In Situ NADH-Activated BODIPY-Based Macrocyclic Supramolecular Photosensitizer for Chemo-Photodynamic Synergistic Tumor Therapy

Photodynamic therapy (PDT) based on supramolecular assembly
has
been receiving wide attention due to its great potential application
in clinical treatment. Herein, we report a supramolecular photoelectron
“reservoir” (SPR) constructed by tetracationic boron
dipyrromethene (BODIPY)-based macrocycle (BBox·4Cl),
doxorubicin (Dox), and tumor-targeted β-cyclodextrin-grafted
hyaluronic acid (HACD). Upon irradiation, BBox·4Cl
can in situ catalyze nicotinamide adenine dinucleotide (NADH) to continuously
generate electrons to inject into SPR, which further transfers electrons
to oxygen, inducing highly efficient hydroxyl radical generation even
under hypoxia. Synergistically, Dox in SPR as “pump”
can be encapsulated by BBox·4Cl and transport photoelectrons
between two BODIPY units, while HACD as “sponge” can
enrich BBox·4Cl by the electrostatic interaction
to concentrate them closer in space, which facilitates intramolecular
and intermolecular photoelectron transfer, respectively, and significantly
enhances the generation of hydroxyl radicals. Meanwhile, electron
replenishment in SPR causes NADH depletion and redox dysfunction,
thereby accelerating the apoptosis and achieving highly effective
synergistic tumor therapy.