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Influence of the Structure of Drug Moieties on the in Vitro Efficacy of HPMA Copolymer–Geldanamycin Derivative Conjugates

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Abstract

Purpose To optimize the structure of geldanamycin (GDM) derivative moieties attached to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers via an enzymatically degradable spacer.

Methods HPMA copolymers containing different AR-GDM (AR = 3-aminopropyl (AP), 6-aminohexyl (AH), and 3-amino-2-hydroxy-propyl AP(OH)) were synthesized and characterized. Their cytotoxicity towards the A2780 human ovarian carcinoma cells was evaluated.

Results The cytotoxic efficacy of HPMA copolymer-AR-GDM conjugates depended on the structure of AR-GDM. Particularly, HPMA copolymer-bound AH-GDM, which possessed the longest substituent at the 17-position, demonstrated the highest efficacy among the polymer-bound GDM derivatives; however the activity of free AH-GDM was lower than that of the other free AR-GDMs. The relative increase of the activity of macromolecular AH-GDM when compared to AP-GDM or AP(OH)-GDM correlated with the enhanced recognition of AH-GDM terminated oligopeptide side-chains by the active site of the lysosomal enzyme, cathepsin B Drug stability and further stabilization upon binding to HPMA copolymer also contributed to the observed phenomena.

Conclusion AH-GDM was found to be a suitable GDM derivative for the design of a drug delivery system based on HPMA copolymers and enzymatically-degradable spacers.

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REFERENCES

  1. L. Neckers, T. W. Schulte, and E. Mimnaugh. Geldanamycin as a potential anti-cancer agent: its molecular target and biochemical activity. Invest New Drugs 17:361–373 (1999).

    Google Scholar 

  2. T. Scheibel and J. Buchner. The Hsp90 complex-a superchaperone machine as novel drug target. Biochem. Pharmacol. 56:675–682 (1998).

    Google Scholar 

  3. E. Sausville. Combining cytotoxics and 17-allylamino, 17-demethoxygeldanamycin: sequence and tumor biology matters. Clin. Cancer Res. 7:2155–2158 (2001).

    Google Scholar 

  4. J. G. Supko, L. R. Hickman, M. R. Grever, and L. Malspeis. Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother. Pharamcol. 36:305–315 (1995).

    Google Scholar 

  5. R. Mandler, E. Dadachova, J. K. Brechbiel, T. A. Waldmann, and M. W. Brechbiel. Synthesis and evaluation of antiproliferative activity of a geldanamycin-Herceptin immunoconjugate. Bioorg. Med. Chem. Lett. 10:1025–1028 (2000).

    Google Scholar 

  6. R. Mandler, C. Wu, E. A. Sausville, A. J. Roettinger, D. J. Newman, D. K. Ho, C. R. King, D. Yang, M. E. Lippman, N. F. Landolfi, E. Dadachova, M. W. Brechbiel, and T. A. Waldmann. Immunoconjugates of geldanamycin and anti-HER2 monoclonal antibodies: antiproliferative activity on human breast carcinoma cell lines. J. Natl. Cancer Inst. 92:1573–1581 (2000).

    Google Scholar 

  7. Y. Kasuya, Z.-R. Lu, P. Kope?ková, T. Minko, S. E. Tabibi, and J. Kope?ek. Synthesis and characterization of HPMA copolymergeldanamycin derivative conjugates. J. Control. Release 74:203–211 (2001).

    Google Scholar 

  8. D. Putnam and J. Kope?ek. Polymer conjugates with anticancer activity. Adv. Polym. Sci. 122:55–123 (1995).

    Google Scholar 

  9. J. Kope?ek, P. Kope?ková, T. Minko, and Z.-R. Lu. HMPA copolymer-anticancer drug conjugates: design, activity, and mechanism of action. Eur. J. Pharm. Biopharm. 50:61–81 (2000).

    Google Scholar 

  10. Y. Matsumura and H. Maeda. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 46:6387–6392 (1986).

    Google Scholar 

  11. P. Rejmanová, J. Kope?ek, R. Duncan, and J. B. Lloyd. Stability in rat plasma and serum of lysosomally degradable oligopeptide sequences in N-(2-hydroxypropyl)methacrylamide copolymers. Biomaterials 6:45–48 (1983).

    Google Scholar 

  12. P. Rejmanová, J. Pohl, M. Baudyš, V. Kostka, and J. Kope?ek. Polymers containing enzymatically degradable bonds 8. Degradation of oligopeptide sequences in N-(2-hydroxypropyl)methacrylamide copolymers by bovine spleen cathepsin B. Makromol. Chem. 184:2009–2020 (1983).

    Google Scholar 

  13. T. Minko, P. Kope?ková, and J. Kope?ek. Comparison of the anticancer effect of free and HPMA copolymer-bound adriamycin in human ovarian carcinoma cells. Pharm. Res. 16:986–996 (1999).

    Google Scholar 

  14. Y. Kasuya, Z.-R. Lu, P. Kope?ková, and J. Kope?k. Improved synthesis and evaluation of 17-substituted aminoalkylgeldanamycin derivatives applicable to drug delivery systems. Bioorg. Med. Chem. Lett. 11:2089–2091 (2001).

    Google Scholar 

  15. J. Kope?ek and H. Bažilová. Poly[N-(2-hydroxypropyl)methacrylamide] I. Radical polymerization and copolymerization. Eur. Polym. J. 9:7–14 (1973).

    Google Scholar 

  16. P. Rejmanoá, J. Labský, and J. Kope?ek. Aminolyses of monomeric and polymeric p-nitrophenyl esters of methacryloylated amino acids. Makromol. Chem. 178:2159–2168 (1977).

    Google Scholar 

  17. J. Kope?ek, P. Rejmanová, J. Strohalm, K. Ulbrich, B. ?íhová, V. Chytrý, J. B. Lloyd, and R. Duncan. Synthetic polymeric drugs. US Pat. 5,037,883 (1991).

  18. E. Eriksson and P.-Å. Albertsson. The effect of the lipid composition on the partition of liposomes in aqueous two-phase systems. Biochim. Biophys. Acta 507:425–432 (1978).

    Google Scholar 

  19. T. Minko, P. Kope?ková, V. Pozharov, and J. Kope?ek. HPMA copolymer bound adriamycin overcomes MDR1 gene encoded resistance in a human ovarian carcinoma cell line. J. Control. Release 54:223–233 (1998).

    Google Scholar 

  20. L. W. Seymour, R. Duncan, J. Strohalm, and J. Kope?ek. Effect of molecular weight (Mw) of N-(2-hydroxypropyl)methacrylamide copolymers on body distribution and rate of excretion after subcutaneous, intraperitoneal, and intravenous administration to rats. J. Biomed. Mater. Res. 21:1341–1358 (1987).

    Google Scholar 

  21. M. Dvo?ák, P. Kope?ková, and J. Kope?ek. High-molecular weight HPMA copolymer-adriamycin conjugates. J. Control. Release 60:321–332 (1999).

    Google Scholar 

  22. J. B. Lloyd. Metabolic efflux and influx across the lysosome membrane. In J. B. Lloyd and R. W. Mason (eds.), Biology of the lysosomes. Subcellular Biochemistry. Vol. 27, Plenum Press, New York, pp. 361–386 (1996).

    Google Scholar 

  23. R. Duncan, H. C. Cable, P. Rejmanová, J. Kope?ek, and J. B. Lloyd. Tyrosinamide residues enhance pinocytotic capture of N-(2-hydroxypropyl)methacrylamide copolymers. Biochim. Biophys. Acta 799:1–8 (1984).

    Google Scholar 

  24. Y. Tabata and Y. Ikada. Effect of surface wettability of microspheres on phagocytosis. J. Colloid Interface Sci. 127:132–140 (1989).

    Google Scholar 

  25. S. Yasukawa, H. Ohshima, N. Muramatsu, and T. Kondo. Electrostatic interaction of microcapsules with guinea-pig polymorphonuclear leucocytes. J. Microencapsul. 7:179–184 (1990).

    Google Scholar 

  26. J. H. Xiu, K.-E. Magnusson, O. Stendahl, and L. Edebo. Physicochemical surface properties and phagocytosis by polymorphonuclear leukocytes of different serogroup of Salmonella. J. Gen. Microbiol. 129:3075–3084 (1983).

    Google Scholar 

  27. J. Senior, C. Delgado, D. Fisher, C. Tilcock, and G. Gregoriadis. Influence of surface hydrophilicity of liposomes on their interaction with plasma protein and clearance from the circulation: studies with poly(ethylene glycol)-coated vesicles. Biochim. Biophys. Acta 1062:77–82 (1991).

    Google Scholar 

  28. M. C. Woodle and D. D. Lasic. Sterically stabilized liposomes. Biochim. Biophys. Acta 1113:171–199 (1992).

    Google Scholar 

  29. I. Schechter and A. Berger. On the active site in proteases. I. Papain. Biochem. Biophys. Res. Commun. 27:157–162 (1967).

    Google Scholar 

  30. M. Baudyš, B. Meloun, T. Gan-Erdene, M. Fusek, M. Mareš, V. Kostka, J. Pohl, and C. C. F. Blake. S-S bridges of cathepsin B and H from bovine spleen: A basis for cathepsin B model building and possible functional implications for discrimination between exo-and endopeptidase activities among cathepsins B, H and L. Biomed. Biochim. Acta 50:569–577 (1991).

    Google Scholar 

  31. O. Quraishi, D. K. Nägler, T. Fox, J. Sivaraman, M. Cygler, J. S. Mort, and A. C. Storer. The occluding loop in cathepsin B defines the pH dependence of inhibition by its propeptide. Biochemistry 38:5017–5023 (1999).

    Google Scholar 

  32. D. Turk, M. Podobnik, T. Popovic, N. Katsunuma, W. Bode, R. Huber, and V. Turk. Crystal structure of cathepsin B inhibited with CA30 at 2.0 Å resolution: A basis for the design of specific epoxysuccyl inhibitors. Biochemistry 34:4791–4797 (1995).

    Google Scholar 

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Authors and Affiliations

  1. Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, Utah, 84112

    Yuji Kasuya, Zheng-Rong Lu, Pavla Kopečková & Jindřich Kopeček

  2. Department of Bioengineering, University of Utah, Salt Lake City, Utah, 84112

    Pavla Kopečková

  3. Pharmaceutical Resources Branch, National Cancer Institute, NIH, Bethesda, Maryland, 20892-7446

    S. Esmail Tabibi

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  1. Yuji Kasuya
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  4. S. Esmail Tabibi
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  5. Jindřich Kopeček
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Kasuya, Y., Lu, ZR., Kopečková, P. et al. Influence of the Structure of Drug Moieties on the in Vitro Efficacy of HPMA Copolymer–Geldanamycin Derivative Conjugates. Pharm Res 19, 115–123 (2002). https://doi.org/10.1023/A:1014216712820

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