D-amino acids boost the selectivity and confer supramolecular hydrogels of a nonsteroidal anti-inflammatory drug (NSAID)

Abstract

As systemically used therapeutics for treating acute or chronic pains or inflammations, nonsteroidal anti-inflammatory drugs (NSAIDs) also associate with the adverse gastrointestinal and renal effects and cardiovascular risks. Thus, it is beneficial to develop topical gels that selectively inhibit cyclooxygenase-2 (COX-2) for the management of local inflammation. In this work, we demonstrate that the covalent conjugation of d-amino acids to naproxen (i.e., a NSAID) not only affords supramolecular hydrogelators for the topical gels but also unexpectedly and significantly elevates the selectivity toward COX-2 about 20× at little expense of the activity of naproxen. This work illustrates a previously unexplored approach that employs d-amino acids for the development of functional molecules that have dual or multiple roles and exceptional biostability, which offers a new class of molecular hydrogels of therapeutic agents.

Figure 1

The binding of (A) Npx and (B) 1 with COX-2 enzyme (the ligands as CPK model and the COX-2 as ribbons).

Figure 2

The TEM images of the hydrogels of (A) 1 (pH 4.0); (B) 2 (pH 7.6); (C) 3 (pH 7.6); (D) 4 (pH 7.6); (E) 5 (pH 7.0); (F) 6 (pH 7.0) (inset: optical images). Hydrogels of 2 and 4 made by adding 0.2 U/mL alkaline phosphatase to the solutions of 2P and 4P. All hydrogels are at 0.8 wt% (f = D-Phe, k = D-Lys, y = D-Try). The scale bar is 100 nm.

Figure 3

(A) The IC₅₀ values of the Npx based hydrogelators for inhibiting COX enzyme (the selectivity, defined as the IC₅₀ ratio of COX-1 and COX-2, is labeled on the top of the bars). (B) The release profiles of the Npx based hydrogelators from hydrogels of 1, 2, 3, 4, 5, and 6.

Scheme 1

The structures of the hydrogelators consisting of D-amino acids and naproxen (Npx).