Preparation Of Thermosensitive Nanoparticles Via Interfacial Miniemulsion Polymerization And Their Controlled Drug Delivery Properties

Functionalized polymer nanoparticles have nano-size effect, surface effect and specific functions, showing highly promising applications in a large variety of fields like drug controlled release, biological materials, separation. Minemulsion polymerization is a simple and effective method to prepare nanoparticles, and also is promising in industrial application. In this thesis, based on minemulsion polymerization technology, N-isopropyl acrylamide (PNIPAM) oligomer radical is used to anchor the oil-water interface for copolymerization. A series of thermosensitive and amphiphilic core-shell structure nanoparticles were synthesized and their drug release performances were studied.The thermosensitive core-shell nanoparticles were synthesized via miniemulsion copolymerization of y-methacryloxy propyltrimethoxysilane (MPS), styrene (St) and NIPAM, using an oily template. The copolymer nanoparticles were characterized by infrared spectrum analysis, X-ray photoelectron spectrometer and electron microscopy. It was found that NIPAM was enrichment in particle surface and tapered in depth direction of copolymer shell. The effects of NIPAM content, feeding method and reaction temperature on thermosensitivity and structural morphology of MPS/St/NIPAM copolymer nanoparticles were investigated. By adding tertiary butyl acrylate (tBA) and then hydrolyzing, the prepared nanoparticles possessed pH sensitivity and thermosensitivity at the same time. The surface of nanoparticles is still hydrophobic after adding tBA. However, the wetting velocity and hydrophilic of nanoparticle surface were greatly improved after hydrolyzing. Adding NIPAM was conducive to wetting velocity and hydrophilic to some extent.Hydration layer of polymer nanoparticles was studied on nanoscale. Structure and composition of hydration layer of thermosensitive nanoparticles were investigated by IR and DSC. It showed that the hydration layer was containing about 3% of non-freezing water and freezable bound water, and the remainder was free freezing water to reach equilibrium state with surroundings. The influence factors of hydration layer thickness of thermosensitive nanoparticles were investigated. The effect of solvent on PNIPAM phase transition was studied by the mixture system of toluene, ethanol and water. It was found that ethanol-water system can reduce the thickness of hydration layer effectively. The hydrogen bonding of solvent and nanoparticles was weakest around ethanol mole fraction of 0.4, and nanoparticles losed thermosensitivity performance almost. The solvent induced interactions were proved to be the major driving force for PNIPAM coil-to-globule transition. The schematic of hydration layer structure of nanocapsule was proposed. The size under ethanol mole fraction of 0.4 was suggested as an appropriate particle size excluded the hydration layer but stable dispersed in the solvent. Moreover, the processes of loading and releasing tracer (cresol red) in nanoparticles were monitored. Infiltration dynamic model of tracer releasing from nanoparticles is established. It was found a sudden increase between the diffusion coefficient at 30℃ and 40 ℃. While the release diffusion coefficient in ethanol is about 50 times of in water, the ethanol solvent showed big effect on drug releasing performance.Hydrophilic thermosensitive monomer NIPAM and hydrophobic crystallizable monomer stearyl methacrylate (SMA) were copolymerized to form amphiphilic block copolymers PNIPAM-PSMA, via PNIPAM thermally induced interfacial miniemulsion polymerization. SMA was used as hydrophobic monomer and to form crystalline core, because it has pendent long alkyl side chain and can form crystalline domain to synthesize comb-like polymers. The chemical structure and composition of PNlPAM-b-PSMA copolymers were analyzed. SMA and NIPAM centered triads sequence and average block length were analyzed to determine the sequence distribution of copolymers. The average block length, particle size, Mn and dispersion of copolymer nanoparticles could be controlled by monomer feed ratio, cosolvent concentration and polymerization temperature. Volatile organic cosolvent was used to enhance the formation process and particles size. The volatile solvent could reduce the size of oil droplets and suppressed the Ostwald ripening. The formation mechanism of thermally induced interfacial miniemulsion polymerization and self-assembled core-shell nanoparticles in situ was investigated. Variables influence the morphology, thermal characteristics, crystallinity and hydrophilic property of copolymer nanoparticles were investigated by SAXS, DSC AFM and TEM.Self-assembled core-shell nanoparticles of PNIPAM-b-PSMA copolymers had a hydrophilic thermosensitive shell and a hydrophobic crystallizable core. Nanoparticles exhibited a volume phase transition temperature (VPTT) of 38℃ and PSMA moiety could form nano size crystals to retain drugs, thus making them good carriers for drugs co-delivery system. Using ibuprofen as hydrophobic model drug and procaine as hydrophilic model drug loaded into amphiphilic block copolymer nanoparticles. Different loading techniques, drugs combined loading and drug-polymer interactions were investigated. The loaded drugs interacted with hydrophilic/hydrophobic polymer chains of nanoparticles and changed the phase transition temperature and particle morphology to some extent. The loading capacity of ibuprofen or procaine in nanoparticles were studied and found that both temperature increasing and ethanol aqueous solution could significantly increase the loading capacity of ibuprofen. Because PSMA moiety was in amorphous state, nanoparticles showed favorable permeability and ethanol increased their intermiscibility with hydrophobic drugs. Loading capacity of procaine was decreased with temperature increasing or ethanol solution, due to the weakening of hydrogen bonds and reducing of hydration layer. Nanoparticles showed a good and controllable drug loading capacity of hydrophilic and hydrophobic drugs. Combined loading showed little effect on loading capacity of ibuprofen or procaine. The loading capacity was only slightly decreased to that in the single loading. This suggested that the loading capacity of ibuprofen or procaine mainly depends on respective interaction between polymer and drugs.Fick’s law of diffusion and Weibull model were combined to analyze the release kinetic and mechanism of drugs releaseing from PNIPAM-b-PSMA nanoparticles, which was adequately fit to the release data. A general method for analyzing drug release kinetics from nanoparticles was proposed. Parameters obtained from models and diffusion coefficients were employed for comparing release profiles and different delivery systems. It was found that the burst release behaviour was greatly improved by drug loaded nanoparticles. Both ibuprofen and procaine continued to release more than 24 h, showing a better sustained release effect of nanoparticles. There were striking changes signified that the temperature has a good control over the release of ibuprofen. However, the effect of temperature on the release of procaine is not so significant. When combined release, the delayed time was more than 30 min difference between ibuprofen and procaine. Delayed time difference was decreased with temperature rising. These implemented temporal control of different drugs. The mechanism of drug release from nanoparticles was proposed. The relative velocity and delayed-release time of different drugs were greatly changed with temperature, thus to make drugs temporal controlled releasing or simultaneously releasing. PNIPAM-PSMA nanoparticles showed great potential in controlled release and co-delivery of hydrophilic and hydrophobic drugs.