Synthesis And Properties Of Degradable Amphiphilic Block Copolymers

Biodegradable amphiphilic block copolymers could self-assemble into different morphologies like vesicle or micelle in an aqueous solution, which are fairly stable compared with low molecular weight ones, including greater thermodynamic and kinetic stabilities. But it is still an equilibrium system between the polymeric aggregations and the corresponding polymers. Once being introduced into the bloodstream, polymeric aggregations might disassemble into free polymeric chains as being subjected to high dilution and other factors such as temperature, pH, ionic strength, which cause the burst release of loaded drugs. For improving the stability of such aggregations, chemical cross-linking methods through either core or shell segments were usually used. However, the encapsulation, release or biodegradable properties of such aggregations might be altered by such chemical cross-linking procedures. To overcome such disadvantages, in this thesis, a seires of biodegradable amphiphilic block copolymers based on poly(ethylene glycol)(PEG) and degradable polyesters have been deisgned and synthesized or the stereocomplex interaction as an physical cross-linking method have been used to improve the stability of the aggregates. Their self-assembly and biocompatibility properties have been studied. Partial of such biodegradable amphiphilic block copolymers’ drug realease properties have been researched.Two linear-dendritic amphiphilic block polymers were synthesized by click chemistry between prepared “clickable” azide-functionalized MPEG and alkyne-functionalized dendrimers based on bis-MPA and their chemical structures have been determined. And their aggregation behaviors were studied. These amphiphilic diblock copolymers can self-assemble into spherical micelles in water. The derived critical micelle concentrations(CMC) value for MPEG(5k)-b-G3-(C2H3O2)8 is 1.03 mg/mL, but for the case of MPEG(5k)-b-G3-(C18H35O2)8, its CMC is 0.097 mg/mL, which is much lower than the former’s. The spherical polymeric micelles of MPEG(5k)-b-G3-(C18H35O2)8 and MPEG(5k)-b-G3-(C2H3O2)8 were observed and their diameters are 70 nm and 160 nm, respectively. The micellar aggregate size was actually dependent on the hydrophobic block length within the dendrons. The calorimetric study of the micellization shows that its micellization process is driven by entropy. In particular, the in vitro cytotoxicity investigation presented that the copolymers MPEG(5k)-b-G3-(C18H35O2)8 exhibited better compatibility with L929 cells.Four new Y-shaped miktoarm amphiphilic copolymers with arelatively low hydrophilic/lipophilic ratio, MPEG1.9K-(PLLA4.5k)2, MPEG1.9K-(PDLA4.5k)2, MPEG5k-(PLLA4.5k)2 and MPEG5K-(PDLA4.5k)2, were synthesized by ring-opening polymerization(ROP) and click chemistry and their chemical structures were determined. Their corresponding stereocomplexes were prepared from by evaporation method and the formation of the stereocomplexes was confirmed by FT-IR, differential scanning calorimeter(DSC) and X-ray diffraction(XRD). Further the aggregation behaviors for these synthesized polymers and their stereocomplexes were studied. These synthesized polymers were worm-like aggregates, while these amphiphilic stereocomplexes could self-assemble into spherical micelles in water with diameters of 160 nm and 222 nm respectively. Their CMC were 0.005 mg/mL for MPEG1.9K-(scPLA4.5k)2 and 0.039 mg/mL for MPEG5K-(scPLA4.5k)2 the spherical micelles, which is much lower than that of P188(4.0 mg/ml). The size distribution of the mixture of micellar solution MPEG-(PLLA)2 and MPEG-(PDLA)2 changed gradually from wide range to narrow range with time and a formation process had been proposed for such changes. The biocompatibility of these copolymers and their stereocomplexes were evaluated with relatively lower cytotoxicity. Finally, the release of doxorubicin(DOX) encapsulated into the micelles in buffer at pH 5.4 and 7.4. The drug loading content of micelles was 7.0 % for MPEG1.9K-(scPLA4.5k)2 and 3.9 % for MPEG5K-(scPLA4.5k)2. The encapsulation efficiency of micelles was 43 % for(scPLA)2-G1-P188-G1-(scPLA)2 and 35 % for scPLA-P188-scPLA. The drug release rate at pH 5.4 was faster than that at pH 7.4.Dumbbell- and linear-shaped amphiphilic copolymers based on P188 and PLA were synthesized and their chemical structures were determined. Their stereocomplexes were prepared by evaporation method and the formation of the stereocomplexes was confirmed by FT-IR, DSC and XRD. The stereocomplex interaction between PLLA and PDLA was first analyzed using a novel technology named microscale thermophoresis(MST) and the obtained dissociation constant(Kd) for PLLA(2.8 K) complex with PDLA(2.8 K) is 342 μM. The aggregation behaviors of the corresponding stereocomplexes were studied by PL, TEM and LS. The two stereocomplexes can self-assemble into spherical micelles in water. The CMC was 0.021 mg/mL for(scPLA)2-G1-P188-G1-(scPLA)2 and 0.042 mg/mL for scPLA-P188-scPLA. The diameters of the spherical stereocomplex micelles obtained from TEM was 181 nm for(scPLA)2-G1-P188-G1-(scPLA)2 and 222 nm for scPLA-P188-scPLA. Furthermore, the biocompatibility of the stereocomplexes was evaluated with a relatively lower cytotoxicity. Finally, the release of doxorubicin(DOX) encapsulated into the micelles in buffer at pH 5.4 and 7.4. The drug loading content of micelles was 9.8 % for(scPLA)2-G1-P188-G1-(scPLA)2 and 8.2 % for scPLA-P188-scPLA. The encapsulation efficiency of micelles was 54 % for(scPLA)2-G1-P188-G1-(scPLA)2 and 45 % for scPLA-P188-scPLA. The pH value has a greater effect on the release rate of DOX from dumbbell-shaped stereocomplex micelles than that from the linear-shaped ones, which ensure the long blood circulation and the higher DOX-release surrounding the tumor site.An ABCBA type linear-dendritic amphiphilic block polymers(C18H35O2)8-G3-P188-G3-(C18H35O2)8 was synthesized by click chemistry and its chemical structures were checked. This amphiphilic copolymer can self-assemble into spherical micelles in water with the diameter 160 nm. The derived CMC value is 0.038 mg/mL, which is much lower than that of P188(4.0 mg/ml). In particular, the in vitro cytotoxicity investigation presented that the copolymers exhibited better compatibility with L929 cells. The drug loading content of micelles was 16 %. The encapsulation efficiency of micelles was 84 %. The pH value has a little effect on the release rate of DOX from the micelles and the releas shows a slow characteristics.