Cell-Specific and pH-Activatable Rubyrin-Loaded Nanoparticles for Highly Selective Near-Infrared Photodynamic Therapy against Cancer

Abstract

Spatiotemporal control of singlet oxygen (¹O₂) release is a major challenge for photodynamic therapy (PDT) against cancer with high therapeutic efficacy and minimum side effects. Here a selenium-rubyrin (NMe₂Se₄N₂)-loaded nanoparticle functionalized with folate (FA) was designed and synthesized as an acidic pH-activatable targeted photosensitizer. The nanoparticles could specifically recognize cancer cells via the FA-FA receptor binding and were selectively taken up by cancer cells via receptor-mediated endocytosis to enter lysosomes, in which NMe₂Se₄N₂ was activated to produce ¹O₂. The pH-controllable release of ¹O₂ specially damaged the lysosomes and thus killed cancer cells in a lysosome-associated pathway. The introduction of selenium into the rubyrin core enhanced the ¹O₂ generation efficiency due to the heavy atom effect, and the substitution of dimethylaminophenyl moiety at <i>meso</i>-position led to the pH-controllable activation of NMe₂Se₄N₂. Under near-infrared (NIR) irradiation, NMe₂Se₄N₂ possessed high singlet oxygen quantum yield (Φ_Δ) at an acidic pH (Φ_Δ = 0.69 at pH 5.0 at 635 nm) and could be deactivated at physiological pH (Φ_Δ = 0.06 at pH 7.4 at 635 nm). The subcellular location-confined pH-activatable photosensitization at NIR region and the cancer cell-targeting feature led to excellent capability to selectively kill cancer cells and prevent the damage to normal cells, which greatly lowered the side effects. Through intravenous injection of FA-NMe₂Se₄N₂ nanoparticles in tumor-bearing mice, tumor elimination was observed after NIR irradiation. This work presents a new paradigm for specific PDT against cancer and provides a new avenue for preparation of highly efficient photosensitizers