Three-in-One Self-Assembled Nanocarrier for Dual-Drug Delivery, Two-Photon Imaging, and Chemo-Photodynamic Synergistic Therapy

We herein present a three-in-one nanoplatform (named Fu/[email protected]) for dual-drug delivery, two-photon imaging, and chemo-photodynamic synergistic therapy, enabled by simple self-assembly between adamantine-functionalized ruthenium complexes ([Ru(phen-ad)3](PF6)2, Ru) and natural cyclodextrin (β-CD) monomers. By host–guest chemistry, nanocarrier RuCD 70–90 nm in diameter is fabricated through a very simple mixing step in water at room temperature, in which the octahedral configuration of Ru complex provides a rigid skeleton and the hydrogen bonding of secondary hydroxyl groups formed between two adjacent β-CD monomers displays a bridging role allowing for three-dimensional architectures. The dual-drug-loaded nanoparticle Fu/[email protected] (Fu: 5-fluorouracil; LD: lonidamine) effectively penetrates into cancer cells in 8 h and selectively accumulates in lysosomes, in which dual-drug release is promoted by the mildly acidic environment. Under visible light irradiation, nanocarrier RuCD exhibits excellent photodynamic therapy capability by producing sufficient reactive oxygen species and damaging lysosomes, accordingly 5-fluorouracil and lonidamine can escape from lysosomes and reach their sites of action, resulting in mitochondria dysfunction and cancer cell apoptosis. Simultaneously, the excellent photophysical properties of the nanocarrier enable the facile track of drug delivery under one-photon and two-photon excitation. Moreover, in vivo anticancer investigations show that Fu/[email protected] can effectively inhibit the tumor growth without systemic side effects by chemo-photodynamic synergistic therapy, and the therapeutic effect is better than the free anticancer drugs and the sole therapeutic modality