A Study On Synthesis Of Fluorinated Macromolecular Prodrug And Their Release Behavior

5-Fluorouracil(5-Fu), a low molecular weight p yrimidine antimetabolites drug, has evolved as an important agent in the treatment of a large spectrum of tumors, including co lon cancer stomach cancer and other gastrointestinal tumors. There are some side effects on human body, in order to achieve a better therapeutic effect and reduce toxicity to humans; the small molecule drug must be maintained at a certain concentration, and with continued drug consumption. In order to overcome the drawbacks, we designed a developed a new macromolecular prodrug, in which poly(HEMA-co-NVP) was used as carrier conjugating to 5-FuAc catalyzed by DMAP and DCC through ester bond.5-fluorouracil reacted with chloroacetic acid in sodium hydroxide solution to prepare the Intermediate 5- fluorouracil acetic acid(5-FuAc). The obtained white crystal was confirmed by analysis of UV, IR, NMR and XRD spectrum. The reaction condition was also studied.P(HEMA-NVP) was synthesized by radical aqueous copolymerization with N-vinyl pyrrolidone(NVP) and hydroxyethyl methacrylate(HEMA) as monomer. The structure of P(HEMA-NVP) was confirmed by UV、FT-IR、NMR、XRD. The effect of reaction conditions on polymerization was studied.5-FuAc and poly(HEMA-co-NVP) through ester linkage catalyzed by DMAP and DCC in the solvent N, N-Dimethylformamide(DMF). The results show that the product with different drug content was synthesized by controlling the ratio of 5-FuAc. The conjugate obtained was confirmed by analysis of FT-IR、NMR、UV、XRD spectra. It was confirmed by the structure characterization that 5-FuAc was successfully grafted onto P(HEMA-NVP) through ester bond.According to UV spectrophotometer method, the contents of 5- were determined and the drug delivery rate of the drug was determined by hydrolysis experiments under alkaline conditions. The drug release behavior of the conjugates in the phosphate buffer solution(PBS) under different p H conditions(p H 2.0, 7.2, and 8.4, respectively) were investigated at 37℃. The stability investigation of the conjugates revealed that the conjugate was more stable at p H 2.0 and more sensitive to hydrolysis when the p H value changed from 2.0 to 8.5, the release rate reached about 85% in 24 hoursThe results demonstrated that the conjugate will remain chemically bonded to the polymer in acid conditions such as those in the stomach and will tend to decompose and release free 5-FuAc under slightly alkaline conditions such as those in the intestinal tract. Precise colonic drug delivery requires that the triggering mechanism in the delivery system only responds to the physiological conditions particular to the intestinal tract.Therefore this conjugates would be suitable for intestinal tract targeting as a polymeric prodrug of 5-FuAc. This polymer is a promising carrier for the sustained-release of antitumor drugs. The conjugate will find application in drug targeting and controlled release in the intestinal tract.