Reduction-Responsive Nanoparticles Self-Assembled from Sericin-ss-Doxorubicin Conjugate for Hydrophobic IR780 Delivery with Integration of Antitumor Chemo-Phototherapy

Background Stimuli-responsive polymer-drug nanoparticles have emerged as a versatile and effective platform for delivering drugs in the treatment of malignant tumors. The integration of chemo-phototherapy has gained increasing prominence due to its remarkable synergistic antitumor effects.Methods Hydrophilic sericin (Ser) was linked to antitumor drug doxorubicin (DOX) via a disulfide bond. The obtained Ser-ss-DOX conjugate was characterized by Fourier-transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (1H NMR) and dynamic light scattering (DLS). The near-infrared (NIR) fluorescent dye IR780 was encapsulated into Ser-ss-DOX by a dialysis method. The physical state of IR780 within Ser-ss-DOX/IR780 nanoparticles was analyzed by differential scanning calorimetry (DSC). The photothermal properties and drug release behavior of IR780-loaded nanoparticles were systematically investigated. Cellular uptake and reactive oxygen species (ROS) generation capacity and in vitro cytotoxicity of IR780-containing nanoparticles were studied in 4T1 breast cancer cells. In addition, 3D multicellular tumor spheroid model was conducted to investigate the antitumor activity of the nanoparticles.Results The Ser-ss-DOX conjugate was successfully synthesized. Ser-ss-DOX and Ser-ss-DOX/IR780 nanoparticles were spherical in shape, and their particle sizes measured by DLS were 326 and 190 nm, respectively. IR780 was in an amorphous state within the Ser-ss-DOX/IR780 nanoparticles. The loading contents of DOX and IR780 were 8.26% and 2.78%, respectively. Ser-ss-DOX/IR780 exhibited ideal photothermal properties in vitro and reduction-sensitive drug release in a high glutathione (GSH) environment. Ser-ss-DOX/IR780 displayed higher cellular uptake in 4T1 cells than Ser-ss-DOX and free DOX. Under 808 nm laser irradiation, Ser-ss-DOX/IR780 showed a strong capacity to generate ROS. Importantly, Ser-ss-DOX/IR780 with laser irradiation effectively inhibited the growth of 4T1 cells and 3D multicellular tumor spheroids.Conclusion This work demonstrated that Ser-ss-DOX/IR780 integrated dual functionalities of chemotherapy and phototherapy, thereby enabling substantial potential for application in tumor treatment.