A new series of poly(
ethylene glycol)(PEG)-
paclitaxel conjugates that increases water solubility of
paclitaxel was synthesized. We developed well-designed self-immolating linkers between a
drug and a water-soluble
polymer moiety which gave an extremely rapid hydrolysis rate to convert a
pro-drug into a parent
drug without any reduction in
drug efficacy. The self-immolating spacer groups were introduced between the solubilizing PEG and C7-OH of
paclitaxel in order to control the rate of enzymatic hydrolysis. All these
pro-drugs had a water-solubility of 400 mg/ml or more compared with a solubility of about 0.01 mg/ml. The rate of hydrolysis for the
pro-drugs in rat plasma showed considerable variation of t((1/2)) ranging from 0.94 min to 42.7 min. To evaluate the anti-
tumor efficacy of the
pro-drug which had the fastest enzymatic hydrolysis rate, the growth inhibitory effect (IC(50)), the anti-
tumor activity and the anti-metastatic potential of the
pro-drug were examined. The
pro-drug was potent to inhibit the growth of various
cancer cell lines, such as human lung, ovarian, colon and
melanoma cancer cells. On the development of
melanoma lung colonies in C57B/6 mice following
intravenous administration of metastatic murine B16/F10
melanoma cells, the
pro-drug seems to be more efficacious than
paclitaxel. The reduction of the number of
melanoma lung colonies was 46.9% (dose: 5 mg/kg) with pure
paclitaxel, and 24.5%, and 40.0% with the
pro-drug in the dose of 0.71 mg
paclitaxel equivalent/kg and 1.42 mg
paclitaxel equivalent/kg, respectively.