Taxol inclusion complexes with a cyclodextrin dimer: Possibilities to detoxify chemotherapeutics and to target drugs specifically to tumors?

The natural drug, paclitaxel (taxol), is highly effective as a tumor chemotherapeutic with a low probability of inducing chemoresistance, but shows severe toxic side effects at the therapeutic dose. How can this toxicity be overcome? Here we report the synthesis of cyclodextrin dimers connected at the secondary face by amide-bonded aliphatic spacers. The spacer length of one of the dimers referred to as di beta CD(2N-A4C5A4) or dimer 7c matches the distance between the two benzoic 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 beta -cyclodextrin are found to be of the order of 10(7) 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 inclusion complexes specifically to tumors using specific biological signals.