Sadek Ahmed, Osama Saher, Rana M. ElBishbishy, Mennatullah M. Ibrahim
Drug-induced liver injury (DILI) represents a critical clinical problem that often necessitates lowering the therapeutic dose or even complete drug withdrawal, ultimately resulting in treatment failure. Curcumin (Cur), a natural polyphenolic compound, demonstrates strong hepatoprotective and antioxidant activity; however, its poor solubility and limited bioavailability hinder its therapeutic use. To overcome these limitations, the present study aimed to develop and optimize curcumin-loaded hyaluronic acid-modified edge-activated spanlastics (Cur-HES) as an efficient delivery system for enhancing the hepatoprotective efficacy of curcumin against carbon tetrachloride (CCl₄)-induced liver damage. Cur-HES were prepared using the ethanol injection method and systematically optimized via a 23 full factorial design, where the independent variables included hyaluronic acid-to-surfactant ratio (X1), edge activator-to-drug ratio (X2), and Span 80 % contribution (X3). Formulations were assessed for entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP). The optimized formulation achieved a desirability value of 0.982, with EE% of 88.4 %, PS of 105.2 nm, PDI of 0.19, and ZP of −20.9 mV. Transmission electron microscopy revealed spherical vesicles. In-vitro release exhibited biphasic Higuchi diffusion kinetics, while stability testing confirmed preservation of physicochemical properties for three months. In-vivo evaluation demonstrated that Cur-HES provided significantly greater hepatoprotection than free Cur in the CCl₄-induced hepatotoxicity model, as evidenced by marked reductions in serum ALT and AST levels. Histopathological examination supported these findings, showing preserved liver architecture in treated groups. Overall, Cur-HES represents a promising nanocarrier platform to boost the hepatoprotective activity of Cur, offering a safe and effective therapeutic strategy against DILI.