Efficient hydroxyl radical generation of an activatable phthalocyanine photosensitizer: oligomer higher than monomer and nanoaggregate.

It remains a challenge to develop a single-component organic photosensitizer that efficiently produces hydroxyl radicals (˙OH) without oxygen involvement, especially while maintaining tumor-targeting capability. Herein, we propose an intelligent molecular design strategy whereby a tumor-targeted phthalocyanine is initially ˙OH-free and can be activated by overexpressed β-nicotinamide adenine dinucleotide sodium salt hydrate (NAD(P)H) in hypoxic tumors to efficiently produce ˙OH under light irradiation. Furthermore, the oligomer models based on the phthalocyanine molecules were constructed by a supramolecular regulation strategy, which were in an intermediate state between monomer and nanoaggregate, to achieve enhanced ˙OH generation. The level of NAD(P)H in cancer cells can be exhausted through two pathways, including spontaneous redox and the photocatalytic redox of phthalocyanines. As a result, the in vivo and in vitro assays illustrated that the oligomeric phthalocyanine containing N-O units (OligPcNOB) can specifically target cancer cells and tumor tissue with overexpressing biotin receptors. OligPcNOB exhibited significant photocytotoxicity even in an extremely low oxygen environment and successfully inhibited tumor progression.