| Hydrogel with a three-dimensional network structure has been widely used in controlled drug release in recent years.Mucoadhesive Drug Delivery System(MDDS)uses natural or synthetic polymer materials with mucoadhesive properties as drug carrier,which is applied to specific parts of the human body to release drugs slowly.In this thesis,mucoadhesive hydrogels and nanogels were synthesized via the thiol-maleimide click reaction using sulfhydryl groups modified hyaluronic acid(HA-SH)with excellent mucoadhesion as the raw material,and 6-maleimide-hexyl ester-terminated Pluronic F127(PF-Mal)a crosslinker,and trethylamine as mild catalyst.The process of synthesizing hydrogels and nanogels is mild and controllable without any side reactions,which is a"green"click reaction.Composite hydrogels were prepared by embedding nanogels in hydrogels,and the controlled drug release properties of hydrogels,nanogels and composite hydrogels were demonstrated.Mucins on the surface of mucus layer and epithelial cells in various cavities of human body are rich in cysteine residues,which can form disulfide bonds with free sulfhydryl groups on the surface of hydrogels and nanogels prepared in this thesis,which can effectively prolong the residence time of drug,improve local drug concentration,and reduce the toxic effect of drug on the whole body.In this thesis,mucoadhesive HA-SH/PF-Mal hydrogels and nanogels with low swelling ratio and controllable drug release in artificial urine were synthesized by thiol-maleimide click reaction are expected to be applied to bladder mucoadhesive drug delivery.In the first part of this thesis,mucoadhesive HA-SH/PF-Mal hydrogels were prepared by thiol-maleimide click reaction.The hydrogels were formed under the physiological conditions of PBS 7.4 with adjusted gelation rate from 50 s to tens of minutes.The gelation rate can be adjusted by changing temperature,catalyst concentration and hydrogel precursor polymer concentration.SEM and hydrogel swelling test showed that the prepared hydrogel had uniform three-dimensional cross-linking network structure.The higher hydrogel precursor polymer concentration resulted in the more dense the cross-linking network structure and the smaller maximum equilibrium swelling rate.Rheological tests showed that HA-SH/PF-Mal hydrogels exhibited excellent mechanical properties.When the concentration of hydrogel precursor increased from 5 wt%to 15 wt%,the storage modulus of hydrogels increased from about 55 Pa to 213 Pa at 25 ℃,and increased from about9.0 Pa to 151 Pa at 37℃.The lap shear strength test showed that HA-SH/PF-Mal hydrogel exhibited strong adhesive property.The higher concentration of hydrogel precursor resulted in the stronger adhesion of hydrogel.The lap shear strength of HA-SH/PF-Mal hydrogel with pig skin was about 2.4 kPa.Drug-loaded HA-SH/PF-Mal hydrogels were prepared using gemcitabine(GEM)as a model drug.Drug controlled release experiments showed that the HA-SH/PF-Mal hydrogel exhibited a sustained release effect on the encapsulated drugs,and its controlled release effect on GEM in artificial urine was better than that in PBS solution,which could achieve controlled release for 10h.In conclusion,the prepared HA-SH/PF-Mal hydrogel is a kind of drug sustained-release carrier material with controllable gelation rate and good application prospect in mucoadhesive drug delivery system,which is expected to be applied to injectable hydrogel for bladder mucoadhesive drug delivery.In the second part of this thesis,HA-SH/PF-Mal nanogels were prepared by emulsification solvent evaporation method.The prepared nanogels were typical spherical structures with uniform particle size distribution and exhibited temperature and pH responsiveness.With increasing temperature,the particle size of HA-SH/PF-Mal nanogels decreased,the absolute value of Zeta potential the stability of HA-SH/PF-Mal nanogels increased.TEM test showed that the particle size of the dry nanogel was about 100 nm,which was suitable for use as a drug nanocarrier.The nanogels exhibited excellent storage stability in PBS and artificial urine with different pH for three days at 4℃,and could stably exist and release drugs in PBS and artificial urine of different pH within 24 h at 37℃,and its particle size and Zeta potential remained almost unchanged.The nanogels exhibited better storage stability in artificial urine than in PBS solution.The mucoadhesion of the nanogel was estimated by binding to porcine gastric mucin particles.The nanogels can interact with the surface of mucin particles through covalent bonds and exhibited excellent mucoadhesion.The composite hydrogels were prepared by embedding the nanogels in the HA-SH/PF-Mal hydrogels.The composite hydrogels system exhibited better sustained drug release effect than single HA-SH/PF-Mal nanogels or HA-SH/PF-Mal hydrogels. |
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