Optimizing Gold Nanoparticles for Combination Therapy: Development of Hydrophobic Nanomedical Devices with Gemcitabine and Ascorbyl Palmitate

Abstract Breast cancer remains a significant global health challenge, often treated with gemcitabine hydrochloride (GEM). However, GEM's short half-life and poor sustained release can lead to severe side effects, including myelosuppression and nephrotoxicity. This study presents a novel nano-drug delivery system using gold nanoparticles (AuNPs) optimized with ascorbyl palmitate (AsP) to enhance GEM stability and efficacy. AuNPs were modified via single-phase emulsification to form a nanoemulsion coated with a hydrophobic AsP layer, improving tumor targeting through the enhanced permeability and retention (EPR) effect. Two formulations were developed: Au-GEM-AsP-COV (prodrug, 128.5 nm, -18.3 mV, 89.5% encapsulation efficiency) and Au-GEM-AsP-Phys (106 nm, -15.9 mV, 87% encapsulation efficiency). The Au-GEM-AsP-COV formulation demonstrated superior hydrophobicity, sustained release, and enhanced cytotoxicity (IC50 of 0.44 µg/mL) in the 4T1 cell line, significantly outperforming free GEM and modified Au-GEM formulations. Notably, it exhibited six months of accelerated stability, attributed to amide bond formation in the functionalized AuNP matrix. The study highlights the synergistic effects of AsP in enhancing the therapeutic efficacy of Au-GEM-based formulations, supporting its role as a key component in combination therapy. This research lays the foundation for future development of hydrophobic nanomedical devices combining GEM and AsP for therapeutic and diagnostic applications in nanomedicine.