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 chemot herapeutic with a low probability of inducing chemoresistance, but shows se vere toxic side effects at the therapeutic dose. How can this toxicity be o vercome? Here we report the synthesis of cyclodextrin dimers connected at t he secondary face by amide-bonded aliphatic spacers. The spacer length of o ne of the dimers referred to as di beta CD(2N-A4C5A4) or dimer 7c matches t he distance between the two benzoic acid residues of paclitaxel. We investi gated the physical inclusion of taxol into this dimer using the TNS-label c ompetition 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 inclu ded into the cyclodextrin dimer, the drug shows a considerable time delay o f 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 chemoth erapeutics and to target their inclusion complexes specifically to tumors u sing specific biological signals.