Synthesis, Drug Release And Molecular Thermodynamic Model Of Polymer Hydrogels

Due to the special three-dimensional network structure of polymer hydrogels, the volunm phase transition will occur by the external stimuli (such as temperature, pH, ionic strength, composition of solvent, etc.). Therefore, polymer hydrogels can be widely used in the controlled drug release system. In this paper, based on the swelling properties of polymer hydrogels, we firstly established a series of molecular thermodynamic models of polymer hydrogels to study their swelling behaviors. Then we used the inorganic nanoparticles to synthesize a series of core-shell inorganic-organic microgels and studied the drug release behavior at different temperature, pH and concentration of microgels. This main work included the following two parts:Part Ⅰ:Development of molecular thermodynamic models of polymer hydrogels(1) Develop a molecular thermodynamic model for describing swelling behavior of temperature-and solvent-sensitive polymer hydrogels in solvent mixtures. The model contained the mixing contribution due to the mixing of polymer network and solvents and the elastic contribution of hudrogel network. The former could be calculated by a modified multiple lattice model and the later could be calculated by Gaussian chain model. There were two kinds of model parameters in this model, which were the energy parameters εij between the polymer and solvent or the two solvents and the volumn parameter V*of the polymer. Two energy parameters and one volume parameter could be determined by the swelling behavior of hydrogels in pure solvents. The energy parameter measuring the interaction between the two solvents was the only adjustable parameter. The calculated results for the swelling curves of PNIPAm hydrogels in ethanol/water mixtures at different temperatures were in good agreement with the experiments. By fitting the adjustable parameters as a function of temperature, the model could predict the swelling behavior of PNIPAm hydrogels in other temperatures. In addition, the equilibrium concentrations of solvent mixtures inside and outside hydrogels could be predicted by this model.(2) Considering the ionic effect containing Donnan equilibrium of small ions distributed inside and outside hydrogels, electrostatic interactions between the charges fixed on the polymer network and the counter ions and the effect of non-Gaussian chain, a new molecular thermodynamic model for swelling behavior of multi-responsive polymer hydrogels was developed. This model contained two kinds of model parameters, which were the interaction energy parameters εij, and a size parameter Mc. It was shown that this model could describe the swelling behavior and volume phase transitions of pH-sensitive and ion-sensitive hydrogels by using fewer model parameters.The different swelling behaviors such as shrinking at low pH and swelling at high pH, swelling at low pH and shrinking at high pH, shrinking at middle pH and swelling at both low pH and high pH could be satisfactorily described. In addition, this model also could return to describe the swelling behavior of temperature-and solvent-sensitive hydrogels.(3) Considering the different monomer component of random copolymer hydrogels,a new molecular thermodynamic model for describing the swelling behavior of random copolymer hydrogels was developed. Besides the interaction energy parameters εij and size parameter Mc, this model also considered the effect of the composition of two polymers f.The results showed that the volume phase transition point of the random copolymer hydrogels would be close to that of pure hydrogels with the increase of this component. This model could describe the swelling behavior of temperature and pH-sensitive random copolymer hydrogels by using fewer model parameters.Part II:Synthesis and Drug Release Behavior of core-shell microgels(1) Core-shell structural microgels were synthesized using amino-modified SiO2nanoparticle as core and the temperature-sensitive glycidyl mcthacrylate-modified hyaluronate/poly(N-isopropylacrylamide)(GMHA/PNIPAM) gel as shell. We studied the size of the core-shell microgels and the load and release behavior of the hydrophilic drug fluorescein in the shell layer with different GMA grafting rates(Dm) and HA molecular weights. The results showed that the phase transition temperatures of these microgels were all307K. and the swelling behaviors were reversible. With the increment of Dm and HA molecular weight, shrinking degree Ad and its fluoreseein loaded amount increased. The cumulative release ratio of fluoreseein also improved and the highest cumulative release ratio was79.9%. With the increment of the concentration of microgels, the release ratio of fluorescein was slower and the slowest was50%when the concentration of microgel was2.5%.(2) Core-shell structural microgels were synthesized using amino-modified mesoporous silica nonaparticle MSN as core and temperature-sensitive GMHA/PNIPAM gel as shell. We studied the loaded abilities and release behavior of two different drugs which was loaded in the core or shell layer with the different GMA graft ratios(Dm). The size d and the shrinkage degree△d of MSN-GMHA/PNIPAm increased with the increment of Dm. For the hydrophilic drug doxorubicin (Dox) loaded in the shell layer, the smaller the△d, the lower the Dox loaded amount. And the cumulative release ratio of Dox was also lower. Because Dox contained the ammo and hydroxy group, which would be absorbed in the shell layer due to electrostatic interaction with carboxylic acid group of HA. When the pH value was lower, due to the protonation of-COO, these absorbed Dox could be released and resulted in a higher cumulative release ratio of Dox. Its release equilibrium time protracted from4h to6h. For the hydrophobic drug rhodamine loaded in the core layer, after the gel layer was coated on MSN, the cumulative release time of rhodamine increased from12h to more than48h. Comparing rhodamine release behavior of microgels with different Dm, we found that the smaller Dm the slower release rate. The reason was that the polyer network in shell layer was denser and the shell layer at shrinking state was thicker at that time. The cumulative release ratio of rhodamine decreased with the increment of microgels’concentrations. Because the higher concentration of the microgels would lead to the aggregation of the microgels when the temperature was higher than the lower critical solution temperature (LCST), the rhodamine release should overcome greater space resistance.