Synthesis and characterization of β-cyclodextrin-conjugated alginate hydrogel for controlled release of hydrocortisone acetate in response to mechanical stimulation

Alginate hydrogels are a class of biomaterials that can be used as local release depots for therapeutic agents. A particular drug that can take advantage of alginate hydrogel for controlled release is hydrocortisone acetate. Hydrocortisone acetate is a widely used anti-inflammatory agent, but is limited in application due to poor solubility and lack of controlled delivery. To overcome this limitation, a mechanically responsive β-cyclodextrin-conjugated alginate (Alg-β-CD) hydrogel was synthesized and characterized for enhanced aqueous solubility and controlled release of hydrocortisone acetate. We demonstrated that mono-6-deoxy-6-ethylenediamine-β-cyclodextrin and hydrocortisone acetate formed a 1:1 inclusion complex, thus resulting in marked increase in hydrocortisone acetate solubility, while causing no significant inhibition to the growth of cultured mouse fibroblasts (L929). More importantly, the release of hydrocortisone acetate from the hydrogel system was increasingly sensitive to mechanical compression, and the mechanical responsiveness of hydrocortisone acetate release increased dramatically as the concentration of mono-6-deoxy-6-ethylenediamine-β-cyclodextrin increased from 0% to 46%, whereas the swelling rate and stiffness of the hydrogel decreased as the concentration of mono-6-deoxy-6-ethylenediamine-β-cyclodextrin increased. The mechanical responsiveness of hydrocortisone acetate release was attributable to conformational distortion of mono-6-deoxy-6-ethylenediamine-β-cyclodextrin moieties and deformation of the polymer network. Moreover, we demonstrated that the hydrogel continuously released and accumulated hydrocortisone acetate in the medium when compressed for up to 72 h, which led to increasing suppression of nitric oxide production in the lipopolysaccharide-stimulated mouse macrophages (RAW264.7), indicating desirable anti-inflammatory effect at the cell level. Hence, this hydrogel system may provide a useful platform for drug delivery, such as hydrocortisone acetate release to wound site, by intentionally generated mechanical force.