Licochalcone A (LicA) is a natural chalcones , well-known for its anti-melanogenic activity, however, its poor solubility leads to a limited topical bioavailability and clinical outcomes. Therefore, LicA-encapsulated glycyrrhiza acid (GA) (GA-LicA) micelles were formulated for higher cellular uptake and improved cutaneous applications. The physicochemical properties (morphology, size and charge), topical penetration, endocytic pathways, cellular uptake amount (CUA) and intracellular distribution of the GA-LicA micelles were studied. Moreover, the anti-melanogenic mechanisms including antioxidant properties, melanogenesis-mediated enzymes and melanin generation as well as cell apoptosis in A375 cells were demonstrated. We found that significant increase amount of LicA was obtained into the epidermis after encapsulated in GA micelles, and the hair follicles were the preferential route for LicA permeation. Moreover, HaCaT and melanocytes possessed a significantly higher effective uptake and CUA for GA-LicA micelles than that of the crude LicA. Caveolae-mediated and actin filaments-mediated endocytosis, caveolae-mediated endocytosis were respectively involved in cellular uptake of GA-LicA micelles for HaCaT cells and melanocytes. Furthermore, GA-LicA micelles possessed a synergistic anti-melanogenic effect by scavenging the free radicals, reducing the activity of α-glucosidase and tyrosinase , and inducing the cell apoptosis. Taken together, GA micelles can enhance the bioavailability and anti-melanogenic effect of LicA, and the article provided principles for rational design of formulations in whitening cosmetics.
Ran Sun,Yuling Chen,Qiang Yang,Wenjun Zhang,Ling Guo,Min Feng
Chemotherapy occupies a prominent position in combination treatments of melanoma . However, the severe systemic side effects and the pro-tumorigenic microenvironment limited its therapeutic efficacy. In the present study, polysaccharide hydrogels (SCOD) were constructed by N-succinyl chitosan and oxidized dextran through Schiff-base formation to deliver doxorubicin (Dox) locally. The gelation time and mechanical properties of SCOD hydrogels could be fine-tuned by varying concentration of precursor solutions. Rheological data revealed that SCOD hydrogels possessed injectable shear-shinning property and remarkable self-healing capability. It also could be degraded by lysozyme widely present in body fluids. Moreover, SCOD hydrogels were readily loaded with Dox in precursor solutions and released drug over 1 week in a pH-dependent manner. The ability of Dox-loaded SCOD hydrogels to inhibit the growth of murine B16 and human A375 melanoma was verified by in vitro assays. Strikingly, Dox-loaded SCOD hydrogels were found to efficiently induce polarization of tumor-associated macrophages towards M1 phenotype that favors an anti-tumorigenic tumor microenvironment . Notably, in vivo experiments demonstrated that locally injected Dox-loaded SCOD hydrogels exhibited excellent anti-tumor activity against B16 melanoma , outperforming Dox at equivalent doses administrated intravenously. Therefore, the injectable and self-healing polysaccharide hydrogels are a promising strategy to improve locoregional control in melanoma.
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