Hydrophobicity-tuned oleic acid-functionalized chitosan nanoparticles for sustained ocular delivery of dapagliflozin in diabetic cataract

Chitosan-based biological macromolecules provide a versatile platform for ocular drug delivery, but their hydrophilic nature limits the encapsulation and sustained release of hydrophobic therapeutics. Here, we designed oleic acid-functionalized chitosan nanoparticles (OA-CS NPs) with tunable hydrophobicity by varying the degree of substitution (DS) of oleic acid from 8% to 19% to regulate the encapsulation and release of dapagliflozin (Dapa), a hydrophobic sodium-glucose cotransporter 2 inhibitor with therapeutic potential for diabetic cataract. The optimized formulation exhibited high drug loading, nanoscale particle size, a positive surface charge, and sustained release under aqueous conditions. In a streptozotocin-induced diabetic rat model, topical administration of Dapa-OA 19 -CS NPs in the NP group was initiated at week 6 and significantly delayed cataract progression and preserved lens transparency during the active treatment period from weeks 6 to 12. The Combo group showed the strongest overall effect; however, because systemic pharmacokinetic profiles following topical administration were not evaluated, an additive systemic contribution from topically administered Dapa could not be excluded. At the molecular level, treatment with the Dapa-OA 19 -CS NP formulation was associated with reduced SGLT2 and receptor for advanced glycation end products (RAGE) signaling and reduced Rac1-GTP activation, accompanied by attenuation of oxidative stress-related changes and inhibition of epithelial-mesenchymal transition. Because a blank OA-CS NP control was not included, these molecular effects should be interpreted as formulation-level effects rather than being attributed exclusively to Dapa. Overall, these findings demonstrate that hydrophobicity-tuned OA-CS NPs provide a practical macromolecular platform for hydrophobic drug loading, controlled release, and ocular delivery.

Abstract from PubMed (PMID 42963024). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.