Polymer-Drug Conjugates: Targeting Cancer

  • Ruth Duncan
Chapter

Abstract

Synthetic polymers are well known through their widespread use in biomedical materials, for example hip prostheses, contact lenses, vascular grafts and most recently as scaffolds for tissue engineering. Polymers are also routinely used as pharmaceutical excipients. Both these applications are far removed from the concept of “disease targeting.” However, the last decade has seen the emergence of several novel classes of therapeutic that exploit the properties of natural or synthetic water soluble polymers to provide opportunities for improved chemotherapy. They include biologically active polymeric drugs, polymer-drug conjugates, block copolymer micelles, polymer-protein conjugates and polymer-based non-viral vectors are currently being designed for gene delivery.

Keywords

Acute Myeloid Leukemia Maximum Tolerate Dose Passive Target Polymer Conjugate Block Copolymer 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.
This is a preview of subscription content, log in to check access

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Duncan R., Dimitrijevic S. and Evagorou E.G. The role of polymer conjugates in the diagnosis and treatment of cancer. S.T.P. Pharma Sciences 1996; 6:237.Google Scholar
  2. 2.
    Duncan, R. Polymer conjugates for tumor targeting and intracytoplasmic delivery. The EPR effect as a common gateway? Pharm. Sci. and Tech. Today 1999; 2(11): 441.Google Scholar
  3. 3.
    Brocchini, S. and Duncan, R. Pendent drugs, release from polymers. In Encyclopaedia of Controlled Drug Delivery, E. Mathiowitz, ed. John Wiley & Sons, New York, 1999.Google Scholar
  4. 4.
    Ringsdorf, H. Structure and properties of pharmacologically active polymers. J. Pharm Sci. Polymer Symp.51; 1975: 135.Google Scholar
  5. 5.
    Duncan, R. Drug-polymer conjugates: potential for improved chemotherapy. AntiCancer Drugs 1992; 3:175.Google Scholar
  6. 6.
    Duncan R., Kopeckova-Rejmanova P., Strohalm J., Hume I.C., Lloyd J.B., Kopecek J. Anticancer agents coupled to N-(2-hydroxypropyl) methacrylamide copolymers. 2. Evaluation of daunomycin conjugates in vivo against L1210 leukemia. Brit J Cancer 1988; 57:147.Google Scholar
  7. 7.
    Duncan, R., Seymour, L.W, O’Hare, K.B., Flanagan, P.A., Wedge, S., Ulbrich, K., Strohalm, J., Subr, V., Spreafico, F., Grandi, M., Ripamonti, M., Farao M. and Suarato, A. Preclinical evaluation of polymer-bound doxorubicin. J. Cont. Rel. 1992; 19: 331.Google Scholar
  8. 8.
    V.R. Caiolfa, V.R., Zamal, M., Fiorini, A., Frigerio, E., D’Argy, R., Ghigleri, A., Farao, M., Angelucci, F. and Suarato, A. Polymer-bound camptothecin: Initial biodistribution and antitumor activity studies. J. Cont. Rel. 2000;65:105.Google Scholar
  9. 9.
    Meerum Terwogt, J.M., ten Bokkel Huinink, W.W., Schellens, J.H.M., Schot, M., Mandjes, I.A.M., Zurlo, M.G., Rocchetti, M., Rosing, H., Koopman, F.J. and Beijnen, J. Phase I clinical and pharmacokinetic study of PNU166945, a novel water soluble polymer-conjugated pro-drug of paclitaxel. Anti-Cancer Drugs 2001;12:315.Google Scholar
  10. 10.
    Dimitrijevic, S. and Duncan R. Synthesis and characterization of N-(2hydroxypropyl)methacrylamide (HPMA) copolymer-ementine conjugates. J. Bioact. Compat. Polymers 1998;3:165.Google Scholar
  11. 11.
    Searle F., Gac-Breton S., Keane R., Dimitrijevic S., Brocchini S., Duncan R. N- (2hydroxypropyl)methacrylamide copolymer-6(3-aminopropyl)-ellipticineconjugates, synthesis, characterization and preliminary in vitro and in vivo studies, Bioconj. Chem. 2001; 2: 711.CrossRefGoogle Scholar
  12. 12.
    Kasuya, Y., Lu, Z-R., Kopekovâ, P., Minko, T., Tabibi, S.E. and Kopecek, J. Synthesis and characterization of HPMA copolymer aminopropylgeldanamycin conjugates. J. Cont. Rel. 2001;74(1–3):203.Google Scholar
  13. 13.
    Gianasi, E., Wasil, M., Evagorou, E.G., Keddle, A., Wilson, G. and Duncan, R. HPMA copolymer platinates as novel antitumour agents: in vitro properties, pharmacokinetics and antitumour activity. Eur. J. Cancer 1999;3:994.Google Scholar
  14. 14.
    Duncan, R., Hume, I.C., Yardley, H.J., Flanagan, P.A., Ulbrich, K., Subr, V., Strohalm, J. Macromolecular pro-drugs for use in targeted cancer chemotherapy: Melphalan covalently coupled to N-(2-hydroxypropyl)methacrylamide copolymers. J Controlled Rel 1991; 16: 121.Google Scholar
  15. 15.
    Ringsdorf, H., Schmidt, B., Ulbrich, K. Bis (2-chloroethyl)amine bound to copolymers of N-(2-hydroxypropyl)methacrylamide and methacryloylated oligopeptides via biodegradable bonds. Makromol Chem 1987;188:257.Google Scholar
  16. 16.
    Krinick, N.L., Rihova, B., Ulbrich, K., Strohalm, J., Kopecek, J. Targetable photoactivatable drugs 2. Synthesis of N-(2-hydroxypropyl)methacrylamide copolymer anti-Thy 1. 2 antibody-chlorin e6 conjugates and a preliminary study of their photodynamic effect on mouse splenocytes in vitro. Makromol Chem 1990;191:839.Google Scholar
  17. 17.
    Musila, R. and Duncan, R. Synthesis and evaluation of HPMA copolymer-melittin as a potential anticancer agent. J. Pharm. Pharmacol. 2000; 52: 51.Google Scholar
  18. 18.
    Przybylski, M., Fell, E., Ringsdorf, H., Zaharko, D. Pharmacologically active polymers. 17. Synthesis and characterization of polymeric derivatives of the antitumour agent methotrexate. Makromol Chem 1978;179.1719.Google Scholar
  19. 19.
    Soyez, H., Schacht, E., Vanderkerken, S: The crucial role of spacer groups in macromolecular pro-drug design. Adv. Drug Delivery Rev.,1996;21:81.Google Scholar
  20. 20.
    Matsumura, Y. and Maeda, H. A new concept for macromolecular therapies in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumour agent SMANCS. Cancer Res. 1986;6:6387.Google Scholar
  21. 21.
    Seymour, L.W., Miyamoto, Y., Brereton, M., Styger, P.S., Maeda, H., Ulbrich, K. and Duncan. R. Influence of molecular size on passive tumor-accumulation of soluble macromolecular drug carriers. Eur. J. Cancer, 1995; 5: 766.CrossRefGoogle Scholar
  22. 22.
    Sat, Y.N., Burger, A.M., Fiebig, H.H., Sausville, E.A. and Duncan, R. Comparison of vascular permeability and enzymatic activation of the polymeric pro-drug HPMA copolymer-doxorubicin (PK1) in human tumor xenografts. American Association for Cancer Research 9O h Annual Meeting, Philadelphia, USA 1999.Google Scholar
  23. 23.
    Seymour, L.W., Ulbrich, K., Styger, P.S., Brereton, M., Subr, V., Strohalm, J. and Duncan, R. Tumoritropism and anticancer efficacy of polymer-based doxorubicin pro-drugs in the treatment of subcutaneous murine B16F10 melanoma. Br. J. Cancer 1994;70.•636.Google Scholar
  24. 24.
    Ke S., Milas L., Charnsangavej C., Wallace S. and Li C. Potentiation of radioresponse by polymer-drug conjugates. J. Cont. Rel. 2001;74(1–3):237.Google Scholar
  25. 25.
    Duncan, R., Seymour, L.C.W., Scarlett, L., Lloyd, J.B., Rejmanova, P. and Kopecek, J. Fate of N-(2-Hydroxypropyl)methacrylamide copolymers with pendant galactosamine residues after intravenous administration to rats. Biochimica et Biophysica Acta 1986;880:62.Google Scholar
  26. 26.
    Seymour, L.W., Ferry, D.R., Anderson, D., Hesslewood, S., Julyan, P.J., Payner, R., Doran, J., Young, A.M., Burtles, S., Kerr, D.J, Hepatic drug targeting: Phase I evaluation of polymer bound doxorubicin. J. Clin. Oncol. 2002;20:1668.Google Scholar
  27. 27.
    O’Hare, K.B., Duncan, R., Strohalm, J., Ulbrich, K. and Kopeckova, P. Polymeric drug-carriers containing doxorubicin and melanocyte-stimulating hormone: In vitro and in vivo evaluation against murine melanoma../. Drug Targeting 1993;1:217.Google Scholar
  28. 28.
    Flanagan, P.A., Duncan, R., Subr, V, Ulbrich, K. Kopeckova, P. and Kopecek, J. Evaluation of protein N-(2-hydroxypropyl)methacrylamide copolymer conjugates as targetable drug-carriers. 2. Body distribution of conjugates containing transferrin, anti-transferrin receptor antibody or anti-Thy 1.2 antibody and effectiveness of transferrin-containing daunomycin conjugates against mouse L1210 leukemia in vivo. J. Cont. Rel. 1992;19.•25.Google Scholar
  29. 29.
    Sunassee, K.R. The evaluation of polymer-peptide and polymer-protein conjugates for targeted melanoma chemotherapy. PhD Thesis University of Keele, UK 1994.Google Scholar
  30. 30.
    Omelyanenko V., Kopeckova P. Prakash R.K., Ebert C.D. Kopecek J. Biorecognition of HPMA copolymer-adriamycin conjugates by lymphoctes mediated by synthetic receptor binding epitopes. Pharm. Res. 1999;16:1010.Google Scholar
  31. 31.
    Krinick, N.L., Rihova, B., Ulbrich, K., Strohalm, J. and Kopecek, J. Targetable photoactive drugs. 2. Synthesis of N-(2-hydroxypropyl)methacrylamide copolymeranti-Thy 1.2 antibody-chlorin e6 conjugates and a preliminary study of their photodynamic effect on mouse splenocytes in vitro. Makromol Chem 1990;191:839.Google Scholar
  32. 32.
    Rihova, B., Jelinkova, M., Strohalm, J., St’astny, M., Hovorka, O., Plocova, D., Kovar, M., Draberova, L. and Ulbrich, K. Antiproliferative effect of a lectin-and anti-Thy-1.2 antibody-targeted HPMA copolymer-bound doxorubicin on primary and metastatic human colorectal carcinoma and on human colorectal carcinoma transfected with the mouse Thy-1.2 gene. Bioconj. Chem. 2000;11(5):664.Google Scholar
  33. 33.
    St’astny, M., Strohalm, J., Plocova D., Ulbrich, K. and Rihova, B. A possibility to overcome P-glycoprotein (PGP)-mediated multidrug resistance by antibody-targeted drugs conjugated to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carrier. Eur. J. Cancer 1999;35(3);459.Google Scholar
  34. 34.
    Rihova, B., Strohalm, J., Kubackova, K., Jelinkova, M., Hovorka, O., Kovar, M., Plocova, D., Sirova, M., St’astny, M., Rozprimova, L. and Ulbrich, K. Acquired and specific immunological mechanisms co-responsible for efficacy of polymer-bound drugs. J. Cont. Rel. 2002; 78 (1–3): 97.CrossRefGoogle Scholar
  35. 35.
    Omelyanenko, V., Gentry, C., Kopeckova, P. and Kopecek, J. HPMA copolymer anticancer drug OV-TL16 antibody conjugates. II. Processing in epithelial ovarian carcinoma cells in vitro. Int. J. Cancer 1998;75(4):600.Google Scholar
  36. 36.
    Danauser-Reidl, S. Hausmann, E. Schick, H., Bender, R., Dietzfelbinger, H., Rastetter J. and Hanauske, A. Phase-I clinical and pharmacokinetic trial of dextran conjugated doxorubicin (AD-70, DOX-OXD). Invest. New Drugs,1993;11:187.Google Scholar
  37. 37.
    Vasey, P., Twelves, C., Kaye, S., Wilson, P., Morrison, R., Duncan, R., Thomson, A., Hilditch, T., Murray, T., Burtles, S. and Cassidy, J. Phase I clinical and pharmacokinetic study of PKI (HPMA copolymer doxorubicin) first member of a new class of chemotherapeutics agents: drug-polymer conjugates. Clin. Cancer Res. 1999; 5: 83.Google Scholar
  38. 38.
    Twelves, C. Clinical experience with MAG-CPT. Proc. 5th Int Symp. Polymer Therap.: Laboratory to Clinic Cardiff, UK 2002.Google Scholar
  39. 39.
    Bolton, M.G., Kudekla, A., Cassidy, J., Calvert, H. Phase I studies of PGpaclitaxel(CT-2103) as a single agent and in combination with cisplatin. Proc. 5th Int Symp. Polymer Therap.: Laboratory to Clinic Cardiff UK 2002.Google Scholar
  40. 40.
    Sabbatini P., Aghajanian C., Hensley M., Pezzulli S., Oflaherty C., Soigner S. Lovegren M., Esch J., Funt S., Odujinrin O., Warner M., Bolton M.G. Spriggs D. Early findings in a Phase I/II study of PG-paclitaxel (CT-2103) in recurrent ovarian or primary peritoneal cancer. Proc. 5th Int Symp. Polymer Therap.: Laboratory to Clinic Cardiff, UK 2002.Google Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Ruth Duncan
    • 1
  1. 1.Centre for Polymer Therapeutics, Welsh School of PharmacyCardiff UniversityCardiffUK

Personalised recommendations