Thermogelling Polyether/polyester Block Copolymers And Its Preliminary Extension As A Drug Delivery Carrier Of Cisplatin

Hydrogels are a kind of synthetic or natural polymers which can absorb a large amount of water and maintain their physically or chemically cross-linked three-dimensional networks. Due to their soft-tissue-like modulus and excellent biocompatibility, hydrogels have been widely applied in biomedical fields such as drug delivery, tissue engineering. Recently, in situ-forming hydrogels with a thermo-reversible sol-gel transition have been drawing increasing attention. Such a system is a free-flowing sol at low or room temperature and spontaneously forms a semi-solid gel upon heating. Bioactive drugs or cells are able to be simply mixed with the aqueous copolymer solution at low temperatures and then form a semisolid matrix after injection into the body at a target site. The reversible sol-gel transition was not triggered by any chemical reaction and the use of any organic solvent was avoided in medical applications. Moreover, an implant depot was formed via injection with minimally surgical wounds.This thesis focuses on the design of injectable PEG/PLGA(PLA) thermogels, their thermogellation behavior and their potential biomedical applications. Although PEG/PLGA(PLA) thermogels have been widely investigated, many basic problems are still open. For example, how to obtain a kind of themogel which can be comfortable to handle, weigh, transfer and even fast dissolve in water? How to design the hydrogel formualtion to precisely control the release of a special drug? To answer these questions constitutes the theme of the thesis.The innovations of this thesis are summarized as follows:1. Thermogelling PLLGA-PEG-PLLGA triblock copolymers were synthesized via ring-opening polymerization for the first time. The effects of L-LA and D,L-LA in PLGA-PEG-PLGA on the bulk states of triblock copolymers, and their thermogellation and biodegradation in water were investigated and compared. Although the sticky morphology of PDLLGA-PEG-PDLLGA at the bulk state was independent of D,L-LA/GA ratio, the different forms of PLLGA-PEG-PLLGA from sticky paste to powder were achieved by varying L-LA/GA ratio to adjust the steric regularity of the PLLGA chain. An expected PLLGA-PEG-PLLGA polymer with a solid-like form at dry state was obtained, which was able to form a stable sol in water at room temperature and transform into a non-flowing gel in response to an increase in temperature. The solid-like morphology was convenient for practical application such as weighing, transferring, and storing. We further revealed the stereo structure influence of L-LA and DL-LA monomers on the thermogellation and degradability of PLGA-PEG-PLGA triblock copolymers. At low LA/GA ratio (LA/GA=1.0), PLLGA-PEG-PLLGA and PDLLGA-PEG-PDLLGA not only presented the same sticky morphology, but also underwent the similar sol-gel transition upon heating. With increasing the LA/GA ratio to 1.8, solid-like PLLGA-PEG-PLLGA was achieved. It showed a similar gel modulus but a higher sol-gel transition temperature and a slower degradation rate compared with the correspondingly sticky PDLLGA-PEG-PDLLGA. The difference is ascribed to the steric regularity of PLGA polyester chains.2. PEG/polyester block copolymers containing selenium were successfully synthesized and the corresponding thermogel was prepared via a physical mixing approach. The mixing thermogel was used to encapsulate and release an antitumor drug cisplatin with a preliminary result. An amphiphilic PEG-PLA-Se-PLA-MPEG conjugate was synthesized via coupling MPEG-PLA with 3,3’-selenobis(propionic acid). The conjugate obtained was only soluble in water and no sol-gel transition was observed as the temperature increased. Subsequently, a thermogel containing selenium was obtained via mixing the conjugate with a hydrophobic PEG/polyester polymer. Finally, the cisplatin-loading thermogel formulation was prepared and the sustained release of drug was achieved due to the complexation of platinum and selenium.