Synthesis and in vitro efficacy of acid-sensitive poly(ethylene glycol) paclitaxel conjugates

Bioorganic and Medicinal Chemistry Letters

Volumn 13, Issue 3, 2003, Pages 355-360

  Rodrigues, Paula C A ^a,c   Scheuermann, Karin ^a   Stockmar, Cornelia ^a   Maier, Gerhard ^b   Fiebig, Heinz H ^b   Unger, Clemens ^a   Mülhaupt, Rolf ^c   Kratz, Felix ^a  

^a TUMOR BIOLOGY CENTER   (Germany)

^b CHARLES RIVER LABORATORIES   (United States)

^c UNIVERSITY OF FREIBURG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; CREMOPHOR; HYDRAZONE DERIVATIVE; MACROGOL 20000; MALEIMIDE DERIVATIVE; PACLITAXEL DERIVATIVE;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER CELL CULTURE; CONTROLLED STUDY; DRUG CONJUGATION; DRUG EFFICACY; DRUG HYPERSENSITIVITY; DRUG SYNTHESIS; HUMAN; HUMAN CELL; NEUROTOXICITY;

ANTINEOPLASTIC AGENTS, PHYTOGENIC; CHEMISTRY, PHYSICAL; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; CULTURE MEDIA, CONDITIONED; HUMANS; HYDROGEN-ION CONCENTRATION; INDICATORS AND REAGENTS; MAGNETIC RESONANCE SPECTROSCOPY; MALEIMIDES; PACLITAXEL; POLYETHYLENE GLYCOLS; SPECTROPHOTOMETRY, ULTRAVIOLET; TUMOR CELLS, CULTURED;

EID: 0037325515     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(02)01002-8     Document Type: Article

References (38)

1. Nicolaou K.C., Yang Z., Liu J.J., Ueno H., Nantermet P.C., Guy R.K., Claiborne C.F., Renaud J., Couladouros E.A., Paulvannan K., Sorensen E.J. Nature. 367:1994;630.
2. Jehn U., Berghof H. Supportive Maßnahmen in der Onkologie. 4th ed. 1995;Georg Thieme Stuttgart, New.
3. Crown J., O'Leary M. The Lancet. 355:2000;1176.
4. McGuire W.P., Rowinsky E.K. Paclitaxel in Cancer Treatment. 1995;Marcel Dekker, Bethesda, MD.
5. Weiss R.B., Donehower R.V., Wiernik P.H., Ohnuma T., Gralla R.J., Trump D.L., Baker J.R., Van Echo D.A., Von Hoff D.D., Leyland-Joness B. J. Clin. Oncol. 8:1990;1263.
6. Brown T., Havlin K., Cagnola J., Koeller J., Kuhn J., Rizzo J., Craig J., Philips J., Von Hoff D. J. Clin. Oncol. 9:1991;1261.
7. Deutsch H.M., Glinski J.A., Hernandez M., Haugwitz R.D., Narayanan V.L., Suffness M., Zalkow L.H. J. Med. Chem. 32:1989;788.
8. de Groot F.M.H., van Berkom L.W.A., Scheeren H.W. J. Med. Chem. 43:2000;3093.
9. Greenwald R.B., Gilbert C.W., Pendri A., Conover C.D., Xia J., Martinez A. J. Med. Chem. 39:1996;424.
10. Safavy A., Raisch K.P., Khazaeli M.B., Buchsbaum D.J., Bonner J.A. J. Med. Chem. 42:1999;4919.
11. Paradis R., Pagé M. Anticancer Res. 18:1998;2711.
12. Maeda H., Wu J., Sawa T., Matsumura Y., Hori K. J. Control. Rel. 65:2000;271.
13. Noguchi Y., Wu J., Duncan R., Strohalm J., Ulbrich K., Akaike T., Maeda H. Jpn. J. Cancer Res. 89:1998;307.
14. Ceruti M., Crosasso P., Brusa P., Arpicco S., Dosio F., Cattel L. J. Control. Rel. 63:2000;141.
15. Greenwald R.B., Conover C.D., Choe Y.H. Crit. Rev. Ther. Drug Carrier Syst. 17:2000;101.
16. Li C., Yu D., Inoue T., Yang D.J., Millas L., Hunter N.R., Kim E.E., Wallace S. Anti-Cancer Drugs. 7:1996;642.
17. Wang D., Kopeckova P., Minko T., Nanayakkara V., Kopecek J. Biomacromolecules. 3:2000;313.
18. Kratz F., Fichtner I., Roth T., Fiebig H.H., Unger C. J. Drug Targeting. 8:2000;305.
19. Kratz F., Müller-Driver R., Hofmann I., Drevs J., Unger C. J. Med. Chem. 43:2000;1253.
20. Kratz F., Beyer U., Schumacher P., Krüger M., Zahn H., Roth T., Fiebig H.H., Unger C. Bioorg. Med. Chem. Lett. 7:1997;617.
21. Beyer U., Roth T., Schumacher P., Maier G., Unold A., Frahm A.W., Fiebig H.H., Unger C., Kratz F. J. Med. Chem. 41:1998;2701.
22. Rodrigues P.A., Schumacher P., Beyer U., Roth T., Fiebig H.H., Unger C., Paper D., Messori L., Orioli P., Mülhaupt R., Kratz F. Bioorg. Med. Chem. 7:1999;2517.
23. Zalipsky S. Adv. Drug Delivery Rev. 16:1995;157.
24. The synthesis of maleimide spacer derivatives 2a and 2c were described previously. 2b was prepared according to 2a and 2c. (see Beyer, U.; Krüger M.; Schumacher, P.; Unger, C.; Kratz, F., Monatshefte Chemie 1997, 128, 91).
25. Paclitaxel was purchased from Hande Tech USA, Inc. Preparation of 1: To 6 g (36.6 mmol) 4-acetylbenzoic acid dissolved in 250 mL toluene were added 80 mL (0.11 mol) thionyl chloride, and the mixture was refluxed for 1 h. Thionyl chloride as well as toluene were removed in vacuo, and the residue crystallized in 100 mL diethylether to yield the acid chloride as yellow crystals.
26. +].
27. 18) M=1213.24 g/mol.
28. Benassi R., Taddei F. Biochemistry. 17:1985;1499.
29. HPLC studies were performed on a reversed-phase RP 18 (Lichrosorb, RT 250-4, Merck); mobile phase: acetonitrile/0.004 M sodium phosphate (pH 6.0)=60/40; Kontron 422 pump (flow 1 mL/min); UV/VIS detector Kontron 535 and integrator (at λ=254 and 230 nm); Auto sampler Merck/Hitachi AS4000, injection volume 50 μL PEEK-Loop.
30. -1.
31. 2 and the product was precipitated with diethylether. The colorless solid was dried in vacuo. The purity of the samples was analyzed through a semi-analytical FPLC-column (Sephadex® LH 20, flow: 0.1 mL/min of 100% Methanol HPLC-grade, retention time: 15-17 min, λ=280 nm).
32. Ellman G.L. Arch. Biochem. Biophys. 82:1959;70.
33. FPLC studies: Studies at pH 4.0 and pH 7.4 were performed with the PEG paclitaxel conjugates. 50 μL of the stock solutions of the conjugates (c 1100±100 μM) in methanol were diluted 1:20 with a 65:35 mixture of buffer pH 4.0 (0.001 M sodium acetate adjusted to pH 4.0 with acetic acid) or pH 7.4 (0.15 M NaCl, 0.004 M sodium phosphate). The solutions were incubated at room temperature and 50 μL samples were analyzed at λ=280 nm on a FPLC column (Sephadex G25), mobile phase: methanol: buffer (0.15 M NaCl, 0.004 M sodium phosphate, pH 7.4)=30:70 every 3 h for 24 h and after 48 h.
34. Kratz F., Beyer U., Schütte M.T. Crit. Rev. Ther. Drug Carrier Sys. 16:1999;245.
35. 2 and 20 μL of the organic phase were added to 480 μL mobile phase [acetonitrile/buffer pH 6.0 (0.004 M sodium phosphate adjusted to pH 6.0)=40:60] and 50 μL sample analyzed at λ=230 nm on an analytical HPLC column (Lichrosorb, RT 250-4, RP-column, mobile phase: acetonitrile/buffer pH 6.0 (0.004 M sodium phosphate adjusted to pH 6.0)=40:60. A UV/VIS detector Kontron 535 and integrator as well as an auto sampler Merck Hitachi AS4000 were used.
36. HPLC stability studies with 1 at pH 4.0 and 7.4: 50 μL of a stock solutions of 1 (c 6500±100 μM) in methanol were diluted 1:50 with a 65:35 mixture of buffer pH 4.0 (0.001 M sodium acetate adjusted to pH 4.0 with acetic acid) or pH 7.4 (0.15 M NaCl, 0.004 M sodium phosphate) and acetonitrile. The solution was incubated at room temperature and analyzed by HPLC every 3 h over a period of 24 h according to ref 36.
37. 1) was measured using a Millipore Cytofluor 4000 microplate reader (excitation 530 nm, emission 620 nm). Growth inhibition was expressed as treated/control×100 (%T/C).
38. Dengler W.A., Schulte J., Berger D.P., Mertelsmann R., Fiebig H.H. Anti-Cancer Drugs. 6:1995;522.