Novel Thermosensitive 5-Fluorouracil-Cyclotriphosphazene Conjugates:Synthesis,Thermosensitivity,Degradability,and in Vitro Antitumor Activity

摘要

A novel thermosensitive macromolecular prodrug of 5-fluorouracil (5-FU) was synthesized using Cyclotriphosphazene,and its thermosensitivity,degradability,and in vitro antitumor activity were studied.A series of a-substituted glycine derivatives of 5-FU containing carboxylic groups were prepared,and cyclotriphosphazenes with amino groups were synthesized via the stepwise substitution of hexachlorocyclotriphosphazene (NPCl_2)_3 with methoxy-poly(ethylene glycol) (MPEG) or alkoxy ethylene oxide and lysine ethyl ester (LysOEt).The coupling reaction of the two derivatives,and their subsequent deprotection,yielded a thermosenstive 5-FU-Cyclotriphosphazene conjugate,which exhibited a unique octopus-shaped molecular structure,in which the three hydrophilic PEG groups (or alkoxy ethylene oxides) were oriented in one direction,opposing the other three hydrophobic groups containing 5-FU,with respect to the trimer ring plane.This conjugate exhibited a reversible and thermosensitive phase transition in an aqueous medium,from soluble to insoluble states.The lower critical solution temperature (LCST) of the conjugate was controlled by substitution with different hydrophilic/hydrophobic side groups,and a few of the conjugates displayed LCSTs which were just below body temperature.This,of course,implies possible applications for local drug delivery by direct intratumoral injection.The conjugate exhibited gradual degradation at 37 deg C in both neutral and acidic buffer solutions,and high temperature significantly facilitated its hydrolytic degradation.All of the conjugates displayed dose-dependent cytotoxicity against the leukemia L1210 cell line and exhibited more pronounced cytotoxic effects than did 5-FU.