Synthesis Of Thermosensitive Polyether/polyester Block Copolymers And Studies Of Reentrant Temperature-induced Physical Gelation And Drug Release Behaviors

In situ hydrogelling systems exist as a sol in vitro and gelate in vivo after injection, and is thus becoming a very promising biomaterial type. Injectable hydrogels can be classified into chemical gels and or physical gels. Formation of a physically cross-linked hydrogels is free of enzymes, cross-linking agents, photoinitiators and organic solvents utilized in the chemically cross-linked hydrogels. Physical gelation is often induced by self-assembly in response to stimuli, such as temperature, ion concentration and so on, offering a mild method for preparing hydrogels. Among the stimulating factors, temperature is very convenient and practical to manipulate. So injectable temperature-sensitive hydrogels have attracted much attention.This thesis is aimed to study the thermohydrogels formed by block copolymers composed of poly(ethylene glycol) (PEG) and aliphatic polyester. The PEG block and polyester block are both approved by American Food and Drug Administration (FDA) to use in human body. Yet the block copolymers are new biomaterials with rich physics to be revealed. This thesis concerns the synthesis of thermogellable block copolymers, their physical gelling properties and potential applications as a sustained release carrier. A reentrant reverse hydrogel was discovered after addition of salts into a normal gelling system for the first time. In the drug release experiment, polyelectrolytes were used to adjust the release behaivor of a hydrophilic small molecular drug.The main innovations and achievements are summarized as follows:(1) A series of thermogelling block copolymers composed of hydrophilic PEG and hydrophobic polyesters were synthesized and a comparative study was carried out. The structures and properties of this kind of copolymers can be adjusted from various aspects. The kinds of aliphatic polyesters, the molecular weights of PEG and the architecture of block copolymers all serve as adjustable parameters. We synthesized four kinds of PEG/polyesters block copolymers via ring-opening polymerization, including triblock copolymers of poly(lactide-co-glycolide)-poly(ethylene glycol)-poly(lactide-co-glycolide) (PLGA-PEG-PLGA) and poly(s-caprolactone-co-lactide)-poly(ethylene glycol)-poly(ε-caprolactone-co-lactide) (PCLA-PEG-PCLA); diblock copolymers of methoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) and methoxy poly(ethylene glycol)-poly(lactide-co-glycolide) (MPEG-PLGA). The differential scanning calorimetry experiment displayed the differences in crystallinity of these copolymers. These copolymer aqueous systems varied in critical micelle concentration, phase diagram and rheological properties. The thermosensitive properties of PEG/polyester block copolymers are mainly caused by the PEG block. While PEG has a good solubility in water at low temperatures, its solubility decreases with increase of temperature.(2) Salt-induced reentrant hydrogel ofpoly(ethylene glycol)-poly(lactide-co-glyco-lide) block copolymers was discovered. A reverse gel refers to a system that is a sol at low temperatures and turns into a gel at high temperatures, while a normal gel means that the system is a gel at low temperatures and becomes a sol when the temperature is increased. Compared with the normal gel, the reverse gel is easily used to encapsulate drugs and cells. Among PEG/polyester block copolymers, the polymers with molecular weight of PEG more than 2000 form a normal gel. In this thesis, we found, without changing the composition of block copolymers, that a normal gelling system could become a reverse gel just by adding salts. These two gels exhibited different microstructures and properties. Through a comprehensive analysis, the underlying different gelation mechanisms were further suggested. The phase transition temperatures of reentrant hydrogels varied with the salt concentration and depended on the type of ions with the trend obeying the Hofineister series.(3) The thermohydrogel system of PLGA-PEG-PLGA triblock copolymers was extended as the drug carriers of the anticancer drug gemcitabine. Compared with systematic therapy, local treatment can increase the drug concentration of the target sites, thus improve the treatment efficacy and reduce the adverse effects. Gemcitabine is a first-line treatment drug for advanced pancreatic cancer, non-small cell lung cancer, local or metastatic bladder cancer and breast cancer. But gemcitabine is metabolized fast in vivo and thus has a short half life. High-dose intravenous drip will bring severe adverse effects. So according to our analysis, building a local therapy of gemcitabine is an effective method to improve the efficacy of treatment. In this thesis, gemcitabine was loaded into the thermohydrogel for the first time. While it was completely released from the PLGA-PEG-PLGA thermohydrogel, a significant burst effect existed at the early release stage. We further tried to use, for the first time, polyelectrolytes to adjust the release of gemcitabine, especially to reduce the burst at the initial stage. Polyelectrolytes with acid radicals could be negatively charged in water, thus interacting with drug molecules with positive chage due to electrostatic interaction and inhibiting the release of drugs. But the experimental results showed that the polyacrylic acid did not effectively decrease the cumulative release at the intial stage while lOmg/g sodium alginate reduced the burst by 15%. By determination of pKa of polyelectrolytes and pH values of thermohydrogel systems, we thought that the strong acidic environment of PLGA-PEG-PLGA thermohydrogel restrained the dissociation of acid radicals. So in the subsequent studies, choosing a more suitable thermohydrogel system or increasing the complex efficiency between drugs and polyelectrolytes might be potential solutions.This thesis investigates PEG/polyester thermosensitive block copolymers from various aspects, including the synthesis of these copolymers, the underlying gelation mechanisms and the potential as a drug carrier. The normal gelling system and reverse gelling system were both studied and a bridge was built by salt between these two systems. The study of developing thermohydrogel as the sustained release carrier for an anticancer drug gemcitabine and using polyelectrolytes to adjust the release behavior provided a promising material technology, and further studies were suggested.