks, Biological activity of catecholamines covalently linked to synthetic polymers: Proof of immobilized drug theory, Proc. Natl. Acad. Sci. U.S.A. 73, 1009–1013 (1976).CrossRefGoogle Scholar
  53. 53.
    W. C. Shen and H.J. P. Ryser, Conjugation of poly(L-lysine) to albumin and horseradish peroxidase: A novel method of enhancing the cellular uptake of proteins, Proc. Natl. Acad. Sci. U.S.A. 75, 1872–1876 (1978).CrossRefGoogle Scholar
  54. 54.
    P. G. Balboni, A. Minia, M. P. Grossi, G. Barbanti-Brodano, A. Mattioli, and L. Fiume, Activity of albumin conjugates of 5-fluorodeoxyuridine and cytosine arabinoside on poxviruses as a lysosomotropic approach to antiviral chemotherapy, Nature 264, 181–183 (1976).CrossRefGoogle Scholar
  55. 55.
    R. L. Blakley, in: The Biochemistry of Folic Acid and Related Pteridines, (A. Neuberger and E. L. Tatum, eds.), p. 93, North-Holland, Amsterdam and London (1969).Google Scholar
  56. 56.
    T. Peters, Serum albumin, in: The Plasma Proteins (F. W. Putnam, ed.), pp. 133–181, Academic Press, New York, San Francisco, and London, (1975).Google Scholar
  57. 57.
    R. C. Jackson, D. Niethammer, and F. M. Huennekens, Enzymic and transport mechanisms of amethopterin resistance in L1210 mouse leukemia cells, Cancer Biochem. Biophys. 1, 151–155 (1975).Google Scholar
  58. 58.
    C. Fan, G. Henderson, K. Vitols, and F. M. Huennekens, Molecular targets for methotrexate, in: Antimetabolites in Biochemistry, Biology and Medicine (J. Skoda and P. Langen, eds.), pp. 313–326, Pergamon Press, Oxford, England and Elmsford, New York (1979).Google Scholar
  59. 59.
    E. Hurwitz, M. Wilchek, and J. Pitha, Soluble molecules as carriers for daunorubicin, Appl. Biochem. 2, 25 (1980).Google Scholar
  60. 60.
    B. C. F. Chu and J. M. Whiteley, Control of solid tumor metastases with a high-molecular-weight derivative of methotrexate, J. Natl. Cancer Inst. 62, 79–82 (1979).Google Scholar
  61. 61.
    B. C. F. Chu and J. M. Whiteley, The interaction of carrier-bound methotrexate with L1210 cells, Mol. Pharmacol. 17, 382–387 (1980).Google Scholar
  62. 62.
    J. L. Rader, D. Niethammer, and F. M. Huennekens, Effect of sulfhydryl inhibitors upon transport of folate compounds into L1210 cells, Biochem. Pharmacol. 23, 2057–2059 (1974).CrossRefGoogle Scholar
  63. 63.
    A. Nahas, P. F. Nixon, and J. R. Bertino, Uptake and metabolism of N5-formyl-tetra-hydrofolate by L1210 leukemia cells, Cancer Res. 32, 1416–1421 (172).Google Scholar
  64. 64.
    J. H. Galivan, Transport and metabolism of methotrexate in normal and resistant cultured rat hepatoma cells, Cancer Res. 39, 735–743 (1979).Google Scholar
  65. 65.
    W.-C. Shen and H. J. P. Ryser, Selective protection against the cytotoxicity of methotrexate and methotrexate-polylysine by thiamine pyrophosphate, heparin and leucovorin, Life Sci. 28, 1209–1214 (1981).CrossRefGoogle Scholar
  66. 66.
    J. H. Galivan, Evidence for the cytotoxic activity of polyglutamate derivatives of methotrexate, Mol. Pharmacol. 17, 105–110 (1980).Google Scholar
  67. 67.
    J. H. Galivan, Transport of methotrexate by primary cultures of rat hepatocytes: Stimulation of uptake in vitro by the presence of hormones in the medium, Arch. Biochem. Biophys. 206, 113–121 (1981).CrossRefGoogle Scholar
  68. 68.
    J. Galivan, M. Balinska, and J. M. Whiteley, Interaction of methotrexate poly(L-lysine) with transformed hepatic cells in culture, Arch. Biochem. Biophys. 216, 544–550 (1982).CrossRefGoogle Scholar
  69. 69.
    J. H. Galivan, Transport and metabolism of methotrexate in normal and resistant cultured rat hepatoma cells, Cancer Res. 39, 735–743 (1979).Google Scholar
  70. 70.
    E. Hurwitz, R. Maron, A. Bernstein, M. Wilchek, M. Sela, and R. Arnon, The effect in vivo of chemotherapeutic drug-antibody conjugates in two murine experimental tumor systems, Int. J. Cancer 21, 747–755 (1978).CrossRefGoogle Scholar
  71. 71.
    R. C. Hughes, How do toxins penetrate cells? Nature 281, 526–527 (1979).CrossRefGoogle Scholar
  72. 72.
    S. Olsnes, C. Fernandez-Puentes, L. Carrasco, and D. Vazquez, Ribosome inactivation by the toxic lectins abrin and ricin. Kinetics of enzymic activities of the toxin A chains, Eur. J. Biochem. 60, 281–288 (1975).CrossRefGoogle Scholar
  73. 73.
    V. Raso and T. Griffin, Hybrid antibodies with dual specificity for the delivery of ricin to immunoglobulin-bearing target cells, Cancer Res. 41, 2073–2078 (1981).Google Scholar
  74. 74.
    F. M. Sirotnak, D. M. Moccio, L. E. Kelleher, and L. J. Goutas, Relative frequency and kinetic properties of transport-defective phenotypes among methotrexate-resistant L1210 clonal cell lines derived in vivo,Cancer Res. 41, 4447–4452 (1981).Google Scholar

Copyright information

© Plenum Press, New York 1985

Authors and Affiliations

  • John M. Whiteley
    • 1
  1. 1.Division of Biochemistry, Scripps Clinic and Research FoundationDepartment of Basic and Clinical ResearchLa JollaUSA

Personalised recommendations