Smart Fe(3)O(4)@ZnO Core-Shell Nanophotosensitizers Potential for Combined Chemo and Photodynamic Skin Cancer Therapy Controlled by UVA Radiation

PURPOSE: Photodynamic therapy (PDT) is a non-invasive therapeutic modality that is used for several types of cancer and involves three essential elements (light, photosensitizer (PS), and oxygen). However, clinical PS is limited by the low yield of reactive oxygen species (ROS) and a long retention time. Therefore, developing a low-cost PS that can significantly increase ROS yield in a short time is of utmost importance. METHODS: In this study, brusatol (Bru) was loaded on the surface of ultraviolet A (UVA)-responsive zinc oxide (ZnO)-coated magnetic nanoparticles (Fe(3)O(4)@ZnO-Bru). The PS was well characterized by transmission electron microscopy (TEM), Fourier Transform infrared spectroscopy (FTIR), a superconducting quantum interference device, and dynamic light scattering (DLS). 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and Hoechst staining were used to determine the inhibitory effect of Fe(3)O(4)@ZnO-Bru on squamous cell carcinoma cells (SCC) with or without UVA radiation. Intracellular ROS levels and expression of the Nrf2 signaling pathway were also determined. RESULTS: FTIR showed that Bru was successfully loaded on Fe(3)O(4)@ZnO. Fe(3)O(4)@ZnO-Bru was superparamagnetic, and the zeta potential was 8.86 ± 0.77 mV. The Bru release behavior was controlled by UVA. Fe(3)O(4)@ZnO-Bru with UVA irradiation induced an increase of 48% ROS productivity compared to Fe(3)O(4)@ZnO-Bru without UVA irradiation, resulting in a strong inhibitory effect on SCC. Furthermore, Fe(3)O(4)@ZnO-Bru nanocomposites (Fe(3)O(4)@ZnO-Bru NCs) had nearly no toxic effect on healthy cells without UVA radiation. The released Bru could significantly inhibit the Nrf2 signaling pathway to reduce the activity of scavenging excess ROS in SCC. CONCLUSION: In this study, Fe(3)O(4)@ZnO-Bru was successfully synthesized. PDT was combined with photochemotherapy, which exhibited a higher inhibitory effect on SCC. It can be inferred that Fe(3)O(4)@ZnO-Bru holds great potential for skin SCC therapy.