Retinoic acid grafted to hyaluronan for skin delivery: Synthesis, stability studies, and biological evaluation

Abstract

All-trans retinoic acid (ATRA) was grafted to hyaluronan (HA) via esterification. The reaction was mediated by mixed anhydrides. A perfect control of the degree of substitution (0.5-7.5%) was obtained by varying the molar ratio of retinoic acid in the feed. The degree of substitution plays a significant role in the long-term stability. The photodegradation of HA-ATRA upon UVA irradiation resulted in β-ionone, β-cyclocitral and 5,6-epoxy-(E)-retinoic acid. The photostability of the conjugate had increased with the combination with morin. The chemical structure of HA-ATRA and its degradation products was elucidated using NMR spectroscopy, SEC-MALLS, and gas chromatography-mass spectrometry (GC-MS). ATRA did not loss its biological activity after conjugation, as demonstrated by gene expression. The derivative was able to penetrate across the stratum corneum. Besides, HA-ATRA downregulated the expression of anti-inflammatory interleukins 6 and 8. HA-ATRA would be expected to be used for transdermal drug delivery or cosmetics.

Keywords: (±)-6-Hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (trolox, PubChem CID: 40634); 2-Ethylhexyl 2-cyano-3,3-diphenylacrylate (PubChem CID: 22571); 2-Ethylhexyl 4-methoxycinnamate (PubChem CID: 21630); Antioxidants; Avobenzone (1-(4-Methoxyphenyl)-3-(4-tert-butylphenyl)-1,3-propanedione, CID: 51040); Butylated hydroxyanisole (BHA, PubChem CID: 517036); Butylated hydroxytoluene (BHT, PubChem CID: 31404); Hyaluronic acid (PubChem CID: 24728612); Morin hydrate (2′,3,4′,5,7-Pentahydroxyflavone, PubChem CID: 16219651); Retinoic acid (PubChem CID: 444795); Retinoids; Retinyl palmitate (PubChem CID: 5280531); Skin; hyaluronan.