Synthesis And Self-assemble Of Stimulus-responsive Block Polymer And Its Applications For Controlling DOX Release

Stimuli-responsive polymers are able to undergo relatively large and abrupt, physical or chemical changes in response to small external changes in the environmental conditions. Many researchers have extensively interested in the field of stimulus response polymer. The combination of living/controlled polymerization and efficient chemical reaction could easily prepare a series of stimulus response of the controlled molecular weight and structure polymer. Amphiphilic block polymers could self-assemble micelles in aqueous solution, and can be used for coating small molecule hydrophobic drugs. This specific polymers exhibited pH- and temperature responsive with controlling release of the drugs depending on the different pH and temperature in the body. It can not only improve the bioavailability of poorly water soluble drugs, but also reduce the side effects of normal tissue. Moreover, stimulus-responsive polymer has a larger market application as a hydrophobic drug delivery system, Based on the research of the precursors, in response to the design of the type of polymer synthesis and applied with some exploring research this dissertation explore research about the synthesis, design and application as drug carrier. The main results of this thesis are as follows:（1）. A well-fined amphiphilic polyhedral oligomeric silsesquioxane（POSS） star-shaped inorganic/organic hybrid block copolymers with poly（ε-caprolactone）-poly（2-（2-methoxyethoxy）ethyl methacrylate）-co-poly（ethylene glycol） methacrylate)(POSS-（PCL-P（MEO₂MA-co-PEGMA））₁₆) were synthesized via click chemistry, ring opening polymerization（ROP） and atom transfer radical polymerization（ATRP）, which were confirmed by fourier transforms infrared spectroscopy（FT-IR）, nuclear magnetic resonance（1H NMR）, gel permeation chromatography（GPC） and X-ray photoelectron spectroscopy（XPS）. These thermo-responsive organic/inorganic hybrid polymeric micelles exhibited critical phase transition temperature in water, which could be finely tuned by changing the feed ratios of PEGMA and MEO₂ MA. The lower critical solution temperature（LCST） of star-shaped POSS-（PCL-P（MEO₂MA-co-PEGMA））₁₆ increased from 34 to 57℃with the increasing of PEGMA content. The results were investigated by ultraviolet-visible spectroscopy（UV-vis）, dynamic light scattering（DLS）, transmission electron microscopy（TEM）.（2）. A well-fined amphiphilic polyhedral oligomeric silsesquioxane（POSS） star-shaped inorganic/organic hybrid block copolymers with poly（ε-caprolactone）-poly（2-（dimethylamino） ethyl methacrylate）-co-poly（ethylene glycol） methacrylate)（POSS-PCL-P（DMAEMA- coPEGMA））₁₆ were synthesized with different PCL segments via thiol-ene click reaction, ROP and ATRP, which were confirmed by FT-IR, 1H NMR, GPC, XPS and TG. The obtained inorganic/organic hybrid copolymers could self-assemble into micelles in aqueous solution owing to the amphiphilic property resulting from the hydrophobic POSS and PCL core and the hydrophilic P（DMAEMA-co-PEGMA） segments, micelles were investigated by DLS, UV-vis and TEM. DOX was used as model drug and the drug release were performed in buffer solution（pH 5.0 and 7.4）, after 55 h for DOX-loaded micelles, the cumulative release was about 82%. CCK-8 assays against He La cells indicated that the blank micelles with different concentrations were nontoxic to HeLa cells and the cell viability was over 90% at all concentrations, and identified the location of the DOX in HeLa cells,（3）. In order to label the location of the drug-loaded micelles in vivo, a well-defined pHresponsive methoxy poly(ethylene glycol-block-poly（ε-caprolactone）-block-poly（2-（dimethylamino） ethyl methacrylate） triblock amphiphilic copolymer（mPEG-b-PCL-bPDMAEMA） were synthesized by ATRP and ROP. Afterwards, the polymers were coupled via click reaction with-propinyloxy coumarin and azido-polymers in order to prepare fluorescent copolymers. The obtained fluorescent copolymers micelles were characterized with UV-vis and fluorescence spectra. The mPEG-b-PCL-b-PDMAEMA-g-PC could self-assemble in aqueous solution at room temperature to form core-shell micelles with hydrophilic the mPEG, PDMAEMA as shell and the hydrophobic PCL as core. Micelles have fluorescent properties been studied by fluorescence microscope. The pH-responsive self-assembly behavior of these triblock copolymers in aqueous solutions were investigated at different pH value of 5.0 and 7.4, After 50 h for the DMPDP2 micelles, the cumulative release was about 88.7%. CCK-8 assays against HeLa cells indicated that the blank micelles with different concentrations were nontoxic to HeLa cells and the cell viability was over 95% at all concentrations, the DOX loaded micelles were found to be taken up by the nuclei of the cells via the endocytosis process using CLSM,which could kill HeLa cells.