Synthesis of well-defined hydrogel network using click chemistry for drug delivery

Xuan Truong (2011). Synthesis of well-defined hydrogel network using click chemistry for drug delivery , Aust Institute for Bioengineering & Nanotechnology, The University of Queensland.

       
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Author Xuan Truong
Thesis Title Synthesis of well-defined hydrogel network using click chemistry for drug delivery
School, Centre or Institute Aust Institute for Bioengineering & Nanotechnology
Institution The University of Queensland
Publication date 2011-02
Subjects 06 Biological Sciences
Abstract/Summary This project aims to examine the methods for synthesis of well-defined networks, and how the properties of these molecules can be tailored for specific end-use applications. Thus, a series of PEG hydrogels and amphiphilic PEG-PTMC hydrogels were prepared with high yield using copper catalysed alkyne-azide cycloaddition, or ‘click’ chemistry, where the molecular weight (MW) and structure of the precursors was varied. FTIR and 1H MAS NMR spectroscopy showed that the ‘click’ reaction reached high conversion of approximately 90 %. Swelling and degradation studies of the hydrogels were performed to relate network structure to the physical properties. The crosslinking efficiency calculated using the Flory-Rehner equation varied from 0.90 to 0.99 which indicates that the networks are close to ‘ideal’ at a molecular level. However at the microscopic level cryo-SEM indicated that some degree of phase separation was occurring during crosslinking. At 37 °C and pH 7.4, the degradation rate of the hydrogels increased with decreasing crosslink density in the network. Introduction of PTMC as the crosslinker produced an amphiphilic gel with higher crosslink density and a longer degradation time. Through control of molecular weight and structure of the precursors the degradability of the resultant hydrogels has been able to be tuned. In the second stage of the project, FITC-dextran was used as a model drug to study the diffusion of solute within the PEG networks. The release of FITC-dextran having hydrodynamic radii ranging from 1.2 to 15.7 nm was seen to correlate well with the swelling profile of the gel, i.e. more drug molecules were released from the gel with high swelling ratio or longer polymer chain length and the release was limited as the size of the drug molecules was increased. This indicates that controlled release of drug from dry PEG gel can be achieved to some extent. The diffusion of FITC-dextrans from fully swollen PEG gels was Fickian in nature and could also be controlled by changing the MW of the polymer precursors. The diffusion coefficients of the FITC-dextrans within the PEG gels, extracted from the diffusion profile using Fick’s equations, were fitted to common expressions derived from three diffusion models: the free volume model developed by Lustig and Peppas, the hydrodynamic model developed by Cukier and the obstruction model developed by Amsden. In the Lustig and Peppas model, a direct prediction of diffusion coefficient could be obtained from a predetermined network mesh size. However, this model is too generic for fitting experimental data. The Amsden model was superior to the Cukier model in fitting of the data of solute diffusivity based on polymer volume fraction for our polymer system. We found that the scaling rule, the correlation of polymer volume fraction with the hydrodynamic screening length and the distance between crosslinks, of κ-1~ φ-1.8 for the Cukier model and either ξ~ φ-1or ξ~ φ-0.75 for the Amsden model can provide a good fit to the experimental data. Since there is no defined scaling rule for all these models, they appear to provide little information on the polymer chain conformation within the network. All three models provide an adequate fit to the experimental data describing the effect of solute size on solute diffusion. Since copper is known to be toxic to microorganism, alternatives to the copper click reaction were investigated for crosslinking of PEG hydrogels. We have synthesised several compounds with electron-deficient alkynes to react with an azide compound. In situ monitoring of the cycloaddition by Raman spectroscopy showed that the consumption of the alkyne followed an exponential decay which is indicative of a pseudo-first order process. Generally, the cycloaddition reached 50-70% conversion in a range of polar solvents after 5 h of reacting. At 50 oC, the reaction was found to proceed to near completion in less than one hour and the cycloaddition adduct was exclusively the 1, 4-regioisomer. This reaction could therefore be a substitute for copper click reaction for applications where the use of copper is not favourable. The cycloaddition of azide with electron-deficient alkyne was use to synthesize a range of poly(ethylene glycol) (PEG) hydrogels with different chain length precursors. Gels could be formed in ethanol within 1-2 h at 70 °C with excellent yields. FTIR and MAS 1H NMR showed that the reaction went to completion with no detectable unreacted functional groups. These gels were found to absorbed less water than copper click PEG gel. SEM studies revealed that the prepared gels have less micron sized pores compared to gels prepared using copper catalysis, suggesting that a tighter network structure had formed. Mechanical testing indicated that these gels possess strong mechanical properties, with compressive strengths ranging from 1.6-6.8 MPa. The gels swelling and mechanical properties were shown to be easily tuned by changing the molecular weight of the polymer precursors. These materials therefore have excellent potential for a range of biomedical applications such as in drug delivery or as artificial cartilage.

 
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Created: Wed, 13 Jul 2011, 10:52:29 EST by Mr Xuan Truong on behalf of Library - Information Access Service