| Hydrogels,which are three dimensional networks of crosslinked hydrophilic polymers,have a significant role in solving the clinical and pharmacological limitations of present systems because of their biocompatibility,ease of preparation and unique physical properties such as a tunable porous nature and affinity for biological fluids.In the field of biomedical materials application,hydrogels have arrosed great attention and extensive research,for instance of the tissue engineering for organism and drug carriers for therapy.Nowadays,malignancy as one of the most difficult to conquer,which is the focus and differcult point of researches' attention and exploration about its therapy.However,the delivery of antitumor drugs is the key of tumor curing.Hydrogels as an ideal drug carrier have contributed to the drug delivery in anti-tumor.Based on the tumor microenvironment,for example,the shortage of blood vessels,lack of oxygen and differences of pH values.The 'smart' hydrogels,which are widely used in drug delivery,can respond to external stimuli,including pH,temperature,light,magnetic,electric,ionic and other sensitive stimulus.The drug delivery system of hydrogels based on the differences of pH values in tumor sites,the blood vessels,ex-and in-tracelluar space as well as lysosome are 7.4,6.5-712 and 5.0-6.0 as well as 4.0-5.0,have been designated.pH-sensitive hydrogels are of great potential value in the control of drug release,so the researchers are mainly using chemical bonds that introduce pH sensitivity into hydrogels,such as acid-labile ortho ester,ketal,acetal,hydrazone bonds and so on.The ortho ester bond is a kind of chemical bond which is super sensitive to the slightly acidic environment,and has been widely used in sustained and controlled release of drug carriers.Especially,the pH-sensitive hydrogels can not only respond to environmental stimulus to realize drug release intelligently,but also increase the concentration and time of drug in tumor site,and greatly reduce the damage caused by chemotherapeutic drugs to the organism.However,to the comprehensive of relevant academic journals,the study on the preparation and application of pH-sensitive hydrogels containing the ortho esters as a drug carrier has not been reported.So that the pH-sensitive hydrogels via acid-labile ortho ester linkage have greatly potential values for the applications of controlled release.In this study,the main contents and conclusions include the following points:First,the five-membered ortho ester cyclohexyl monomer of OEDe with epoxy rings was synthesized successfully by three-step reaction with diglycerol and trimethyl orthoformate as starting materials.The structure of the monomer OEDe was analyzed by NMR and GC,and its molecular formula is C22H38O13 which denotes the theoretic molecular weight(Mw)is 510.2,and the actually measured molecular weight(Mw)was 533.2 which was calculated from the theoretic molecular plus sodion.Under a mild condition,a series pH-sensitive hydrogels(hydrogel-1,hydrogel-2 and hydrogel-3)were obtained using the crosslinking recation between the crosslinking agent of OEDe and carboxymethyl chitosan(CMCS)by different feed molar ratio.The structure of crosslinked hydrogels were detected and confirmed by solid phase NMR and FT-IR,and the results showed that the crosslinking agent(OEDe)and carboxymethyl chitosan were successfully crosslinked and the structure was correct.The crosslinked hydrogels can be seen that their shape like a sponge,the internal pore size was regular and moderate and the structure was easy to operate from the observed pictures of macroscopic topography and scanning electron microscope(SEM).The viscoelasticity of the prepared hydrogels with different crosslinking degree were analyzed by the storage modulus(G')and loss modulus(G")of the rheological property,and its results depicted that the viscoelasticity of hysrogels will be gradually ameliorated with the increasing of crosslinking agent in a certain range.However,once excessed this range,the corresponding hydrogels were not suitable for next experiment,which due to the elastic was too small to possess a stable structure.So the best specimen of hydrogel-2 was selected to do the further study.The results of stability test showed that the prepared hydrogels could be kept stable in the temperature around 200?,and could be placed for a long time at room temperature,indicating that hydrogels could be easily stored and transported.The results of X-ray diffraction(XRD)showed that the carboxymethyl chitosan was crosslinked by OEDe and the peak of crystal was raised with the increase of crosslinking agent.Under the neutral conditions,the results of swelling test denoted that the hydrogels(hydrogel-1,hydrogel-2 and hydrogel-3)have good swelling property.And the higher degree of crosslinking,its equilibrium swelling would be lower,which denoted hydrogel-1>hydrogel-2>hydrogel-3 and the corresponding value was about 10,6.3 and 4.9,respectively.Under the conditions with different pH values(pH 5.0,6.5 and 7.4),firstly,at the acid condition(pH 5.0 and 6.5),it can be seen that the ortho ester bonds were entirely degraded during 24 h and the degradative peaks of ortho ester were not observed which denoted the crosslinker and hydrogels were stable at the neutral condition of pH 7.4.Through the degradation of gel samples at different pH PBS,it could be seen that the degradation was pH-dependant from its weightlessness and the degradative peaks of NMR.Moreover,with the increase of crosslinker,the speed of degradation was increased.Second,after those characterizations of materials have been finished,the hydrogel-2 with excellent viscoelasticity was selected as the object for futher study.Furthermore,the hydrosoluble antitumor drug(DOX·HCl)as the model was efficiently and largely encapsulated into hydrogels using its profile of high water content through two ways,which were the process of gelation and swelling adsorption,respectively,to obtain two kinds of hydrogels.The drug release of loaded hydrogels obtained by swelling adsorption were conducted in different pH conditions(pH 5.0,6.5 and 7.4)which mimicked the physiological environment in vivo,and the results revealed that the large amounts of drug were capsulated and its drug release behavior was significantly accelerated by acid conditins.During 24 h,the accumulative release was approximately reached to 40%and 36.2%in pH 5.0 and 6.5,respectively.In neutral condition,the cumulative release only was about 28%,which was clearly lower than that in acid condition.After the sustained release of 7 days,the ultimate amounts of release were separately reached to about 81.6%and 71.3%in pH 5.0 and 6.5,while the accumulative release finally was about 39%,which showed the drug release of loaded hydrogels was pH-dependant and sustained under acid conditions,while the amounts of release were very little and could not be continuously released in neutral condition.Third,H22 tumor in the armpit of mice were used to evaluate the degradation of hydrogel-2 and antitumor effect of DOX-loaded hydrogel-2 which was loaded during the gelation,and the blank hydrogel-2 was set as control group.After 5 days,in vivo,the results of degradation showed that the hydrogel-2 was nearly completely degraded and there was no obvious toxicity to the mice.Compared with the blank hydrogel-2,the results of antitumor in vivo demonstrated that the drug loaded hydrogel-2 had a significant antitumor effect and could not obviously influence the growth of normal mice.In a word,the acid-labile carboxylmethyl chitosan-based hydrogels which possessed the excellent profile of biocompatibility and biodegradability as drug carrier have potential application in antitumor field. |
PDF Full Text Request