A New Class of 5-Fluoro-2′-deoxyuridine Prodrugs Conjugated with a Tumor-Homing Cyclic Peptide CNGRC by Ester Linkers: Synthesis, Reactivity, and Tumor-Cell–Selective Cytotoxicity
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Tumor-targeting prodrugs of 5-fluoro-2′-deoxyuridine (5-FdUrd), which are chemical conjugations of 5-FdUrd with a tumor-homing cyclic peptide CNGRC by succinate and glutarate linkers, were synthesized to investigate the structural effects of linkers on the hydrolytic release of 5-FdUrd and the tumor-cell–selective cytotoxicity.
A solid phase synthesis method was used to produce 5-FdUrd prodrugs. The kinetics and efficiency of hydrolytic 5-FdUrd release from the prodrugs were investigated in phosphate buffer (PB), fetal bovine serum (FBS), HT-1080 cell lysate, MDA-MB-231 cell lysate, and MEM containing 10% FBS. The tumor-cell–selective cytotoxicity of prodrugs was evaluated by an MTT method.
Two tumor-targeting prodrugs CNF1 and CNF2 bearing 5-FdUrd conjugated with a common cyclic peptide CNGRC by succinate and glutarate linkers, respectively, and their control compounds CN1 and CN2 without 5-FdUrd moiety were synthesized and identified. CNF1 underwent hydrolysis to release 5-FdUrd more rapidly and efficiently than CNF2. Both prodrugs were of lower cytotoxicity compared to 5-FdUrd, showing more selective cytotoxicity toward APN/CD13 positive cells (HT-1080) than toward APN/CD13 negative cells (HT-29, MDA-MB-231).
A new class of tumor-targeting 5-FdUrd prodrugs CNF1 and CNF2 were successfully synthesized. These prodrugs targeted a tumor marker APN/CD13 to cause tumor-cell–selective cyctotoxicity due to 5-FdUrd release, the rate of which could be controlled by the structure of ester linker.
- 1. E. Chu, A. Mota, and M. C. Fogarasi. Pharmacology of cancer chemotherapy. In V. T. DeVita, S. Hellman and S. A. Rosenberg (eds.), Cancer Principles & Practice of Oncology, 6th ed., Vol. 1, Lippincott Williams & Wilkins: Philadelphia, 2001, pp. 388–415.
- 2. C. E. Myers. The pharmacology of the fluoropyrimidines. Pharmacol. Rev. 33:1–15 (1981).
- 3. J. A. van Laar, Y. M. Rustum, S. P. Ackland, C. J. van Groeningen, and G. J. Peters. Comparison of 5-fluoro-2′-deoxyuridine with 5-fluorouracil and their role in the treatment of colorectal cancer. Eur. J. Cancer 34:296–306 (1998).
- 4. S. Fukushima, T. Kawaguchi, M. Nishida, K. Juni, Y. Yamshita, M. Takahashi, and M. Nakano. Selective anticancer effects of 3′,5′-dioctanoyl-5-fluoro-2′-deoxyuridine, a lipophilic prodrug of 5-fluoro-2′-deoxyuridine, dissolved in an oily lymphographic agent on hepatic cancer of rabbits bearing VX-2 tumor. Cancer Res. 47:1930–1934 (1987).
- 5. B. S. Vig, P. J. Lorenzi, S. Mittal, C. P. Landowski, H. Shin, H. Mosberg, J. M. Hilfinger, and G. L. Amidon. Amino acid ester prodrugs of fluorodeoxyuridine: synthesis and effects of structure, stereochemistry, and site of esterification on rate of hydrolysis. Pharm. Res. 20:1381–1388 (2003).
- 6. Z. Xia, L. I. Wiebe, G. G. Miller, and E. E. Knaus. Synthesis and biological evaluation of butanoate, retinoate, and bis(2,2,2-trichloroethyl)phosphate derivatives of 5-fluoro-2′-deoxyuridine and 2′,5-difluoro-2′-deoxyuridine as potential dual action anticancer prodrugs. Arch. Pharm. (Weiheim) 332:286–294 (1999).
- 7. K. Tanabe, Y. Mimasu, A. Eto, Y. Tachi, S. Sakakibara, M. Mori, H. Hatta, and S. Nishimoto. One-electron reduction characteristics of N(3)-substituted 5-fluorodeoxyuridines synthesized as radiation-activated prodrugs. Bioorg. Med. Chem. 11:4551–4556 (2003).
- 8. Y. Shibamoto, Y. Tachi, K. Tanabe, H. Hatta, and S. Nishimoto. In vitro and in vivo evaluation of novel antitumor prodrugs of 5-fluoro-2′-deoxyuridine activated by hypoxic irradiation. Int. J. Radiat. Oncol. Biol. Phys. 58:397–402 (2004).
- 9. Y. Wei, Y. Yan, D. Pei, and B. Gong. A photoactivated prodrug. Bioorg. Med. Chem. Lett. 8:2419–2422 (1998).
- 10. G. A. Koning, J. A. Kamps, and G. L. Scherphof. Efficient intracellular delivery of 5-fluorodeoxyuridine into colon cancer cells by targeted immunoliposomes. Cancer Detect. Prev. 26:299–307 (2002).
- 11. G. A. Koning, A. Gorter, G. L. Scherphof, and J. A. Kamps. Antiproliferative effect of immunoliposomes containing 5-fluorodeoxyuridine-dipalmitate on colon cancer cells. Br. J. Cancer 80:1718–1725 (1999).
- 12. A. Goerlach, K. G. Krauer, I. F. McKenzie, and G. A. Pietersz. In vitro antitumor activity of 2′-deoxy-5-fluorouridine-monoclonal antibody conjugates. Bioconjug. Chem. 2:96–101 (1991).
- 13. D. C. Drummond, O. Meyer, K. Hong, D. B. Kirpotin, and D. Papahadjopoulos. Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmaco. Rev. 51:691–743 (1999).
- 14. 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. USA 95:4607–4612 (1998).
- 15. I. Brigger, C. Dubernet, and P. Couvreur. Nanoparticles in cancer therapy and diagnosis. Adv. Drug Deliv. Rev. 54:631–651 (2002).
- 16. P. D. Senter and C. J. Springer. Selective activation of anticancer prodrugs by monoclonal antibody-enzyme conjugates. Adv. Drug Deliv. Rev. 53:247–264 (2001).
- 17. E. C. Ko, X. Wang, and S. Ferrone. Immunotherapy of malignant diseases. Challenges and strategies. Int. Arch. Allergy Immunol. 132:294–309 (2003).
- 18. E. Ruoslahti. Specialization of tumor vasculature. Nat. Rev. Cancer 2:83–90 (2002).
- 19. P. Alessi, C. Ebbinghaus, and D. Neri. Molecular targeting of angiogenesis. Biochim. Biophys. Acta 1654:39–49 (2004).
- 20. E. Ruoslahti and D. Rajotte. An address system in the vasculature of normal tissues and tumors Annu. Rev. Immunol. 18:813–827 (2000).
- 21. R. Pasqualini and E. Ruoslahti. Organ targeting in vivo using phage display peptide libraries. Nature 380:364–366 (1996). CrossRef
- 22. K. Porkka, P. Laakkonen, J. A. Hoffman, M. Bernasconi, and E. Ruoslahti. A fragment of the HMGN2 protein homes to the nuclei of tumor cells and tumor endothelial cells in vivo. Proc. Natl. Acad. Sci. USA 99:7444–7449 (2002).
- 23. L. A. Landon and S. L. Deutscher. Combinatorial discovery of tumor targeting peptides using phage display. J. Cell. Biochem. 90:509–517 (2003).
- 24. W. Arap, R. Pasqualini, and E. Ruoslahti. Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 279:377–380 (1998). CrossRef
- 25. M. Trepel, W. Arap, and R. Pasqualini. In vivo phage display and vascular heterogeneity: implications for targeted medicine. Curr. Opin. Chem. Biol. 6:399–404 (2002).
- 26. R. Pasqualini, E. Koivunen, R. Kain, J. Lahdenranta, M. Sakamoto, A. Stryhn, R. A. Ashmun, L. H. Shapiro, W. Arap, and E. Ruoslahti. Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis. Cancer Res. 60:722–727 (2000).
- 27. F. Curnis, G. Arrigoni, A. Sacchi, L. Fischetti, W. Arap, R. Pasqualini, and A. Corti. Differential binding of drugs containing the NGR motif to CD13 isoforms in tumor vessels, epithelia, and myeloid cells. Cancer Res. 62:867–874 (2002).
- 28. H. Tamamura, A. Omagari, K. Hiramatsu, T. Kanamoto, K. Gotoh, K. Kanbara, N. Yamamoto, H. Nakashima, A. Otaka, and N. Fuji. Synthesis and evaluation of biofunctional anti-HIV agents based on specific CXCR4 antagonist-AZT conjugation. Bioorg. Med. Chem. 9:2179–2187 (2001).
- 29. A. Nagy, A. Polnowski, and A. V. Schally. Stability of cytotoxic luteinizing hormone-releasing hormone conjugate (AN-152) containing doxorubicin 14-O-hemiglutarate in mouse and human serum in vitro: implications for the design of preclinical studies. Proc. Natl. Acad. Sci. USA 97:829–834 (2000).
- 30. H. Tamamura, T. Ishihara, H. Oyake, M. Imai, A. Otaka, T. Ibuka, R. Arakaki, H. Nakashima, T. Murakami, M. Waki, A. Matsumoto, N. Yamamoto, and N. Fujii. Convenient one-pot synthesis of cystine-containing peptides using the trimethylsilyl chloride-dimethyl sulfoxide/trifluoroacetic acid system and its application to the synthesis of bifunctional anti-HIV compounds. J. Chem. Soc., Perkin Trans. 1 1:495–500 (1998).
- 31. T. Mosmann. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods 65:55–63 (1983). CrossRef
- 32. Y. Shibamoto, Y. Mimasu, Y. Tachi, H. Hatta, and S. Nishimoto. Comparison of 5-fluorouracil and 5-fluoro-2′-deoxyuridine as an effector in radiation-activated prodrugs. J. Chemother. 14:390–396 (2002).
- 33. Y. van Hensbergen, H. J. Broxterman, Y. W. Elderkamp, J. Lankelma, J. C. Beers, M. Heijn, E. Boven, K. Hoekman, and H. M. Pinedo. A doxorubicin-CNGRC-peptide conjugate with prodrug properties. Biochem. Pharmacol. 63:897–908 (2002).
- 34. J. S. Shim, J. H. Kim, H. Y. Cho, Y. N. Yum, S. H. Kim, H. J. Park, B. S. Shim, S. H. Choi, and H. J. Kwon. Irreversible inhibition of CD13/aminopeptidase N by the antiangiogenic agent curcumin. Chem. Biol. 10:695–704 (2003).
- 35. D. Riemann, A. Kehlen, K. Thiele, M. Löhn, and J. Langner. Induction of aminopeptidase N/CD13 on human lymphocytes after adhesion to fibroblast-like synoviocytes, endothelial cells, epithelial cells, and monocytes/macrophages. J. Immunol. 158:3425–3432 (1997).
- 36. F. Curnis, A. Sacchi, L. Borgna, F. Magni, A. Gasparri, and A. Corti. Enhancement of tumor necrosis factor alpha antitumor immunotherapeutic properties by targeted delivery to aminopeptidase N (CD13). Nat. Biotechnol. 18:1185–1190 (2000).
- 37. W. Arap, M. G. Kolonin, M. Trepel, J. Lahdenranta, M. Cardo-Vila, R. J. Giordano, P. J. Mintz, P. U. Ardelt, V. J. Yao, C. I. Vidal, L. Chen, A. Flamm, H. Valtanen, L. M. Weavind, M. E. Hicks, R. E. Pollock, G. H. Botz, C. D. Bucana, E. Koivunen, D. Cahill, P. Troncoso, K. A. Baggerly, R. D. Pentz, K. A. Do, C. J. Logothetis, and R. Pasqualini. Steps toward mapping the human vasculature by phage display. Nat. Med. 8:121–127 (2002).
- 38. F. Pastorino, C. Brignole, D. Marimpietri, M. Cilli, C. Gambini, D. Ribatti, R. Longhi, T. M. Allen, A. Corti, and M. Ponzoni. Vascular damage and anti-angiogenic effects of tumor vessel-targeted liposomal chemotherapy. Cancer Res. 63:7400–7409 (2003).
- A New Class of 5-Fluoro-2′-deoxyuridine Prodrugs Conjugated with a Tumor-Homing Cyclic Peptide CNGRC by Ester Linkers: Synthesis, Reactivity, and Tumor-Cell–Selective Cytotoxicity
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