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

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 beta-ionone, beta-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.