Oligomeric hyaluronic acid-modified liposomes effectively improved skin permeability and anti-ageing activity of ellagic acid

Abstract

To overcome natural skin barrier, deliver ellagic acid (EA) to the dermis, and promote its anti-ageing efficacy, oligomeric hyaluronic acid (HA) modified EA-loaded liposomes (EA-HA-L) were constructed via self-synthesized different molecular weights of HA linked cholesterol (HA-Chol), and then the effect of HA molecular weight on the skin permeability of EA was explored to clarify the optimal molecular weight of HA with best transdermal delivery effectiveness. Finally, a series of in vitro and in vivo experiments were conducted to survey the transdermal mechanism, skin irritation, antioxidant, anti-photo ageing and antiwrinkle effects of EA-loaded liposomes modified with the optimal molecular weight of HA. The results showed that EA-HA-L had less than 200 nm particle size and high encapsulation efficiency. Among them, 5 kDa of oligomeric HA-modified liposomes (EA-HA5k-L) maximized the skin penetration and retention of EA and promoted the distribution width of EA in the skin far beyond the thickness of the epidermal layer, indicating its good ability to deliver EA to the dermis. EA-HA5k-L displayed uniformly sized nanosphere morphology and slow-release behavior in neutral and acidic environments that simulated skin. The transdermal mechanism of EA-HA5k-L was proven to be related to the loosening of the stratum corneum, reduction of calcium adhesion proteins, and recognition of CD44 receptor. EA-HA5k-L had no irritant effect on the chicken embryo chorioallantoic membrane, with an irritant index close to 0.9% NaCl. EA-HA5k-L not only improved the clearance rate of EA on DPPH and hydroxyl radicals but also elevated its inhibition effect on elastase. Significantly, compared to free EA and EA-loaded liposomes without oligomeric HA modification (EA-L), EA-HA5k-L significantly increased the cellular uptake of EA through receptor-mediated endocytosis, and effectively blocked the increase in metalloproteinase-1 (MMP-1) content and decrease in type I collagen content induced by UVB in human dermal fibroblasts (HDFs), demonstrating better anti-photo ageing effectiveness. Moreover, EA-HA5k-L upregulated the relative expression of the elastin gene and three types of type I collagen gene (col1a1a, col1a1b, and col1a2) in zebrafish, and its expression promotion rates in col1a1b, col1a2 and elastin were remarkably higher than those of free EA, EA-L, and acetyl hexapeptide-8 as positive control. Conclusively, EA-HA5k-L ameliorated the anti-ageing effectiveness of EA due to the successful transdermal delivery and efficient cellular uptake, and 5 kDa of oligomeric HA-modified liposomes may be a promising transdermal delivery carrier to overcome skin barrier and upgrade the application prospects of EA in anti-skin ageing.