Development of a Hyaluronic Acid-Retinol Conjugate for Enhanced Photostability and Transdermal Delivery.

Despite its potent anti-aging efficacy, the practical application of retinol (ROH) remains highly restricted by its poor photostability, low aqueous solubility, and concentration-dependent cytotoxicity. Herein, we report the synthesis of a hyaluronic acid-retinol (HA-ROH) conjugate to overcome these limitations and improve transdermal delivery. The successful conjugation was confirmed via proton nuclear magnetic resonance (1H NMR) spectroscopy, high-performance liquid chromatography (HPLC) and Fourier-transform infrared spectroscopy (FT-IR). Notably, the HA-ROH conjugate exhibited remarkable photostability under UVA irradiation compared to free retinol. HA-ROH presented a sustained, hyaluronidase-responsive ROH release profile, indicating its potential as an enzyme-responsive controlled delivery system. Furthermore, the conjugation significantly mitigated the cytotoxicity of retinol in both HaCaT keratinocytes and human dermal fibroblasts. The conjugate suppressed matrix metalloproteinase-1 (MMP-1) expression more effectively than free ROH. In vitro cellular uptake and ex vivo skin permeation studies demonstrated enhanced transdermal delivery of the HA-ROH conjugate. Taken together, these results suggest that the HA-ROH conjugate is a highly promising, stable, and safe candidate for advanced dermatologic and cosmetic applications.