Preparation Of PH-responsive Block Copolymer Micelles For Controlled Drug Delivery

During the past two decades, amphiphilic block copolymers could self-assemble into "Core-Shell" nano-micelles as drug/gene delivery systems in selective solution, which have gained more and more attentions in research area. With the advent of controlled radical polymerization (CRP) techniques, especially with the application of reversible addition fragmentation chain transfer (RAFT) method, more and more stimuli-responsive functional monomers (for example, pH, temperature, ionic strength, magnetic field, light, redox and enzyme) could be easily polymerized through precise regulation. In recent years, great progress has been made in the synthesis of amphiphilic copolymer. The high selectivity and sensitivity of fluorescent sensors make people pay more attention on the stimuli-responsive fluorescent block copolymers which have wide application prospect in biomarkers, cell imaging and dye. 8-hydroxyquinoline and its derivatives are often used as functional materials for their unique properties, such as thermal stability, higher fluorescence quantum efficiency and lower toxicity. In this dissertation, we first designed and prepared a series of fluorescent copolymer nano-micelles via RAFT polymerization of fluorescent monomer 8-methacryloyloxyquinoline (MAQ), pH-sensitive monomer and biocompatible monomer. Then, the drug delivery behaviors on model drugs and in vitro cytotoxicity were also investigated. The main contents are listed as follows.First, a novel amphiphilic diblock pH/fluorescent copolymer, poly(8-methacryloyloxyquinoline-co-(N,N-dimethylamino)ethylmethacrylate)-b-poly(poly(ethyleneglycol) methyl ether methacrylate) (P(MAQ-co-DMAEMA)-b-PMAPEG), was designed and synthesized by RAFT polymerization, and subsequently characterized with fourier transform infrared spectroscopy (FT-IR),1H nuclear magnetic resonance spectroscopy (’H-NMR) and gel permeation chromatography (GPC). Scanning electron microscopy (SEM) and dynamic laser light scattering (DLS) tests showed that P(MAQ-co-DMAEMA)-b-PMAPEG micelles exhibited spherical core-shell structure, with a mean diameter around 100 nm and a narrow size distribution. In addition, both the initial concentration of the polymer and the proportion of hydrophobic and hydrophilic segments have effect on the formation of micelles. The copolymer micelles with unique fluorescent properties exhibited remarkable pH-responsive control-release of model drug folic acid (FA), with the drug loading content and efficiency of 32% and 52%, respectively. In addition, polymeric micelles possess significantly fluorescent characteristics no matter before or after drug-loading.Second, amphiphilic diblock pH/fluorescent copolymer, poly(8-methacryloyloxyquinoline-co-isobutylacrylate)-b-poly(2-(N,N-dimethylamino)ethyl methacrylate) (P(MAQ-co-IBA)-b-PDMAEMA), was designed and synthesized by RAFT polymerization, and subsequently characterized with fourier transform infrared spectroscopy (FT-IR),1H nuclear magnetic resonance spectroscopy (1H-NMR) and gel permeation chromatography (GPC). Transmission electron microscope (TEM) and dynamic laser light scattering (DLS) tests showed that the P(MAQ-co-IBA)-b-PDMAEMA micelles exhibited spherical core-shell structure, with a mean diameter around 90 nm and a narrow size distribution. The copolymer micelles with unique fluorescent properties exhibited remarkable pH-responsive control-release of model drug doxorubicin (DOX), with the drug loading content and efficiency of 27% and 71%, respectively. In addition, polymeric micelles possess significantly fluorescence characteristics no matter before or after drug-loading. The in vitro cytotoxicity assay of the polymeric micelles against MCF-7 and CT-26 cells showed that the polymeric micelles had little cytotoxicity with the cell survival rate more than 90%, and the DOX could be efficiently released from the loaded-micelles to inhibit the proliferation of cancer cells.Third, amphiphilic diblock copolymer, poly(N-benzoylphenyl methacrylamide)-b-poly(2-(N,N-dimethylamino) ethyl methacrylate) (PBPMA-b-PDMAEMA), was designed and synthesized by RAFT polymerization, and subsequently characterized with fourier transform infrared spectroscopy (FT-IR),1H nuclear magnetic resonance spectroscopy (1H-NMR) and gel permeation chromatography (GPC). Scanning electron microscopy (SEM) and dynamic laser light scattering (DLS) tests showed that the PBPMA-b-PDMAEMA micelles exhibited spherical core-shell structure, with a mean diameter around 80 nm and a narrow size distribution. DLS tests also indicated that the diameter of the micelles varied with changing of the pH values at room temperature. The copolymer micelles exhibited remarkable pH-responsive control-release of model drug FA, with the drug loading content and efficiency of 39% and 72%, respectively.