| Amphiphilic copolymer has shown wide application prospects in the field of nano-devices, polymeric surfactants, drugs and gene delivery. In recent years, with the development of controlled/living radical polymerization, great progress has been achieved in the synthesis of amphiphilic copolymer, as well as its self-assembly and applications in drug delivery. Micelles self-assembled from amphiphilic block copolymer or graft copolymer are among the greatest potential drug carrier systems, because of its good biocompatibility, high drug loading efficiency and targeting capabilities. However, there is still plenty of room for more smart and integrated drug carriers. In this dissertation, several amphiphilic triblock copolymers were synthesized via controlled/living radical polymerization, ring-opening polymerization and radical polymerization. Proper modifacations were made to obtain supermolecular polymeric micelles with functions, such as redox and thermal responsibility. Anticancer drugs were loaded in two ways:covalently bonded and non-covalent loaded. The main works summary as bellows:(1)Diblock copolymer PEG-b-PLA with a hydroxyl end group of the PLA block was synthesized by ring-opening polymerization (ROP). Then, amphiphilic triblock copolymers, PEG-b-PLA-b-PHEMAs with different molecular weights were synthesized by atom transfer radical polymerization (ATRP), using PEG-b-PCL-Br as macroinitiator and hydroxyethyl methacrylate as monomer. After that, a series of polymeric micelles were prepared by dialysis method. The block copolymers and micelles were characterized by GPC, NMR, DLS, as well as TEM. The experiment results indicated that the size of the polymeric micelles increase with the increase of the length of the PHEMA chain.(2) Amphiphilic triblock copolymer PEG-b-PLA-b-(PtBA-co-PNIPAAM) with low molecular weight distribution was prepared by a combination of ROP and ATRP. After treatment with trifluoroacetic acid, tert-butyl groups were removed, and triblock copolymer PEG-b-PLA-b-(PAA-co-PNIPAAM) was obtained. The supermolecular polymeric micelles were prepared after self-assembly of partial hydrolyzed copolymer, PEG114-b-PLA57-b-(PtBA45-co-PAA44-co-PNIPAAM58) together with doxorubicine(DOX) in water, followed by crosslinking the polymer chain with cystamine (a cross-linker with disulfide bond). The core cross-linked micelles is steady against PBS buffer (pH=7.4), and the drug loading efficiency is36.7%. The in vitro drug release experiments showed that the polymeric micelles were redox and thermal responsive. What’s more, the micelles were remarkably stable in the absence of GSH at37℃, DOX was rarely released.(3) A azide-terminal PTX prodrug based on a disulfide linker was synthesized, and its drug delivery mechanism was determined through HPLC characterization. On the other hand, amphiphilic random copolymer, POEGMA-co-P(TMS-PgMA), was synthesized by radical polymerization. After treatment with tetrabutylammonium fluoride, TMS was removed and POEGMA-co-PPgMA was obtained. Utilizing the azide group of the prodrug, PTX was covalently conjugated to polymer chain by azide-alkyne1,3-dipolar cycloaddition reaction, thus, graft copolymer POEGMA-co-PPgMA-g-PTX was prepared. The drug loading efficiency is19.2%. The supermolecular polymeric micelles were prepared after self-assembly of the graft copolymer. The polymers and micelles were characterized using GPC, NMR, DLS, as well as TEM. To prove the drug delivery efficiency of this system, glutathione-mediated intracellular drug delivery was investigated against the HeLa cell line, and the results indicated that the drug-loaded graft copolymer micelles showed higher cellular proliferation inhibition against glutathione moniester(GSH-Oet) pretreated cells than against untreated cells, which means the cytotoxicity increased with increasing intracellular glutathione concentration. In a word, the drug-loaded graft copolymer micelles can release PTX to kill cancer cells and the release behavior is GSH-dependent. |
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