Development and in vitro evaluation of glycyrrhetinic acid and alpha-lipoic acid co-loaded nanophytosomes: a strategy to mitigate cisplatin-induced hepatocellular damage.

Abstract

Cisplatin (CDDP) remains a cornerstone chemotherapeutic agent; however, its clinical use is limited by dose-dependent systemic toxicities, particularly hepatotoxicity mediated by oxidative stress, mitochondrial dysfunction, and inflammatory signaling. Glycyrrhetinic acid (GA) and α-lipoic acid (ALA) provide complementary hepatoprotective mechanisms. Nevertheless, both compounds suffer from poor aqueous solubility, high crystallinity, and limited bioavailability. To address these biopharmaceutical limitations, a dual-drug nanophytosome (GALP) was engineered using a crystalline-to-amorphous phase transition strategy to enhance dissolution, loading efficiency, and hepatocellular delivery. GALP nanophytosomes were prepared via solvent evaporation using Soy Phospholipid (SPC). The optimized formulation exhibited a mean particle size of 93.3 ± 1.99 nm, a narrow polydispersity index, and a negative zeta potential  -33.7 ± 0.28 mV). X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analyses confirmed the complete elimination of GA and ALA crystalline peaks, demonstrating successful amorphization within the phospholipid matrix. Functionally, pretreatment with GALP significantly reduced CDDP-induced cytotoxicity in an optimized HepG2/LX-2 co-culture model, restoring overall cell viability to approximately 78%, which was statistically superior to the free drug combinations (P < 0.05). The engineered GALP platform addresses the shared biopharmaceutical limitations of GA and ALA, offering a physicochemical profile (sub-100 nm diameter and negative surface charge) well-suited for future in vivo pharmacokinetic and liver distribution studies.