Synthesis And Properties Of Polymeric Drugs Containing 5-Fluorouracil

5-Fluorouracil(5-FU) has been widely used as an antitumor drug, but it has theshortcoming of having toxicity, the shortage of active group, and lower solubility in water.This disadvantage limited its usage. The aim of this paper was to choose appropriatepolymeric carriers to react with 5-FU for introducing target group, reducing toxicity andimproving solubility. A series of functionalized of 5-FU were applied for this purposc.Tumor targeting polymeric prodrugs SF-PGA-FU, SF-PLA-FU were succcssfullysynthesized by the method of conjugation and phase transfer catalysis (PTC). The synthcsizedcopolymer were characterized by FT-IR,~1H-NMR,GPC,DSC,XRD and UV measurement.The drug release and degradation performance in vitro were also studied. The introduction of5-FU and sulfadiazine to PGA and PLA resulted in a decrease in crystallinity and animproving of solubility compared with polymeric carriers. Tg and Tm ofSF-PGA-FU(Mn=1345) also changed from 152.7℃to 112.3℃and from 219.2℃to 126.1℃, respectively. The changing of Tg and Tm of SF-PLA-FU(Mn=2320) was from 42.4℃to67.4℃and 73.1℃to 127.6℃. The drug release rate and degradation rate were controlled bychanging the molelucar weights of carriers. The degradation rate of SF-PGA-FU andSF-PLA-FU were declined by the introduction of sulfadiazine and 5-fluorouracil to prodrugs'terminal. And a slower speed of degradation was obtained compared with polymeric carriers.Because of the hydrophobicity and crystallinity of the polymer, the degradation speed ofhomopolymer can not be controlled easily, which restricts the application of them. Differentcontents of SF-PLGA-FU were successfully synthesized in order to improve its hydrophilicityand adjust its degradation rate. The synthesized copolymers were characterized by FT-IR,~1H-NMR,GPC,DSC,XRD and UV measurement. The drug release and degradationperformance in vitro were also studied. The hydrophilicity of SF-PLGA-FU was influencedby the contents of LA and GA units of the copolymers. As the contents of GA increased, thehydrophilicity of SF-PLGA-FU improved. SF-PLGA(5050)-FU had the optimumhydrophilicity. The drug release rate and degradation rate were accelerated as the increasingof hydrophilicity. The drug release rate and degradation rate could be controlled by changingthe proportion of LA and GA in copolymers.PEG/ester/5-FU and PEG/amide/5-FU conjugates were synthesized to reduce the toxicity and improve the hydrophilicity of 5-FU. Based on the result of orthogonal experiment, theoptimum condition of the esterification reaction of chloroacetic acid with polyethylene glycolwas determined. The synthesized conjugates were characterized by FT-IR,~1H-NMR and UVmeasurement. The hydrophilicity and stability of conjugates were evaluated. And it gainedremarkable improving in hydrophilicity compared with 5-FU and prolonged stability. And thedrug release performance in different pH solution and enzyme solution were also studied. Theconjugates could release 5-FU and its units. The drug release rate of PEG/amide/5-FU wasfast compared with PEG/ester/5-FU, and had a differents drug release rate as the changing ofmolecular weight of PEG carriers. The result of enzyme hydrolysis showed the drug releaserate of prodrugs was accelerated in enzyme solution compared with in aqueous solution.Lactic acid(LA), glycolic acid(GA) andε-caprolactone(CL) was used to synthesizepolyesteramide containing 5-FU in the main chain. The results showed that the optimalreaction temperature was 140℃, DMSO was used as solvent, the optimal duration of reactionwas 18h. Under the optimal condition the polymers have the highest yield and molecularweights. The copolymers were characterized by FT-IR,~1H-NMR,GPC,DSC,XRD andUV measurements. The different contents of copolymers on the property of thehydrophilicity,degradation rate and drug release rate in vitro were studied. The resultsshowed that the increasing of hydrophilic group result in a great water absorption rate, a fasterdegradation reate and drug release rate. The result of enzyme hydrolysis showed the enzymesolution has significant acceleration to drug release of PEA.Polyesters, polyesteramide and polyurethane were synthesized by polycondensationreaction and hydrophilic group were introduced to polymeric chain to improve the watersolubility of 5-FU. The copolymers were characterized by FT-IR,~1H-NMR,VPO and UV.The optimum condition of the polycondensation reaction was determined. And thedegradation and drug release performance of different copolymers were compared. The resultsshowed that increasing of different type hydrophilic groups could change the drug release rate.The result of enzyme hydrolysis showed the enzyme solution has no distinct promotion todrug release of polymers.