Preparation Of Multi-functional Polymeric Hollow Spheres And Application In Drug Controlled Release

Polymeric hollow nano/microspheres have attracted intense research interest in recent years, because of their unique hollow structure, special properties of colloid and physicochemical and potential applications. Until now, various methods have been established to fabricate hollow nano/microspheres with different morphologies and various physicochemical properties. Multi-functional polymeric hollow spheres have ability to reply to the change of external environment, and the responsive functions have potential application in drug delivery system (DDS). So the multi-functional polymeric hollow spheres have become one of the highlights in polymer science and biomedical fields. The polymeric hollow spheres can be responsive to the external stimuli by adjusting the permeability of the hollow spheres after introducing the functional properties into the polymer hollow spheres, the introduction of functions can control the release properties of the hollow spheres loaded with drug molecules. Additionally, polymeric hollow spheres supply a new strategy for their potential applications in drug delivery, targeted therapy, controlled release, and so on. Now, various environmental stimuli factors have been reported and used for multi-functional polymer particles, which mainly contain:temperature, pH, glucose, magnetic targeting, fluorescence, intensity of ion, and so on. In this thesis, multi-functional polymeric hollow spheres were mainly fabricated by template polymerization method and Layer-by-Layer (LBL) assembly method. The research content mainly included several sections as follows:1. In order to simplify the preparation procedure for polymeric hollow spheres and to prepare the hollow spheres with glucose sensitive function. The self-moved template method was used to prepare the glucose and temperature dual-responsive hollow spheres. The poly(N-isopropylacrylamide) (PNIPAM) could precipitate to form sphere templates in high temperature aqueous solution after polymerization. Then the glucose responsive monomer and cros slinking agent were added to the suspension solution for preparing the crosslinked polymeric shell. Finally, the PNIPAM free chains became hydrophilic part and moved outside of the polymeric spheres to form hollow polymeric spheres as long as the temperature decreased to room temperature. The hollow spheres have potential application in controlled release of insulin for diabetes therapy.2. The Fe3O4 nanoparticles were prepared using chemical precipitation as the cores, then the SiO2 layer was coated on surface of the FesO4 nanoparticles to fabricate the Fe3O4/SiO2 core-shell particles by sol-gel method. After the core-shell microspheres were modified with C=C group, the PMAA layer was encapsulated on surface of the Fe3O4/SiO2 core-shell particles by precipitation method. Then another silica layer with C=C group was used to modify the core-shell particles for further polymerization, and the temperature sensitive PNIPAM layer was coated on the surface by precipitation polymerization. The pH and temperature dual-responsive double-walled hollow polymeric microspheres with movable magnetic cores could be prepared by removal of the silica with HF. The dual-responsive double-walled hollow polymeric microspheres owned pH and temperature dual-stimuli, and the magnetic cores could introduce the magnetic targeting property to the hollow polymeric microspheres.3. In order to enhance the drug loading capacity of the DOX molecular, the poly(methacrylic acid-coethyleneglycol dimethacrylate) (P(MAA-co-EGDMA)) microgel cores prepared by distillation precipitation polymerization were used as the polymer cores, then the SiO2 layer was coated on surface of the (MAA-co-EGDMA) microgel cores for NIPAM polymerization by distillation precipitation polymerization. The targeting molecule (Folic acid, FA) was introduced to modify the surface of the core-shell microspheres for targeted therapy. The temperature and pH dual-responsive yolk/shell microspheres could enhance the drug loading capacity of the DOX molecular because of the P(MAA-co-EGDMA) cores; at the same time, the yolk/shell microspheres could show pH and temperature dual-responsive controlled release properties. Additionally, the yolk/shell microspheres owned targeted delivery characteristic due to the introduction of targeting molecular (FA).4. The pH responsive monodisperse poly(methacrylic acid-coethyleneglycol dimethacrylate) (P(MAA-co-EGDMA)) microgel cores expressed obvious pH stimulus, which were prepared by a facile distillation precipitation polymerization method, then SiO2 layer with C=C group was used to coat on surface of the P(MAA-co-EGDMA) microgel cores for further PNIPAM precipitation polymerization reaction. In the polymerization process, the MAA monomer was introduced as a doped monomer to adjust the volume phase transition temperature (VPTT) of the yolk/shell microspheres. The yolk/shell microspheres were prepared after etching the SiO2 layer with HF, and expressed pH-induced thermally responsive stimulus. The introduction of P(MAA-co-EGDMA) cores could enhance the drug loading capacity of the anticancer drug DOX. Importantly, the yolk/shell microspheres exhibited a low leakage at high pH values but significantly enhanced the drug release quantity at lower pH values solution, which showed the apparent tumor-environment-responsive controlled "on-off" drug release characteristics. The yolk/shell microspheres with responsive properties offer promise for tumor therapy.5. Firstly, the carboxyl group modified polystyrene (PS) particles as the template for Layer-by-Layer (LBL) process were prepared with soap-free emulsion polymerization method. Then the Fe3O4 nanoparticles were coated on the surface of PS particles to prepare Fe3O4 modified PS hybrid particles. When the chitosan (CS) was absorbed onto the surface to form CS layer, the magnetic sensitive single-layer chitosan hybrid hollow spheres were successfully prepared by etching the PS templates with DMF after crosslinking the CS layer with glutaraldehyde (GA).6. Firstly, the monodisperse templates (polystyrene sulfonate, PSS) microspheres for Layer-by-Layer (LBL) assembly were fabricated with soap-free emulsion polymerization method. In the process, the chitosan (cationic polyelectrolyte) and the Fe3O4 nanoparticles (anionic hybrid nanoparticles) were used as the assembly material for LBL process. The well-defined biocompatible polyelectrolyte hybrid hollow microspheres with magnetic and molecular targeting functions were fabricated by the LBL self-assembly technique and surface modification with PEG and targeting molecules (FA) after etching the PSS microspheres templates with DMF. The polyelectrolyte hybrid hollow microspheres exhibited biocompatible and molecular targeting due to the introduction of the PEG and FA. The hybrid hollow microspheres owned exciting pH stimuli response and stability in high salt-concentration media characterized by DLS technique. And the pH-dependent controlled release property of the DOX was investigated in different human body fluids.