Physical Cross-linking And Physical-chemical Double Cross-linking And Properties Of Temperature/pH Dual-sensitive Amphiphilic Co-network Gels

The sensitivity of stimuli-responsive hydrogels to a variety of environmental conditions(such as electric fields,solution pH,temperature,and chemicals)has made them extensive exploration in drug release control,microscale sensors,microfluidics,filtration/separation.As one of the important stimuli-responsive hydrogels,temperature and pH-sensitive hydrogels can respond to temperature and pH,which are important physiological parameters of the human body.Therefore,it is widely used in drug delivery systems.Polylactic acid(PLA)is hydrophobic polymer with non-toxic,non-irritating and good biocompatibility,which can be completely degraded to H2O and CO2 after use,and the intermediate product lactic acid is also normal sugar metabolite in vivo.The two enantiomers of polylactic acid,L-polylactic acid and D-polylactic acid,can form stereocomplexed microcrystals by hydrogen bond physical crosslinking when the process of gel synthesis,which makes the gel have high melting point,high mechanical strength,good thermal stability and so on.It is beneficial for the gel to carry out drug delivery in human body.2-(2-methoxy ethoxy)ethyl methacrylate(MEO2MA)and oligoethylene glycolmethyl methacrylate(OEGMA)are PEG analogue copolymer.Not only do they have temperature sensitivity,hydrophilicity and biocompatibility,but also the low critical solution temperature(LCST)can be adjusted between 26? and 90?by adjusting the feeding ratio of the two monomers.Because the pKa of the amino groups of poly(diethylaminoethyl methacrylate)(PDEAEMA)is about 6.9,PDEAEMA is soluble in water at pH below 6.9,and becomes hydrophobic and insoluble under normal physiological conditions.Responsiveness to weakly acidic conditions indicates that PDEAEMA may be pH-sensitive material for tumor-targeted pH drug delivery.Based on the above,in this paper,biocompatible L-lactide and D-lactide,temperature-sensitive monomers MEO2MA and OEGMA,and pH-sensitive monomer DEAEMA were selected.Physically cross-linked amphiphilic conetwork gel with temperature and pH dual sensitivity was synthesized by ring-opening polymerization(ROP)and free radical copolymerization.Then,based on the first part,the chemical cross-linker ethylene glycol dimethacrylate(EGDMA)was added to synthesize double-crosslinked hydrogel with dual response of temperature and pH.The swelling properties,mechanical properties,thermodynamic properties and drug release behavior of drug-loaded gels in vitro under different conditions were mainly studied.The specific work is as follows:1.HEMA-PLLA and HEMA-PDLA were synthesized by ring-opening polymerization(ROP)of L-lactide and D-lactide with hydroxyethyl methacrylate(HEMA)as the initiator and 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU)as the catalyst.Then,using azobisisobutyronitrile(A1BN)as the initiator,HEMA-PLLA,HEMA-PDLA,MEO2MA,OEGMA and DEAEMA were radically polymerized to synthesize physically cross-linked amphiphilic conetwork gel with temperature and pH dual sensitivity.The successful synthesis of macromolecular monomers and physical cross-linked hydrogels was demonstrated by proton nuclear magnetic resonance(1H NMR),Fourier transform infrared spectroscopy(FT-IR),and X-ray diffraction(XRD).The temperature and pH dual responsiveness of the hydrogel were studied by digital photo taking,swelling and deswelling properties;The thermodynamic properties of the hydrogel were measured by differential scanning calorimeter(DSC);the mechanical properties of the hydrogel were studied by dynamic viscoelastic spectrometer;the micromorphology of the hydrogel were studied by desktop scanning electron microscope(SEM).By loading the hydrophobic drug doxorubicin into the gel,the cumulative release of DOX in different environments of the drug-loaded gel was studied.The results show that the synthetic physical crosslinked hydrogel can achieve effective controlled release of the hydrophobic drug.In summary,the results of these studies show that the physical cross-linked amphiphilic co-network gels with temperature-and pH-sensitivity based on the stereocomplex of polylactic acid have good temperature sensitivity and pH sensitivity,which is sufficient for the controlled release of hydrophobic drugs.It is expected to be used as a hydrophobic drug carrier in medicine.2.On the basis of the first work,macromers HEMA-PLLA20 and HEMA-PDLA20 were selected,stereocomplexation was used as physical cross-linking agent,and EGDMA was selected as chemical cross-linking agent.Then,HEMA-PLLA20,HEMA-PDLA20,EGDMA,MEO2MA,OEGMA and DEAEMA are polymerized together by radically polymerized to synthesize double crosslinked hydrogel with temperature and pH dual sensitivity.The successful synthesis of double crosslinked hydrogels was demonstrated by Fourier transform infrared spectroscopy(FT-IR),and X-ray diffraction(XRD).The temperature and pH dual responsiveness of the hydrogel were studied by digital photo taking,swelling and deswelling properties;The thermodynamic properties of the hydrogel were measured by differential scanning calorimeter(DSC);the mechanical properties of the hydrogel were studied by dynamic viscoelastic spectrometer;the micromorphology of the hydrogel were studied by desktop scanning electron microscope(SEM).The release rate of doxorubicin of double-crosslinked hydrogels under different environments was studied by embedding doxorubicin in the gel.The above results indicate that the dual-crosslinking amphiphilic co-network gel with temperature and pH dual sensitivity synthesized by combination of physical crosslinking and chemical crosslinking have good biocompatibility,good mechanical properties and stability,which is sufficient for the controlled release of hydrophobic drugs.It will be expected to have greater application irt the drug delivery system.