Preparation Of Chitosan-based Temperature/pH Responsive Intelligent Hydrogels And Their Drug Release Property

Cancer,commonly caused by uncontrolled growth and spreading of abnormal cells,would seriously threaten human's health and has become the first cause of death in the world.Oral chemotherapy is one of the most important cancer treatments.Unfortunately,most anticancer drugs have some deficiencies,such as poor water-solubilioty,side effects and fast metabolism.A major approach,among attempts underway to face this challenge,is to formulate anticancer drugs in a carrier that will improve oral bioavailability.Recently,stimuli-responsive hydrogels,which can undergo reversible changes in response to environmental stimuli such as temperature,pH,solvent composition,light and magnetic field,have attracted great interests as a drug carrier.However,many stimuli-responsive hydrogels have low mechanical strength and narrow range of temperature and pH,which severely hinders the application of stimuli-responsive hydrogels for drug delivery.Commonly,scientists have attempted to enhance mechanical strength of hydrogels by copolymerization via chemical cross-linking,yet these techniques have limitations such as inherent toxicity of chemical cross-linkers,which can possibly damage entrapped bioactive substance and lead to a loss of activity.More recently,procedure consisting of multi-step polymerization has been developed,whereas such approaches are usually time-consuming.To address these issues,this thesis reports a novel,facile and cost-effective technique of single step aqueous copolymerization to achieve two different kinds of physically cross-linked,intelligent hydrogels with enhanced mechanical strength,i.e.,pH-responsive hydrogel P?CS-co-AA-co-DMAMEA?and both pH-and thermally responsive hydrogel P?CS-co-AA-co-MEO₂MA-co-OEGMA?,employing free radical solution polymerization without any cross-linking agent.The effects of monomeric components,temperature and pH on swelling behavior of hydrogels were studied,Furthermore,rapid response properties and drug delivery of hydrogels were investigated in detail,from which key conclusions can be derived as follows:1.A novel physically cross-linked pH-responsive semi-interpenetrating polymer network?semi-IPN?hydrogel(P?CS-co-AA-co-DMAMEA?with enhanced mechanical performance was prepared from chitosan?CS?,acrylic acid?AA?and?2-dimethylamino?ethyl methacrylate?DMAEMA?via in situ free radical polymerization for controlled drug delivery.Successful fabrication of designed hydrogels was verified by Fourier transform infrared spectroscopy?FT-IR?,X-ray diffraction?XRD?,differential scanning calorimetry?DSC?and thermogravimetric analysis?TGA?measurements.Scanning electron microscopy?SEM?and mechanical analyses demonstrated that morphological and mechanical behaviors of the resultant hydrogels were strongly affected by content of AA and DMAEMA in hydrogels.Moreover,swelling properties of these hydrogels were systematically investigated,and the results indicated that such hydrogels exhibited strong pH sensitivity.Applications of thus fabricated hydrogels in drug delivery were further evaluated,from which bovine serum albumin?BSA?and 5-fluorouracil?5-Fu?were chosen as model drugs for in vitro release.Experimental results showed that the released amount of 5-Fu and BSA can be tuned by varying composition of hydrogel and pH of the medium,denoting that these hydrogels can be used as a drug carrier.Moreover,in vitro cytotoxicity studies,it verified that such hydrogels display excellent compatibility with cells,while 5-Fu-loaded hydrogels exhibited lower cell growth inhibition efficiency for normal L02 cells but higher cell growth inhibition efficiency for cancer HepG-2 cells as compared with pure 5-Fu at equivalent drug concentration.With these excellent features,this CS-based pH-responsive hydrogel reveals great potential to be utilized as a vehicle for anticancer drug delivery.2.Novel dual stimuli-responsive sem i-interpenetrating polymer network?semi-IPN?chitosan-based hydrogelP?CS-co-AA-co-MEO₂MA-co-OEGMA?were prepared by free-radical polymerzation of 2-?2-methoxy-ethoxy?ethyl methacrylate?MEO₂MA?and oligo?ethyleneglycol?methacrylate?OEGMA?,both as thermosensitive monomers,and acrylic acid?AA?,as a pH-sensitive monomer.The resultant hydrogels were characterized in detail by FT-IR,XRD,DSC,TGA,SEM,etc,.The effect of temperature,pH and monomeric composition on swelling properties of thus prepared CS-based hydrogels has been discussed.The obtained hydrogels showed excellent temperture/pH responsive behaviors.For instance,such hydrogels displayed good pH sensitivity in stimulated intestinal gastric fluid and good swelling and deswelling properties in aqueous solution at different temperatures.In addition,varied monomeric componnents would render an important impact on physical properties of hydrogels.It has also been noticed that absorption and release behaviors of model drugs,BSA and 5-Fu,were found dependent on hydrogel composition,pH and envionmental temperature.MTT results revealed that hydrogels displayed excellent compatibility with cells,and that 5-Fu-loaded hydrogels exhibited lower cell growth inhibition efficiency for normal L02 cells but higher cell growth inhibition efficiency for cancer HepG2 cells as compared with pure 5-Fu at equivalent drug concentration,demonstrating potential application of these hydrogels as intelligent drug carriers.