Bespoke doxorubicin-loaded gold nanoparticles for ultrasound-guided cancer cell killing

Both doxorubicin and gold nanoparticles (GNPs) exhibit sonosensitising properties, significantly increasing the production of cytotoxic reactive oxygen species (ROS) when exposed to ultrasound (US). Ultrasound-responsive, targeted GNPs decorated with a pH-releasable doxorubicin prodrug (FDGNPs) have been developed to exploit this synergistic effect, enabling highly selective and effective anticancer activity. The GNPs were produced using the Turkevich method and functionalised with folate-PEG_{3.5 kDa}-SH as the targeting agent (FGNPs). These were then decorated with doxorubicin derivatised with lipoic acid via a pH-sensitive linker and stabilised with a mPEG_{2 kDa}-SH coating. The FDGNPs' cell targeting, uptake and anticancer effects were evaluated in an epidermoid carcinoma cell line expressing a high level of folate receptor (KB-hFR), which was cultured as monolayers and three-dimensional spheroids. The anticancer effects of the US-exposed FDGNPs were evaluated in terms of cell viability, ROS production and cell death. FDGNPs selectively associated to KB cells in a folate-dependent manner. Ultrasound-exposed FDGNPs resulted in a significant decrease in KB-hFR cell viability of up to 70 %, increased ROS of up to 50 %, and increased necrotic cells of up to 45 %, compared to untreated cells. Furthermore, switching from a custom-built US device to a standardised US scanning device confirmed that US exposure effectively elicits the anticancer activity of FDGNPs in KB-hFR spheroids, resulting in a 45 % decrease in cell viability. GNPs have been engineered to provide active targeting and controlled drug release while exploiting their sonosensitising properties; therefore, this platform shows promise in improving the selectivity and efficacy of cancer therapy.