Controllable Singlet Oxygen Generation in Water Based on Cyclodextrin Secondary Assembly for Targeted Photodynamic Therapy.

The construction of supramolecular assembly whose singlet oxygen (1O2) generation capability can be controllably regulated in water still remains challenging. Herein, a novel cyclodextrin secondary assembly was fabricated from the photochromic-switch moiety diarylethene-bridged dicyclodextrin, the adamantane-polypyridyl ruthenium photosensitizer, and the cancer-cell-targeting ligand β-cyclodextrin-grafted hyaluronic acid, which not only possessed cancer-cell-targeting ability but also served as cell imaging and photodynamic therapy agents with noninvasive controllability. In virtue of the multivalent interactions between the three components, they could self-assemble in two stages to form uniform spherical nanoparticles (OF-NPs) with average diameters of about 80 nm, as indicated by scanning electron microscopy, high-resolution transmission electron microscopy, atomic force microscopy, and dynamic light scattering. Significantly, the prepared OF-NPs exhibited excellent photochromic performance and can transform into their ring-closed form (CF-NPs), accompanied by the efficient energy transfer from donor 2 to CF-1 and gradual quenching of 1O2 generation. Cellular imaging experiments showed that OF-NPs could specifically target the mitochondria of A549 cancer cells, while CF-NPs displayed a negligible red fluorescence signal in A549 cells due to the energy-transfer process. Furthermore, in vitro cytotoxicity tests revealed that upon irradiation with 450 nm light, OF-NPs with 10 μM concentration displayed a remarkable higher cytotoxicity with the cell death rate of up to 88% toward A549 cancer cells, which was approximately 4.4 times higher than that of CF-NPs. Additionally, the apoptosis rate of A549 cells induced by OF-NPs under light irradiation was 4.68 times higher than that of CF-NPs. These well-designed cyclodextrin secondary assemblies successfully achieve noninvasive control over the generation of 1O2 both in water and in cancer cells by irradiation at distinct wavelengths and are further applied in targeted PDT, which avoid the inadvertent photosensitizer activation and provide a new approach for cancer therapy with more safety and high efficiency.