Characterization of the pH-Dependent Disintegration of Chemically Modified Alginate Hydrogels

Abstract Introduction We previously showed that chemical modification of alginate with 4-(2-aminoethyl) benzoic acid (ABA) results in the generation of alginate hydrogel microbeads that are resistant to disintegration in acidic pH but sensitive in near-neutral and basic pH conditions. Aim In the present study, we sought to better understand the chemical origin of the pH dependence of the ABA-modified alginate. We had hypothesized that ABA-modified alginate would be stable at acidic pH where the carboxylic acid functional group would be protonated and more unstable/water soluble at near-neutral to basic pH where the carboxylate would be ionic. Materials and Method To test this hypothesis, we added three separate small molecule attachments to the same alginate backbone in addition to the ABA-modified alginate so that their pH-dependent disintegration rates could be compared. Results We found that the disintegration profiles of phenethylamine- and ABA-modified alginates were similar, but different from those of methyl 4-(2-aminoethyl) benzoate- and 1-[4-(2-aminoethyl)-phenyl] ethanone-alginates. Conclusion In summary, we have developed an effective platform suitable for oral delivery of therapeutic agents, which normally would not be considered for oral administration. Through simple chemical alginate modifications, we have prepared a small family of new alginates that can disintegrate over 30–120 min at near-neutral pHs, thus providing useful information on how the polyanionic alginate polymer can be functionalized for enhanced oral delivery of therapeutic substances. Lay Summary We recently developed a macromolecule in which 4-(2-aminoethyl) benzoic acid (ABA) was attached to the alginate backbone. In the present study, we have compared the disintegration profiles of ABA-modified alginate with those of three separate small molecule attachments to alginate. The disintegration of phenethylamine- and ABA-modified alginate hydrogels were similar but different from those of methyl 4-(2-aminoethyl) benzoate- and 1-[4-(2-aminoethyl)-phenyl] ethanone-alginates. In conclusion, we have prepared a small family of new alginates that can disintegrate over 30–120 min at near-neutral pH, thus providing useful information on how alginate can be chemically altered for enhanced oral delivery of therapeutic substances. Future Work In further studies, we will examine the efficacy of using these compounds for oral delivery of therapeutic proteins and peptides in an appropriate preclinical animal model to set the stage for application in human trials.