Abstract
The natural drug, paclitaxel (taxol), is highly effectiveas a tumor chemotherapeuticwith a low probability of inducing chemoresistance,but shows severe toxic side effectsat the therapeutic dose. How can this toxicitybe overcome? Here we report the synthesisof cyclodextrin dimers connected at thesecondary face by amide-bonded aliphatic spacers.
The spacer length of one of the dimers referred to asdiβCD(2N-A4C5A4) or dimer 7cmatches the distance between the twobenzoic acid residues of paclitaxel. We investigated the physical inclusion of taxol into this dimer using the TNS-label competition method. Affinity constants with the dimer in comparison to free β-cyclodextrin are found to be of the order of 107 l/mole.When included into the cyclodextrin dimer, the drug shows a considerable time delay of incorporation into human tumor cell cultures (OAT SCLC cells) or a total exclusion from the cells. This is the prerequisite to avoid intoxication of other organs of a patient. Possibilities are discussed to detoxify chemotherapeutics and to target their inclusioncomplexes specifically to tumors using specific biological signals.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
S.B. Horwitz: Annals Oncology 5(6), S3 (1994).
Y. Toyama, S. Forry-Schaudies, B. Hoffman, and H. Holtzer: Proc. Natl. Acad. Sci. USA 79, 6556 (1982).
J. Szente, M. Viukmon, J. Szemán, and J. Szeijtli: Pharmaceutical Applications Conference. Kansas City, USA. Poster Abstr. 32 (1997).
U.S. Sharma, S.V. Balasubramanian, and R.M. Straubinger: J. Pharmaceutic. Sci. 84, 1223 (1995).
G. Antlsperger and G. Schmid: 8th Int. Symp. on Cyclodextrins [Budapest] (1996). pp. 149-156.
K. D. Bagshawe: Br. J. Cancer 56, 531 (1987).
K. Bosslet, A. Steinstraesser, A. Schwarz, H.P. Harthus, G. Lueben, L. Kuhlmann, and H.H. Sedlacek: Eur J. Nucl. Med. 14, 523 (1988).
K. Bosslet, J. Czech, P. Lorenz, H.H. Sedlacek, M. Schuermann, and G. Seemann: Br J. Cancer 65, 234 (1992).
F. Fazio and G. Paganelli: Eur J. Nucl. Med. 20, 1138 (1993).
J.G. Moser, A. Heuermann, P. Oehr, H. Scheer, A. Vervoorts and S. Andrees: SPIE Biomed. Optics 2523, 92 (1994).
J.G. Moser, A. Ruebner-Heuermann, A. Weitemeyer, U. Michelsen, D. Woehrle, A. Rueck, W.S.L. Strauss, D. Kirsch, S. Andrees, and C. Schroers: SPIE Biomed. Optics 2625, 138 (1995).
R. Breslow, S. Halfon, and B. Zhang: Tetrahedron 51, 377 (1995).
A. Ruebner, D. Kirsch, S. Andrees, W. Decker, B. Roeder, B. Spengler, R. Kaufmann, and J.G. Moser: J. Incl. Phenom. Mol. Recogn. 37, 69 (1997).
M.D. Johnson and V.C. Reinsborough: Austr. J. Chem. 45, 1961 (1992).
H. Benesi and J.H. Hildebrand: J. Am. Chem. Soc. 71, 2703 (1949).
K. A. Connors: Binding Constants. The Measurement of Molecular Complex Stability, New York: J. Wiley & Sons (1987), pp. 175-187.
R.C. Campbell: Statistics for Biologists, London: Cambridge University Press (1974).
A. Linder: Handliche Sammlung mathematisch-statistischer Tafeln, Basel: Birkhaeuser (1961).
B. Manunza, S. Deiana, M. Pintore, and C. Geesa: Http://antas.agraria.uniss.it/electronic_papers/eccc3/bcd/welcome.htm (1998), 12 pp.
R. Feederle, M. Pajatsch, E. Kremmer, and A. Boeck: Arch. Microbiol. 165, 206 (1996).
H.J. Schneider, T. Blatter, and S. Simova: J. Am. Chem. Soc. 113, 1996 (1991).
A.P. Savitzki, I.G. Meerovich, J.G. Moser, R.I. Yakubovskaya, O.L. Kaliya, and E.A. Luk'yanets: SPIEBiomed. Optics 3191, 34 (1998).
Rights and permissions
About this article
Cite this article
Moser, J.G., Rose, I., Wagner, B. et al. Taxol Inclusion Complexes with a Cyclodextrin Dimer: Possibilities to Detoxify Chemotherapeutics and to Target Drugs Specifically to Tumors?. Journal of Inclusion Phenomena 39, 13–18 (2001). https://doi.org/10.1023/A:1008114826524
Issue Date:
DOI: https://doi.org/10.1023/A:1008114826524