Study On Synthesis And Applications Of Biodegradable Polyurethane As A Drug Sustained-release Material Loaded With5-fluorouracil

5-fluorouracil is one of broad-spectrum antimetabolite clinically applied. However,its half-life is just10-20min in vivo with significant efficacy. Therefore its application hasbeen restrictly limited. Nowadays, the aims of most studies are to directly fast-releasedrugs near the targeted cells with different carriers. However, relatively fewer researchesconcentrated on carriers both with the long-term sustained release effect and with envi-ronmental-responsive intelligent-release effect. To deal with such problems, biocompatible,biodegradable, and pH sensitive materials were applied to prepare two kinds of polyure-thane (PU), and then5-Fu is coated with such polyurethane microspheres (5Fu/PUMs),and certain effect has been achieved. This main research content and the method in thethesis included:1. pH sensitive PETU was prepared with hexamethylene diisocyanate (HDI), po-lyethylene glycol (PEG),1,4-bis(2-hydroxyethyl) piperazine(HEP) as main materials.Thermal performance and structural of polyurethane were investigated with different cha-racteristic method. And different factors influencing such properties were discussed. Ac-cording to the study purposes, the swelling and pH sensitivity were investigated with titra-tion test and swelling test. Degradation of PETU property in vitro was tested in phosphatebuffer solution (PBS) with different pH and studied.2. First,poly(ε-caprolactone) with two terminated carboxyl groups (PCLC) was pre-pared with ε-caprolactone and succinic acid. Then PCLC interacted with PEG to synthesisP(PEG-b-PCLC-b-PEG) block copolymers (PEST). Finally, PEST, HEP, HDI were usedas main material to synthesis polyether-ester-urethane (PESTU). Chemical construction,material structure and thermal properties were investigated as mentioned above. Swellingproperty and pH sensitivity were investigated as mentioned above. Both degradation bothof enzymolysis and of hydrolysis were tested with PBS and PBS added with lipase.3.5-Fu was coated with synthesized polyurethane to prepare polyether urethane mi-crospheres loaded with5-Fu(5-Fu/PETUMs) and polyether-ester urethane loaded with5-Fu (5-Fu/PESTUMs). The5-Fu release behavior was investigated with cumulative re-lease test in vitro in PBS with different pH. And the PBS with different pH were selectedto stimulate the environment both of the normal cells and abnormal cells. The release be-havior was discussed via the test results analyzed. With the help of different drug release model, the results were stimulated to further discuss the release behavior of2-Fu in PUcarriers in different environment.The research results showed:(1) at optimal reaction condition, synthesized PETUwith better pH sensitivity and certain swelling property according to PETU-3、PETU-4、PETU-6. With the help of different characteristic methods and through the analysis of thecharacteristic results, the swelling property of PETU was promoted, while pH sensitivitywas suppressed as the MPEGincreasing、the relative mounts of PEG in nHDI/nBDO/nPEG+HEPand R(PEG/HEP) were rising.(2)Compared with PETU, PESTU possessed much betterhydrolysis degradation property. At the optimal reaction condition, PESTU prepared ac-cording the PE200STU-3, PE400STU-2scheme presented with much better pH sensitivityand swelling property. Through the analysis of the test results, the influences of soft seg-ment content of PESTU on the pH sensitivity and swelling properties were as same asthese of PETU, however the pH sensitivity, swelling properties were suppressed and de-gradation rate was enhanced compared with that of PETU due to the PCL segment intro-duced. In vitro enzymolysis degradation test, when MPEGwas less than600, the degrada-tion degree and rate were promoted because lipase destroy crystalline region of PCLC.Through analyzing the study of release test in vitro of5-Fu/PETU,5-Fu/PESTU prepared atoptimal condition, release curve of two kinds PU both possessed three stages:burst-releasing stage, plateau stage, sustained-releasing stage. Plateau stage was becomingshorter even disappeared as the pH value decreased. at264h pH=7.6PBS in vitro releasetest,the maximum accumulative release rates of5-Fu in5-Fu/PETU,5-Fu/PESTU were29.22%(PETU),51.87%(PESTU) respectively, compared with these at pH=6.5decreasedby34.82%,32.37%respectively. The PU materials possessed excellent sustained releaseeffect and pH sensitivity. Through analyzing test results, the pKa, swelling rate, degradationdegree, and drug loading efficiency all had influences on the cumulative rates and drugreleasing behavior. Via fitting the release results in vitro with different kinds of drug model,the release curves of PETU possessed much higher fitting degree of ambiexponent equation,while these of PESTU possess much lower fitting degree.