Synthesis And Characterization Of 5-fluorouracil Comb Polymer Carrier Prodrugs

Cancer chemotherapy, especially the use of small anticancer drugs that mainly arelow molecule compounds, are still the most used and effective way in clinical therapy.Although the significant anti-tumor effect of these small drugs are indubitable, but thevarious serious side effect coming with become the biggest impidements of smallchemical anticancer drugs development. Drug delivery system (DDS) has beendeveloped to overcome those problems, and become the hot point of drug researchand development (R&D), particularly the study of polymer prodrugs. A polymerprodrug is composed of the small chemical compounds and polymer carrier, whichconnected by covalent bond to each other, and such the connection may endow thosechemicals with better stability, solubility and other some special performance, such asdelay&control release and targeting by using special linkers or bonds.A large number of studies have shown that polyethylene glycol (PEG) is a goodcandidate of polymeric carrier, which with the advantages of non-toxic,non-immunogenic and high solubility in water, and also has been approved by FDA tomodify such as peptide drugs, anti-tumor drugs, liposome, microspheres andnanoparticles in attempt to lower their immunogenicity, increase solubility andextending half-life, etc. PEG is readily availbable in a variety of molecular weight,from1000to20000Da, and the most commonly used PEG is a linear polymer witheither one or two functional groups at the two distal. Simple conjugation with suchlinear PEG will attach up to two drugs molecular per PEG conjugate, which limite thedrug loading. Subsequently, a large amount of the compound was given to patientsduring clinical trials. To increase the drug loading of PEG polymeric carrier, weoriginally use5-fluorouracil (5-Fu) as a model drug to designed and synthesiszed5-Fu containing polyethylene glycol methacrylate monomer (MAA-PEG-5Fu) underthe guidance of the polymeric prodrug principle, and further synthesieszed thecomb-like polymer (p(MAA-PEG-5Fu)) that with multiple branched chains and could enhance drug loading very much in theory. Luckyly, the results of its performancehave confirmed our assumption.In the process of such prodrug synthesis, olefinic bond was first introduced to oneterminal of PEG by methyacrylation, and then prepared a series MAA-PEG-OHMAA-PEG-5Fu monomer in different molecular weight (MAA-PEG400-5Fu,MAA-PEG2000-5Fu). By using atom transfer radical polymerization(ATRP) andAIBN induced traditional radical polymerization, two comb-like polymeric prodrugs(p(MAA-PEG400-5Fu), p(MAA-PEG2000-5Fu)) were synthesized respectively,which structures were confirmed by means of IR，1HNMR，UV-Vis，Ms，GPCandDSC. Finally, in order to determine drug conjugation and drug release of twocomb-like polymeric prodrugs, UV-Vis and HPLC method were established.Results showed that (1) two high water solubility comb-like polymeric prodrugs(p(MAA-PEG400-5Fu), p(MAA-PEG2000-5Fu)) were achieved by AIBN inducedtraditional radical polymerization;(2) drug loading and reaction extent were25.51%，10%and86%,100%of p(MAA-PEG400-5Fu), p(MAA-PEG2000-5Fu) respectively,which further indicates that we can enhanced the loading performance throughpolymerizing the drug containing monomers;(3)5-Fu-1-acetic was steadly andslowly released from polymeric prodrugs in different microenvironment,characterized by sustained release effect.(4) Drug release curve of polymericprodrugs at pH1.2(gastric fluid mimics), pH5.5(tumor microenvironment mimics),pH6.8(intestinal fluid mimics), pH7.4(blood mimics) and pH8.0(pancreatic fluidmimics) buffers found that the higher pH, the higher release rate. In detail, thecumulative release percentage of prodrug in pH1.2and pH8.0buffers at144h were8%,14%and78%,88%respectively, bear the characteristics of pH-sensitive releaseand colon targeting.In summary, the two comb-like polymer prodrugs systhesised can significantlyincrease drug loading, improve5-Fu release behavior, and with the characteristics ofpH-sensitive, sustained drug release and colon targeting. More in vitro and in vivoanti-cancer studies will be done in further.