Synthesis, Physical Gelling Behaviors Of Injectable Hydrogels And Their Underlying Application As A Sustained Drug Release Carrier

As a viscoelastic and bimimetic "wet material", polymeric hydrogels now constitute an important issue of research in the field of biomedical materials. In situ injectable hydrogel formation makes it more feasible to apply hydrogels for drug delivery systems. This Ph. D thesis is focused on the injectable physically-crosslinked hydrogels based on synthetic polymer and their underlying applications in drug delivery systems. Physical gelation is quite unique and the associated sol-gel transition is usually reversible. Compared to in situ chemically crosslinking, physical thermogelling of a polymer aqueous solution at the body temperature is especially attractive due either to free of initiator and organic solvents, or to much convenience of drug formulation. On the other hand, spontaneous physical gelling is a challenging topic of soft matter with self-assembly. Hence, the physical gels and associated applications in drug delivery systems are interdisciplinary researches related to polymer chemistry, polymer physics, and pharmacy.This Ph. D thesis concerns the synthesis, characterization, physical gelling properties of injectable polyester/polyether hydrogels and their potential applicationsas a sustained release carrier. For such a kind of novel promising injectable biomaterials, many fundamental and important problems are still open, for example, will the end groups of the synthetic polyester/polyether block polymers have a subtle effect on the physical gelation in water? How about the mechanism of spontaneous hydrogel formation is? Will this physical gel be feasible for encapsulation and sustained release of a PEGylated drug?The present thesis aims at answering these questions. A series of thermogelling PLGA-PEG-PLGA triblock copolymers and their different derivatives end-capped by small alkyl groups were synthesized and characterized. Most of the virgin triblock copolymers and their derivatives exhibited a temperature-dependent reversible sol-gel transition in water. The sol-gel transition temperature was determined via the vial inverting method. Dynamic rheological measurements were employed to quantify the viscoelastic properties during the physical gelation. Dynamic light scattering and ¹³C-NMR were used to detect the self-assembled nano-structures. The degradation and biocompatibility of this material was preliminary examined both in vitro and in vivo. We also tried to combine the sustained release property of the hydrogel and the long-circulating property of PEGylated drugs. The PEGylated Camptothecin (CPT) was synthesized as the model of PEGylated drug; the model drug was successfully entrapped into and sustained released from the polymeric hydrogels both in vitro and in vivo examinations.The main achievements are summarized as follows:1. A subtle end-group effect upon the macroscopic self-assembly behaviors of blockcopolymers in water was found. An ABA-type triblock copolymer composed of the central poly(ethylene glycol) (PEG) block and two poly(lactic acid-co-glycolic acid) (PLGA) blocks was synthesized. The remaining two hydrophilic hydroxyl groups were end-capped with hydrophobic acetate, propionate or butyrate groups. The aqueous solution of the PLGA-PEG-PLGA triblock copolymer synthesized in this part of research exhibited a sol state in the temperature range examined. In contrast to it, those polymer derivatives end-capped with the acetate or propionate groups underwent a reversible sol-gel transition as a function of temperature, while the block copolymer capped with the butyrate group precipitated in water. The work reveals that a small end group in a moderately lyophilic amphiphilic polymer can adjust not only the microscopic self-assembled nano-structures, but also the macroscopic condensed-state behavior of the underlying soft matter as a result of large-sale self-assembly. Thus, this research gives some new insights into the relationship between physical gelation and chemical composition, and affords a molecule-design approach to preparing novel injectable biomedical materials and intelligent wet devices.2. The factors influencing the physical gelation of this sort of block polymers were examined and the underlying gelling mechanism was assumed. The virgin PLGA-PEG-PLGA with suitable molecular weight and composition also can exhibit the sol-gel transition, and both the PLGA MW and end alkyl group were found to have a significant influence on critical micellization concentration (CMC) and critical gelation concentration (CGC). Whatever the gelling occurred with alteration of endgroups or PLGA block MW, the CMCs were much lower than the associated CGCs. The ¹³C-NMR confirmed that the micellar structure was kept intact during the sol-gel transition. A hierarchic mechanism was assumed, by which, the sol-gel transition with the increase of temperature might be induced not simply via the self-assembly of amphiphilic polymer chains, but via the further hydrophobic aggregation of micelles resulting in a "micelle-network" due to a large-scaled self-assembly. The coarsening of the micelle-network was further suggested to account for the transition from a transparent gel to an opaque gel.3. The system of this spontaneous physical gelling of block polymers was successfully extended for a sustained release of a PEGylated drug, and the PEGylated drug was found to have an influence on the physical gelling behaviors of the material. The degradation and biocompatibility of this material was preliminary confirmed both in vitro and in vivo. The PEGylated Camptothecin (CPT) was synthesized as the model PEGylated drug. The synthesized MPEG-CPT was soluble in water over 150 mg/ml, whereas the solubility of the raw drug was just about 1.3 μg/ml in water. Since monomethoxypoly(ethylene glycol) (MPEG) is hydrophilic, the MPEG-CPT is an amphiphathic molecule. The amphiphilic MPEG-CPTs form micelles in water. The hydrophobic CPTs form cores, and the hydrophilic PEG blocks constitute coronas. Our work also found that the CGC and the viscosity were altered due to loading a PEGylated drug into the biomaterial, and the optimum conditions as an injectable sustained release carrier were further determined. The model drug was completely entrapped into the polymeric hydrogel, and the sustained release lasted for one month.The release profile was basically divided into two stages, controlled by drug diffusion and material degradation, respectively. In vivo anti-tumor tests in mice further confirmed the efficacy of the model PEGylated drug released from the hydrogel.