Controlled Synthesis of Stimuli-Responsive Network Alginate

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Chan, Ariel Wan-Ju
Semisynthesis , Alginate , Hydrogel , Acetalization , Diffusion , Swelling
Stimuli-responsive hydrogels swell or contract in response to external pH, ionic strength or temperature, and are of considerable interest as pharmaceutical controlled release devices. Alginate, a linear polysaccharide consisting of mannuronic and guluronic acids, was used as starting material in semisynthesis of pH-responsive hydrogel. Linear alginate was chemically modified with di-aldehyde via acid-catalyzed acetalization, forming a tetrafunctional acetal-linked semisynthetic network alginate polymer (SNAP) with carboxylate moieties preserved as stimuli-responsive sensors. The kinetics of acetalization were found to undergo zero and second-order reaction with respect to di-aldehyde and alginate respectively. With the determined rate constant of 19.06 L•mole-1•s-1 at 40oC and activation energy of 78.58 kJ•mol-1, a proposed predictive reaction model may be used a priori to select reaction conditions providing specific polymer properties. Gel swelling and average pore size were then able to be kinetically or thermodynamically controlled between 80-1000 fold and 30 nm-1 m respectively. As a proof of concept, SNAP hydrogel was fine-tuned with specific swelling and pore sizes for absorptive encapsulation and controlled release of a wide spectrum of molecular sizes of proteins ranging between 1.3 to 546 kDa. SNAP hydrogels/granules demonstrated limited swelling in the simulated gastric environment, protecting proteins from enzymatic and acid degradation, while swelling in alkaline media, releasing active therapeutics in a simulated intestinal lumen (pH ~ 7.8), so is under the consideration as an oral delivery vehicle for protein therapeutics. A constitutive polyelectrolyte gel model based on non-Gaussian polymer elasticity, Flory-Huggins liquid lattice theory, and non-ideal Donnan-membrane equilibria was derived, to describe SNAP gel swelling in dilute and ionic solutions. The derived model accurately describes the SNAP hydrogel swelling in acid and alkaline solutions of wide range of ionic strength. The pore sizes of SNAP hydrogel were estimated by the derived model and were comparable to those determined experimentally by thermoporometry and protein diffusion. The derived model can characterize hydrogel structure such as molecular weight between crosslinks, or can be used as predictive model for swelling and pore size if gel structural information is known, and can potentially be applied to other point-link network polyelectrolytes such as hyaluronic acid gel.
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