Redox/photo dual-responsive, self-targeted, and photosensitizer-laden bismuth sulfide nanourchins for combination therapy in cancer

Abstract

Targeted and stimuli-sensitive nanobombs for the release of therapeutic agents after laser irradiation of the tumor site are gaining widespread attention as personalized anticancer regimens. In this study, redox and photo dual-responsive, folate receptor-targeted nanourchin carriers for chemo-, photodynamic, and photothermal therapy were constructed by the amalgamation of an outer layer of polyethylene glycol (PEG)-S-S-methotrexate (MTX) and an inner core of indocyanine green (ICG)-loaded bismuth sulfide (Bi₂S₃) nanoparticles for cancer treatment. MTX introduces the carrier to folate receptors resulting in the internalization of nanoparticles into cancer cells, specifically and increasingly. In the reducing environment inside cancer cells, MTX was cleaved, resulting in a burst release that effectively inhibited tumor growth. Simultaneously, the fusion of Bi₂S₃ and ICG in the inner core absorbed energy from a near-infrared radiation (NIR) laser to generate heat and reactive oxygen species, which further ablated the tumors and synergistically enhanced the anticancer activity of MTX. These results indicate the successful preparation of combined nanourchins (NUs) showing GSH-induced and laser-responsive release of MTX and ICG, accompanied by hyperthermia via Bi₂S₃ and ICG. Effective in vitro cellular internalization, cellular cytotoxicity, and pro-apoptotic behavior of the nanosystem were achieved through a targeting, redox, and NIR-responsive combination strategy. In vivo biodistribution and photothermal imaging also revealed tumor-selective and -retentive, as well as thermally responsive attributes. Ultimately, this in vivo antitumor study shows an effective tumor ablation by these nanourchins without affecting the vital organs. Our findings indicate that using these targeted redox- and laser-responsive combination therapeutic carriers can be a promising strategy in folate receptor-expressing tumors.