β- Cyclodextrin Polymer Synthesis, Self-assembly And Use As Study Drug / Gene Carrier

Cyclodextrin (CD) is characteristic of a hydrophilic exterior surface and hydrophobic interior cavity, which can accommodate a wide range of guest molecules. In pharmaceutical field, CD has been widely utilized to complex with the hydrophobic drugs via host-guest interactions to improve their solubility, stability and bioavailability. CD-based polymer (CDP), the polymer composed of multiple CD rings threaded or tethered on a polymer chain, are able to bind guest molecules that are too large to be accommodated in a single CD cavity, due to the cooperation of adjacent CD moieties on a polymer chain. Thus, CDP has inspired much interest in the fields of nanostructure fabrication, pharmaceutics and biomedicine.In this thesis, well-defined β-CDPs with various structures including star shape, linear shape and coil-comb shape are prepared by atom transfer radical polymerization (ATRP). The properties of self-assemblies formed by the CDPs in the presence of various guest molecules are studied in detail. Moreover, the potential application of CDPs in drug and gene delivery system is evaluated as well. The main contents of this work are as follows:1. Cyclodextrin-based star polymer is synthesized using the "arm-first" method by ATRP. Copolymerization of a mixture of mono-and multi-methacrylate substituted (3-cyclodextrin (GECD) and2-(dimethylamino) ethyl methacrylate (DMAEMA) initiated by poly(ethylene glycol) macroinitiator produces a core cross-linked star polymer PEG-P(CD-co-PDMAEMA). The star polymer can self-assemble into nanostructures via host-guest interactions between the cyclodextrin polymers and hydrophobic guest molecules. The morphologies of these nanostructures showed regular transitions by altering the type of guest molecules, the ratio of star polymer to guest, and the pH of the solution.2. Doxorubicin (DOX), as the model drug, can be loaded into the star polymer to form nanoparticles (DOX-NPs) via host-guest interactions. The size, drug loading content, stability and drug release kinetics of DOX-NPs are investigated in detail and the cellular uptake and cytotoxicity are evaluated in HeLa, HepG2and L929cells as well. The cellular uptake of DOX-NPs is in a concentration-, time-and cell type-dependent manner. DOX is distributed both in the cytoplasm and nucleus for DOX-NPs, while it is mainly located in the cell nucleus for the free drug. Moreover, a significantly higher level of cytotoxicity is achieved with DOX-NPs towards HeLa and HepG2cancer cells than that towards L929non-cancer cells. The in vivo anti-tumor experiment is conducted on BALB/c mice bearing cervical tumor, which shows that DOX-NPs suppress the growth of tumor significantly. These findings suggest that the cyclodextrin-based pH-responsive star polymer shows potential in developing novel drug delivery system for cancer therapy.3. A new mono-methacrylate substituted β-cyclodextrin (GACD) is prepared in a mild condition. Thus, well-defined hydrophilic diblock copolymer poly(ethylene glycol)-b-poly(cyclodextrin)(PEG-b-PCD) with high CD density can be easily synthesized via ATRP of GACD from poly(ethylene glycol) macro initiator. The block copolymer is able to include a variety of guest molecules and self-assemble into advanced nanostructures due to the synergistic effect of CD moieties. By altering the type of guest molecules and the ratio of PEG-b-PCD to guest, the self-assembled nanostructures show different size and morphology.4. The CD moieties on diblock copolymer PEG-b-PCD are then reacted with2-bromoisobutyryl bromide to obtain macroinitiator PEG-b-P(CD-Br). Well-defined coil-comb polycationic brushes PEG-b-P(CD-g-PDMAEMA) are synthesized via ATRP of DMAEMA and used as gene carriers. The side chains of the comb block are composed of star polymers with β-CD as the core and PDMAEMA as the arm. With such super-high grafting density of PDMAEMA, the brushes effectively condense pDNA into spherical nanoparticles of100-200nm in size and exhibit significantly higher transfection capability compared to the single star polymer. In some cases, they also show comparable or higher transfection efficiency and lower cytotoxicity than PEI25K. The results indicate these brushes have good promise for the potential gene therapy.In summary, a series of well-defined β-CDPs are synthesized via ATRP in this thesis. Advanced nanostructures can be formed by the inclusion interactions between these CDPs and various guest molecules. And these nanostructures show good promise for the potential drug and gene therapy. Actually, this strategy provides a facile method to prepare well-defined CDPs with various structures and a versatile method for the design of nanostructures based on CDPs. These CDPs and the self-assembled nanostructures may find attractive applications in the fields of drug and gene delivery, self-healing materials, catalysts and coatings, etc.