Preparation And Properties Of Biodegradable Polypeptide-based Thermogels

Thermosensitive gels are flowable liquids at low temperature but become solid gels at body temperature, which have wide applications in biomedical fields such as drug delivery carriers and tissue engineering scaffolds. Compared with traditional polyester thermosensitive gels, thermogels based on polypeptides are advantageous in biocompatibility and interaction with cells, due to its similarity in component and structure to natural tissues. Furthermore, the diversity of secondary structures and amino acids for polypeptides favors the built-up of complex, multi-responsive, multi-ordered, intelligent gels.In this thesis, we focused on the polypeptides composed of hydrophobic amino acids(leucine, valine, alanine), and designed and synthesized a series of poly(ethylene glycol)-polypeptide thermosensitive copolymers. By means of 1H-NMR、 DMA、DLS、TEM、FTIR、13C-NMR, we systemically studied the effects of side group of amino acid, block length of polypeptide, composition of copolypeptide, and block sequence on the assembled structures and sol-gel transition behavior of copolymers in aqueous solutions. We also discussed the mechanism of sol-gel transition for different gel systems.First of all, monomer amino acid N-carboxyl-α-amino anhydrides(NCAs) have been prepared using amino acids and triphosgene. Meanwhile, α-Methoxy-ω-amino-poly(ethylene glycol) with just one terminal hydroxyl groups was modified and the terminal groups were converted to amino groups so that it can be used as initiator. The yield and purity of both monomer and initiator are qualified to meet the requirements of the research afterwards.Then we synthesized a series of mPEG-PA, mPEG-PV, mPEG-PL diblock copolymers with different polypeptide side groups and block lengths. Three types of copolymers all displayed a predominant β-sheet secondary structure, and could self-assemble into rod-like structures. For mPEG-PA and mPEG-PV copolymers, the morphology of self-assembled structures were much more regular, which favored good sol-gel transition for the solutions. While for mPEG-PL copolymer, the morphology of self-assembled structures was very irregular without sol-gel transition of the solutions. The occurrence of thermoresponsive sol-gel transition for mPEG-PV solution was due to the dehydration of PEG segments. While for mPEG-PA solution, except for the dehydration of PEG segments, the change of polypeptide secondary structure also contributed to the thermo-responsiveness. With the increase of PV block length, the morphology of self-assembled structures changed from regular short rods, long rods to irregular fibers, which was in agreement with the change of sol-gel transition temperature.Finally, we synthesized a series of mPEG-PAV di-block copolymers with different compositions, and mPEG-PA-PV and mPEG-PV-PA tri-block copolymers with different block sequences. For mPEG-PAV copolymers with L-valine as the major component of polypeptide, a predominant β-sheet secondary structure was observed, which leading to the formation of regular rod-like self-assembled structures and good thermo-responsiveness of the solutions. In contrast, for the copolymers with L-alanine as the major component of polypeptide, they tend to form irregular fiber structures, with no stable gel formed when the temperature increased. Copolymerization between amino acids with different side groups could decrease the β-sheet hydrogen bond, and enhance the reversibility of thermo-responsive gels. The block sequence could significantly affect the morphology and regularity of self-assembled structures and thermo-responsive behavior.In summary, we synthesized new types of biodegradable two-component and three-component copolymers containing amino acid units and acquired new thermogelling copolymer with suitable sol-gel transition. This paper not only provides novel polypeptide based thermogelling hydrogels with well-defined sol-to-gel transition behavior, but also improves our fundamental understanding of polypeptide self-assembly behavior for the design of promising biomaterials.