A quality-by-design approach for optimizing the functionalization of gold nanoparticles onto the surface of doxorubicin-encapsulated liposomes

Stimulus-responsive liposomes (L) are increasingly recognized for their potential in enhancing therapies, especially in cancer nanomedicine, owing to their ability to encapsulate drugs of diverse properties efficiently. In this study, a quality-by-design (QbD) strategy was proposed to optimize the surface functionalization of gold nanoparticles (AuNPs) on doxorubicin (Dox)-loaded L intended for improving cancer treatment. Thin-film hydration and pH-gradient methods were applied for L preparation and Dox loading, respectively. Through a Taguchi design (L9), the AuNPs surface functionalization was optimized by studying variables such as L-Dox:AuNPs ratio, stirring time, temperature, and post-functionalization period, and their impact on various L properties including size, polydispersity, and loading efficiency. This approach allowed thedevelopment of an AuNPs-L-Dox nanoplatform capable of controlled Dox release under bio-relevant conditions and dual pH/photothermal responsiveness for triggering drug release. Upon light irradiation, the nanoplatform exhibited enhanced anticancer efficacy against ovarian cancer cells, showcasing its potential for photothermal hyperthermia therapies. Biocompatibility assessment in absence of irradiation against keratinocytes confirmed safety without increased drug cytotoxicity. This study underscores the effectiveness of the QbD approach in optimizing key parameters for the functionalization of L-Dox with AuNPs, highlighting the potential of this nanoplatform for triggered Dox delivery in cancer nanomedicine, particularly in photothermal hyperthermia therapies.