Preparation And Property Of Environmental Sensitive Polymer Carriers For Controlled Drug Release Via Photoinitiated Polymerization

In recent years, polymer-based nanocarriers have attracted increasing attention due to their widely application in the drug-loaded and controlled drug release systems.Specially, stimuli-responsive amphiphilic polymer drug carriers can be used for controlled drug release triggered by external stimuli such as pH, CO2, temperature,glucose and so on. These stimuli-sensitive polymeric drug delivery vehicles are promising for targeting treatment of some diseases. Currently, during the preparation process of amphiphilic polymeric drug carriers, it inevitably uses organic solvents as reaction solvents. It also has some disadvantages, such as long reaction time,complicated steps, low product yield, which is restricted in the practical application in the biomedical aspects. Therefore, seeking for a simple, low toxicity, aqueous preparing conditions is more attractive. Aliphatic and aromatic ketones are water-soluble photoinitiator. And they are also used as emulsifiers to solubilize oil-soluble monomers. In addition, They can produce active species under UV irradiation at room temperature. Using ketones as photoinitiator to synthesize amphiphilic copolymers in one-pot not only avoids using emulsifier, reducing the use of organic solvents, but also has the advantages such as high efficiency,environmental protection, non-pollution. Thus, it is of great practical significance for promising drug delivery systems to prepare polymer-based nanocarriers via photoinitiated polymerization. In this thesis, phenylboronic acid-based sensitive drug carriers were prepared using three different photoinitiators, respectively. The drug release properties were also investigated in vitro triggered by external stimuli. More specifically, it contains three parts as follows:1. The multi-sensitive copolymeric micelles poly(DMAEMA-co-AAPBA) were prepared based on hydrophilic monomer N, N-dimethylaminoethyl methacrylate(DMAEMA) and hydrophobic monomer acrylamide phenylboronic acid(AAPBA) by photoinitiated microemulsion polymerization using 2-ketobutyric acid(2-KBA) as photoinitiator and emulsifier. The structure and morphology of as-preparedcopolymers were characterized by 1H NMR、FT-IR and TEM. The variation of the nanoparticle size of polymer micelles were investigated under different glucose, pH and temperature conditions. The controlled drug release from sensitive micelles was realized under pH、temperature and different glucose concentration conditions.2. The glucose-responsive amphiphilic poly(PEGMA-co-AAPBA) copolymer micelles have been developed using 3-phenylpyruvic acid(3-PPA) as aromatic ketones photoinitiator. Poly(ethylene glycol) methyl ether methacrylate(PEGMA)was designed as biocompatible, non-toxic hydrophilic monomer. The glucose-sensitive hydrophobic monomer 3-acrylamide phenylboronic acid(AAPBA)was introduced. The self-polymerize product of 3-PPA was analyzed by gas chromatographic-mass spectrum(GC-MS). The as-prepared copolymers can be self-assemblied to form micelles to encapsulate insulin(INS), a hydrophobic drug.The loaded insulin could be released from micelles triggered by regulation of glucose concentration and temperature in the environment. In addition, CD spectra indicated that secondary structure of the insulin had not been distorted after the release.3. The glucose-sensitive and fluorescent amphiphilic copolymer poly(MAAM-co-MAPEG-co-VPBA) was synthesized by combination of photoinitiated polymerization and enzymatic transesterification. The drug-insulin was loaded into the as-prepared copolymers to study the glucose-reponsive release behaviors. The polymerization of glucose-sensitive monomer 4-vinyl benzeneboronic acid(4-VPBA) and hydrophobic monomer trifluoroethyl methacrylate(TFEMA)monomers were initiated by water-soluble 2-oxooctanoic acid(2-OOA). The fluorescent group and hydrophilic group could be introduced by chemoenzymatic(CALB enzyme) transesterification. The fluorescent property and glucose sensitivity of polymeric micelles were investigated by fluorescence spectrophotometry 、fluorescence microscopy、confocal laser scanning microscopy(CLSM) and dynamic light scattering(DLS). The release of insulin can be triggered by glucose. The drug carriers showed low cytotoxicity estimated by MTT analysis. The insulin-delivery system is promising for diabetes therapy.