Nanosecond Laser Pulses Facilitating Efficient and Specific Cell Killing with Doxorubicin‐Loaded Gold Nanoparticles Targeted to the Folate Receptor

Nanoparticle-based drug carrier systems with active targeting and a controlled release capacity are of considerable interest to bypass side effects of conventional chemotherapy. One appealing approach involves chemotherapeutic-loaded photothermal nanoparticles, where laser irradiation can release the loaded anticancer drug while also inducing local cytotoxicity through photothermal effects. This study investigates the potential of using nanosecond-pulsed laser light for efficient and specific killing of folate receptor (FR)-overexpressing cancer cells in combination with FR-targeted doxorubicin-loaded gold nanoparticles (AuNPs). Nanosecond pulsed laser irradiation allows the induction of mechanical forces alongside thermal effects. The effect of nanoparticle concentrations and laser fluences on cytotoxicity is systematically tested, achieving near-complete tumor cell killing under the most stringent conditions. FR targeting is confirmed using FR-positive and -negative cell lines, showing that folic acid functionalization of AuNPs results in more favorable nanoparticle-cell interactions and more efficient photothermal effects. Additionally, doxorubicin could be efficiently released from the AuNPs and endosomal compartments upon laser irradiation, adding to the observed cytotoxicity. Cell killing was precisely confined to irradiated cells, leaving surrounding cells unharmed. Overall, the significant reduction of tumor cell viability following the proposed combination demonstrates this approach to be a promising step toward safer, more effective anticancer therapies.