Cross-Linked Thiolated Hydroxypropil-β-Cyclodextrin for Pulmonary Drug Delivery

Inhalable formulations with cyclodextrins (CDs) as solubility and absorption enhancers show promise for pulmonary delivery. Thiolated hydroxypropyl-β-cyclodextrin (HP-β-CD-SH) has mucoadhesive properties, enhancing drug absorption. Moreover, it has self-aggregation capability, which could further improve absorption and drug stability, as well as reduce irritation. This study aims to stabilize CD nanoaggregates using bifunctional cross-linkers and evaluate their benefits for lung drug delivery compared to pristine HP-β-CD-SH. Methods: The effectiveness of cross-linked HP-β-CD-SH nanoparticles (HP-β-CD-SH-NP) was compared to transient nanoaggregates in enhancing the activity of dexamethasone (DMS) and olive leaf extracts (OLE). DMS, a poorly soluble drug commonly used in lung treatments, and OLE, known for its antioxidant properties, were chosen. Drug-loaded HP-β-CD-SH-NP were prepared and nebulized onto a lung epithelial Air–Liquid Interface (ALI) model, assessing drug permeation and activity. Results: HP-β-CD-SH with 25% thiolation was synthesized via microwave reaction, forming 150 nm nanoaggregates and stabilized 400 nm HP-β-CD-SH-NP. All carriers showed good complexing ability with DMS and OLE and were biocompatible in the lung ALI model. HP-β-CD-SH promoted DMS absorption, while stabilized HP-β-CD-SH-NP protected against oxidative stress. Conclusion: HP-β-CD-SH is promising for lung delivery, especially as stabilized nanoaggregates, offering versatile administration for labile molecules like natural extracts.