Structure–Activity Relationships of Cyclodextrin-Included Quercetin and Naringenin and the Protective Effect of the Inclusion Complexes against UVB-Induced Photodamage

Quercetin (Que) and naringenin (Nar) are natural compounds with potent antioxidant and anti-inflammatory activities, showing promise for alleviating ultraviolet B (UVB)-induced skin photoaging. The presence or absence of a C═C bond in the C-ring defines whether the compound is a flavonol or a flavanone. To overcome poor water solubility and low bioavailability of the two flavonoids, we prepared inclusion complexes using β-cyclodextrin (β-CD), hydroxyethyl-β-cyclodextrin (HE-β-CD), and hydroxypropyl-β-CD (HP-β-CD). These complexes leverage the cyclodextrins' hydrophilic exterior and hydrophobic interior to encapsulate Que and Nar, respectively. Through integrated analyses─including molecular docking, phase solubility studies, characterization (UV, Fourier-transform infrared (FT-IR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and NMR), solubility tests, and antioxidant (2,2-diphenyl-1-picrylhydrazyl (DPPH)) assays─we systematically elucidated the structure-activity relationships of these flavonoid-cyclodextrin interactions. The therapeutic potential was further evaluated in a UVB-induced mouse model of skin photoaging. Results confirmed the spontaneous formation of stable 1:1 molar ratio inclusion complexes between the flavonoids and cyclodextrins. The enhancement of complex stability, water solubility, and antioxidant activity consistently followed the order: HP-β-CD > HE-β-CD > β-CD. Owing to Que's conjugated planar structure, it exhibited weaker binding to β-CD than did Nar. However, Que formed more stable complexes with HE-β-CD and HP-β-CD than Nar did. In vivo, the Que/HP-β-CD complex demonstrated superior efficacy, most effectively reducing malondialdehyde (MDA) levels, alleviating epidermal hyperplasia, and increasing collagen fiber content. Furthermore, the inclusion complexes amplified the regulatory effects of Que and Nar on mitogen-activated protein kinase (MAPK) and TGF-β/Smad pathways: they enhanced the downregulation of p-p38 and MMP-1 to inhibit collagen degradation and promoted the upregulation of Smad2/3 and COL1A1 to stimulate collagen synthesis. In conclusion, the β-cyclodextrin inclusion complexes of flavonoids, designed based on structure-activity relationship studies, significantly improve the compounds' solubility, stability, and bioactivity. This leads to enhanced protective efficacy against UVB-induced photodamage through the concurrent modulation of multiple signaling pathways.