Pegylated curcumin for cigarette smoke induced oxidative stress: From nasal epithelial cells to fast dissolving microneedle patches.

Oxidative stress induced by inhaled oxidants, particularly cigarette smoke, contributes to the development of several acute and chronic respiratory diseases through oxidative damage and epigenetic alterations. Curcumin (CUR), a well-characterized natural polyphenol with potent antioxidant and anti-inflammatory properties, is considered a promising agent for modulating oxidative stress-related signaling pathways and epigenetic mechanisms; however, its poor aqueous solubility and bioavailability limit its clinical application. Therefore, in the present study, PEGylated curcumin (PEG-CUR) was investigated as a modified CUR formulation for subsequent incorporation into a dissolving microneedle-based intranasal delivery system. Exposure to cigarette smoke resulted in significant alterations in the expression of oxidative stress-related genes (SEPP1, NCF2, SFTPD, CCL5, and PTGS1) in nasal epithelial cells. However, pretreatment with curcumin (CUR) and polyethylene glycol-curcumin (PEG-CUR) mitigated these gene expression changes. Both treatments also reduced global DNA methylation, with PEG-CUR showing a more pronounced effect than CUR. Following the demonstration of the beneficial effects of PEG-CUR, we developed PEG-CUR-loaded dissolving microneedle patches (PEG-CUR-DMNPs) as a localized intranasal delivery platform designed to facilitate PEG-CUR delivery through rapid dissolution of the microneedle tips. The mechanical robustness and penetration capability of the patches were initially evaluated using Parafilm® and ex vivo rat dorsal skin models. To further confirm their appropriateness for intranasal use, PEG-CUR-DMNPs were subsequently tested on ex vivo sheep nasal mucosa to evaluate microneedle penetration and dissolution kinetics. Overall, these results indicate that PEG-CUR-DMNPs represent a promising approach for localized intranasal drug delivery targeting oxidative stress-related respiratory diseases.