Synthesis and Physico-Chemical Properties of Cyclotriphosphazene-Paclitaxel Conjugate

Abstract

Paclitaxel (Taxol) is a diterpenoid isolated from Taxus brevifolia, used clinically for treatment of ovarian and breast cancer. Due to its aqueous insolubility it is administered as a formulated solution in ethanol and Cremophore EL(polyethoxylated caster oil), which has serious side effects. Water soluble cyclotriphosphazene derivatives have been studied in order to improve water solubility and the chemotherapeutical potency of paclitaxel. Cyclotriphosphazene derivatives were synthesized by stepwise nucleophilic substitutions of hexachlorocyclotriphosphazene with a hydrophilic poly(ethylene glycol) as a solubilizing group and Glycyl lysine methyl ester as a spacer group. They were found to form a micelle in the presence of 2′-succinyl taxol. It is presumed that the cyclic trimer may form an ion pair adduct with carboxylic acid of 2′-succinyl taxol through the epsilon-amine group of lysine. We also synthesized water soluble cyclotriphosphazene-taxol conjugates by conjugating succinyl taxol to glycyl lysine spacer group through amide linkage bonding. The conjugate was found to undergo hydrolytic degradation in PBS solution and exhibited lower but reasonably good cytotoxicity compared with free taxol. The conjugate was found to enter the cell by endocytosis mechanism and to induce very efficient apoptosis by stopping the G2/M step in the cell cycle. The biodistribution experiment did not show high tumor selectivity of the conjugate, but the conjugate has shown organ selectivity to lung.