Preparation Of Polymeric Micro/Nanocapsules And Application In The Controlled Release Of Drugs

In recent years, the "smart" polymeric micro/nanocapsules have received increasing attentions due to their potential applications in drug delivery and biomedical fields. The stimuli-responsive polymeric micro/nanocapsules permit the adjustable permeability of the guest molecules with the controllable release based on a designed mechanism under a given environmental stimulus. The release rate of the guest molecules was usually controlled by the diffusion rate of the guest molecules across the wall of the micro/nanocapsules. Therefore, the fast response of the wall structure of the micro/nanocapsules to the external factors was indispensable. At present, the stimuli-responsive micro/nanocapsules have been reported in response to specific stimuli, such as pH, temperature, glucose, ionic strength and so on. In this paper, the functionalizated micro/nanocapsules have been prepared by polymerization from template technique and layer-by-layer assembly based on the various templates, respectively. Furthermore, the controlled release of the obtained micro/nanocapsules was also investigated. It mainly included several senctions as follows.1. The crosslinked polymeric nanocapsules with inner diameter of about 20-50 nm were prepared by surface-initiated atom transfer radical polymerization (SI-ATRP) technique based on the silica templates. Then SiO2 were removed by being etched with HF to produce the crosslinked polymeric nanocapsules after the ester groups of the grafted poly(methyl acrylate) (PMA) were transformed into amides by interesterification with diethylamine to complete crosslinking with hexamethylene diisocyanate (HDI). To optimize above the process of preparation crosslinked polymeric nanocapsules, we designed and prepared a crosslinked temperature-sensitive polymeric nanocapsules with inner diameter of about 10 nm based on the above grafted PMA silica nanoparticle with diethylamine as crosslinker after removing the silica templates. The obtained crosslinked nanocapsules had a higher lower critical solution temperature (LCST) about 35℃compared with other poly-(N-alkyl acrylamides).2. The crosslinked polystyrene nanocapsules with controllable shell were prepared by UV treatment the polystyrene grafted silica nanoparticles (SN-PS) to achieve polystyrene crosslinking after HF etching of the silica templates. The degree of crosslinking of polystyrene shell was well controlled by adjusting the time of UV irradiation. Furthermore, the degradation of grafted polymer was also investigated during the process of UV-induce crosslinking.And then the carboxyl groups functionalized crosslinked polystyrene nanocapsules with the inner diameter about 30～40 nm were prepared via combination of surface-initiated atom transfer radical polymerization and ultraviolet irradiated crosslinking techniques, while the ester groups of poly(tert-butyl acrylate) in the nanocapsules were transformed chemically into carboxyl ones after etching the silica templates by HF. Furthermore, we also investigated the controlled release of the carboxyl groups functionalized crosslinked polystyrene nanocapsules. The results of UV-vis spectra showed that the dye adsorbed amounts of the carboxyl group functional crosslinked polymeric nanocapsules (PAA-CPS nanocapsules) were superior to the PtBA-CPS nanocapsules due to the electrostatic interaction between the carboxyl group of PAA-CPS nanocapsules and the alkaline dye (MB). Furthermore, the release behavior of dye molecules of MB-load nanocapsules is quicker under acid medium compared to the neutral medium becaus of the electrostatic interaction between the carboxyl group of PAA-CPS nanocapsules and the dye was destroyed.3. The novel intelligent nanocapsules with the temperature-responsive crosslinked polymer shells and the pH- responsive polymer brushes on their inner walls have been designed and fabricated by using the "polymerization from template" strategy via the surface-initiated atom transfer radical polymerization (SI-ATRP) technique from the silica nanoparticles as sacrificial templates. The two steps sequential SI-ATRP procedures could provide the poly(tert-butyl acrylate) (PtBA) brushes on the inner walls of the temperature responsive crosslinked poly(N-isopropyacrylamide) (PNIPAm) shells. Then the tert-butyl ester groups in the nanocapsules were transformed chemically into acrylic acid groups after etching the silica templates with hydrofluoric acid (HF). The hollow structures and the multiple environmental stimuli responsive properties were validated with TEM and DLS techniques, respectively. In the strategy developed, the inner diameter, the crosslinking degree and the thickness of the shells, the length of the functional brushes could be controlled by adjusting the preparation conditions.4. The magnetic hybrid polyelectrolyte microcapsules with pH-sensitive shell and targeted controlled release have been prepared via the layer-by-layer self-assembly technique by electrostatic interaction between amino groups of chitosan (CS) and carboxyl groups of citrate onto the sacrificial templates (PSS) after etching above templates by dialysis. The behavior of loading and targeted controlled release of the magnetic hybrid polyelectrolyte microcapsules was researched by UV-vis spectrometer in methylene blue as a model molecule. It is found that the dye adsorbed capacity of the magnetic hybrid polyelectrolyte microcapsules was higher under basic medium compared with the acid medium. In contrast, the releasing raio of methylene blue from the MB-loaded magnetic hybrid hollow spheres was up to 76% after 48 h at pH= 4 without releasing under basic medium.5. The pH/temperature/ionic strength multi-sensitive polyelectrolyte microcapsules with controllable thermoresponsive layer were successfully prepared via combination of layer-by-layer assembly and Ce (Ⅳ) initiated grafting polymerization techniques after etching the templates by dialysis. The hollow structure of the obtained multi-sensitive polyelectrolyte microcapsules was characterized by transmission electron microscopy (TEM), which indicated the inner diameter of hollow microspheres is about 200 nm. The introduction of PNIPAm in pH-sensitive polyelectrolyte shell achieved the controlled release of drug molecules (a model hydrophobic drug, dipyridamole) could be dually controlled by the solution pH and temperature. Furthermore, the PNIPAm layer also could prevent from flocculation among the obtained multi-responsive polyelectrolyte microcapsules in the solution of higher salt concentration according to the results of DLS. This represents the first reported of pH/temperature/ionic strength multi-sensitive hollow microspheres prepared by layer-by-layer assembly, which might find practical application such as drug delivery and smart release in clinical application.6. The disintegration-controllable stimuli-responsive polyelectrolyte multilayer microcapsules have been fabricated via the covalent layer-by-layer assembly between the amino groups of chitosan (CS) and the aldehyde groups of the oxidized sodium alginate (OSA) onto the sacrificial templates (PSS), which was removed by dialysis subsequently. The introduction of Schiff base between the polyelectrolyte shells could increase the stability of microcapsules in the solution compared with noncovalent polyelectrolyte microcapsules. The diameter of the multilayer microcapsules decreased with the increasing of the pH values or the ionic strength. The pH and ionic strength dual-responsive multilayer microcapsules were stable in acidic and neutral media while they could disintegrate only at strong basic media.7. Novel magnetic-targeted pH-responsive drug-delivery system have been designed and prepared via layer-by-layer self-assembly of polyelectrolytes (oligochitosan as polycation and sodium alginate as polyanion) via electrostatic interaction with the oil-in-water type hybrid emulsion droplets containing superparamagnetic ferroferric oxide nanoparticles and drug molecules (Dipyridamole (DIP)) as cores. And the drug molecules were directly encapsulated into the interior of droplets without etching the templates and refilling with the desired guest molecules. The drug-delivery system showed high encapsulation efficiency of drugs and drug-loading capacity. The cumulative release ratio of dipyridamole from the oligochitosan/sodium alginate multilayer encapsulated magnetic hybrid emulsion droplets (DIP/Fe3O4-OA/OA)@(OCS/SAL)4 was up to almost 100% after 31 h at pH= 1.8. However, the cumulative release ratio was only 3.3% at pH= 7.4 even after 48 h.Furthermore, the dipyridamole microparticles with a size about 300 nm have been encapsulated by magnetic nanoparticles and polyelectrolyte hybrid multilayers via layer-by-layer assembly technique for the purpose of targeted controlled release. UV-vis spectroscopy was employed to monitor the drug release processes in both pH 1.8 and pH 7.4 buffer solutions. It was found that the release of drug molecules from magnetic hybrid multilayers coated drug-delivery was mainly dependent on the following factors such as the permeability of the hybrid polyelectrolyte shell and the solubility of the drug molecules in the bulk solutions. The results revealed that it could achieve the quick and continuous controlled release by magnetically-guide to the target tissue of the organism.