Effects of Terminal Motif on the Self-Assembly of Dexamethasone Derivatives

Abstract

Tailoring the terminal motif of molecules including drugs might significantly affect their self-assembly tendency in aqueous solution, thus providing a rational strategy to modulate its macroscopic characteristics of supramolecular assembly. A model drug of dexamethasone (Dex) was esterified by different fatty acids [succinic acid (SA), glutaric acid (GA), and adipic acid (AA)] and aromatic acid [phthalic acid (PA)] to generate a series of Dex derivatives. Aqueous solution of Dex-SA, Dex-GA, and Dex-AA turned into hydrogel spontaneously after a period time of incubation (24, 48, and 72 h, respectively) via the auto-hydrolytic strategy, while aqueous solution of Dex-PA did not result in hydrogelation during 3 days of incubation. Aqueous solutions of Dex-SA, Dex-GA, and Dex-AA underwent apparent hydrolysis (10.73 ± 0.64%, 15.17 ± 2.24%, and 17.29 ± 1.39%, respectively), while Dex-PA exhibited a minimal hydrolysis (<1%) in a period of 28 days study, as indicated by in vitro hydrolytic test. Morphological observation showed that the hydrogel formed by Dex-SA was composed of uniform nanofibers, while hydrogels formed by Dex-GA, and Dex-AA were derived from irregular particles. The mechanical strength of hydrogel formed by Dex-SA was much bigger than that of hydrogels formed by Dex-GA and Dex-AA, as indicated by rheological test. Moreover, the acylation of Dex did not compromise its potent anti-inflammatory activity in a lipopolysaccharide (LPS)-activated RAW 264.7 macrophage.