Synthesis, Characterization And Application Of Aliphatic Polyesters And Their Amphiphilic Block Copolymer

Chemical synthetic degradable aliphatic polyesters and their amphiphilic copolymers have attracted much attention in drug controlled release systems and tissue engineering due to their excellent biodegradable, biocompatible, permeable and low toxicity properties. However, in current strategy for the synthesis of aliphatic polyesters there are various problems, which primarily involve low catalytic activity, higher toxicity, the sluggish polymerization reaction rate, lower monomer conversion and lower polymer molecule weight etc. Therefore, to investigate a more efficient, inexpensive, simpler polymerization process, more controllable and non-toxic catalytic systems have developed an important subject.In recent years, biodegradable aliphatic polyesters and their amphiphilic copolymers have been used to prepare nano or macroscopic scale drug delivery carrier with various morphologies by various technologies, such as solvent evaporation method. These drug delivery carrier prossess many ascendancies, on the one hand, it can prolong the drug circulation times in vivo, and make its effectiveness in an enough times, on the other hand, the long-acting circulation of drug-loaded particles is favored to improve the interaction between drug and diseased region. Meanwhile, there is an increasing evidence to suggest that the drug release behaviors of drug-loaded particles in different diseased region or tissues dependent not only on their size and stability but also on their morphology. Based on these, the thesis including several aspects:(1) Syntheis of biodegradable star-shaped poly(ε-caprolactone) and poly (lactide-b-caprolactone) block copolymer.In present study, four-arm star-shaped aliphatic polyesters poly(ε-caprolactone)(PCL) was synthesized via using tetrabutyl titanate (TBT) and isopropyl titanate (iPT) as initiator to mediate controlled ring-opening polymerization (ROP) of ε-caprolactone (CL) at ambient temperature of10-40℃under the normal atmosphere. The kinetic indicated that tetrabutyl titanate(TBT) and isopropyl titanate (iPT) controlled ring-opening polymerization (ROP) of ε-CL exhibited living and controlling features. Moreover, the star-shaped Ti(O-PCL)4can act as a macroinitiator for successive propagation and block copolymerization with CL and LA, respectively. The mechanism of titanium ester controlled ring-opening polymerization (ROP) of ε-CL is accorded with the "coordination-insertion". The polymerization kinetics comparison of CL initiated by tetrabutyl titanate and isopropyl titanate manifested that the isopropyl titanate-catalyzed ROP of CL is faster than the tetrabutyl titanate initiated ROP at40℃.Meanwhile, we found that Ti-alkoxide bonds included in the polymer chains was relative stabilized when the crude polymer precipitated in de-ionized water or alcohol, and it hydrolyzed to linear PCL when precipitated in acidic alcoholic solution. The star-shaped Ti(O-PCL)4and Ti(O-PLA-PCL)4block copolymers were characterized by1H NMR, gel permeation chromatography (GPC), differential scanning calorimetry (DSC) and ZeTa particle-size analyzer.(2) Synthesis of star-shaped poly (caprolactone-b-propylene oxide) block copolymer.Firstly, four-arm star-shaped poly(propylene oxide) macroinitiator was synthesized via using isopropyl titanate (iPT) as initiator to mediate controlled ring-opening polymerization (ROP) of propylene oxide (PO) at room temperature under the normal atmosphere. Then, the star-shaped poly(propylene oxide) act as a macroinitiator for successive block copolymerization with CL at40℃. The results indicated that only oligomer could be obtained after polymerization of PO iniated by iPT, and the obtained star-shaped poly(propylene oxide) prossess much lower molecule weight and stability. The kinetic indicated that four-arm star-shaped poly(propylene oxide) macroinitiator still sustained much higher activity, which can achive the controlling synthesis of poly (caprolactone-b-propylene oxide) block copolymer.(3) Synthesis and characterization of poly(ε-caprolactone)-b-poly(ethylene oxide)-b-poly(ε-caprolactone) amphiphilic triblock copolymer and their self-assembly behavior.A serials of poly(s-caprolactone)-b-poly(ethylene oxide)-b-poly(s-caprolactone)(PCL-PEO-PCL) triblock copolymers were synthesized by a ring-opening polymerization of ε-caprolactone in the presence of hydroxyl-terminated poly(ethylene oxide) with stannous octoate catalyst, where PEO served as initiator. The self-assembly behavior of amphiphilic block copolymers in THF/H2O and THF/a certain concentration of alkali metal ions aqueous solution are carried out by a O/W modified solvent extraction method. The morphologies transform of PCL-PEO-PCL triblock copolymers self-assembly from aqueous media to condensed aggregates is extensively investigated. It was found that the monoporous spherical micelles formed both in di-ionized water and alkali metal ions aqueous solution. However, with the increase of alkali metal ions concentration, the spherical micelles assembled into different hierarchical mesostructures during the water evaporation from the block copolymer. The morphologies of aggregates included "sisal-like" and "satr-shaped" mesostructures. The morphologies of mesostructures aggregates strongly depended on the addition of different alkali metal ions, but the size of aggregates have to do with the alkali metal ions concentrations.The mechanism for the self-assembly of PCL-PEO-PCL amphiphilic triblock copolymer are attributed to the continuous increase of alkali metal salt concentration and thus the stronger coordination between alkali metal ions and PEO ligands in the block copolymer during water evaporation process. The strong binding of PEO with alkali metal ion leads to the decrease of free energy in the system. In this case, with the support of the driving force from the strong coordination between PEO and alkali metal ions, a large number of spherical micelles move and merge, and some of the micelles possibly fuse together, resulting the formation of aggregates mesostructures.(4) Preparation of porous drug-loaded poly(lactide-co-glycolide-b-ethylene glycol-b-lactide-co-glycolide)(PLGA-PEO-PLGA) microspheres and their drug release behavior under ultrasound in vitro.A series of amphiphilic tri-block copolymer PLGA-PEO-PLGA were synthesized by a ring-opening polymerization of LA and GA in the presence of hydroxyl-terminated poly(ethylene oxide) with stannous octoate catalyst, where PEO served as initiator. The drug-loaded porous microspheres was successfully prepared by a modified double emulsion (W/O/W)-solvent evaporation technique without any porogen present. The spontaneous and ultrasound promoted drug releases were studied. Compared with spontaneous drug release behavior, the capacity of ultrasonic drug release was significantly faster from PLGA-PEO-PLGA porous microspheres. It was found that the compositions of PLGA-PEO-PLGA have great influence on the morphologies of microspheres, size, surface apertures and drug entrapment efficiency. Moreover, the initially bursts could be controlled by adjusting the surface apertures of microspheres. The PLGA-PEO-PLGA could be used as a novel acoustic control "passive target" pharmaceutical agent, which can not only contrast-enhanced under ultrasound, but also promote the drug release. Finally, the formation mechanism of PLGA-PEO-PLGA porous microspheres was discussed.