Constructing Heavy-Atom-Free Photosensitizers for Hypoxic Tumor Phototherapy Based on Donor-Excited Photoinduced Electron-Transfer-Driven Type-I and Type-II Mechanisms.

The spin-orbit charge transfer intersystem crossing (SOCT-ISC) photophysical process has shown great potential for constructing heavy-atom-free photosensitizers (PSs) for photodynamic therapy (PDT) of tumors. However, for almost all such PSs reported to date, the SOCT-ISC is driven by the acceptor-excited photoinduced electron transfer (-PeT). In this work, for the first time the donor-excited photoinduced electron transfer (-PeT)-driven SOCT-ISC mechanism is utilized to construct the heavy-atom-free PSs for PDT of tumors by directly installing the electron-deficient -alkylquinolinium unit (as an electron acceptor) into the -position of the near-infrared (NIR) distyryl Bodipy chromophore (as an electron donor). In the less polar environment, the PSs exist as the monomer and promote the production of singlet oxygen (O) (Type-II) relying on the -PeT-driven population of the triplet excited state via SOCT-ISC, whereas in the aqueous environment, they exist as nanoaggregates and induce the generation of superoxides (O) and hydroxyl radicals (HO) (Type-I) via the -PeT-driven formation of the delocalized charge-separated state. The PSs could rapidly be internalized into cancer cells and induce the simultaneous production of intracellular O, O, and HO upon NIR light irradiation, endowing the PSs with superb photocytotoxicity with IC values up to submicromolar levels whether under normoxia or under hypoxia. Based on the PSs platform, a tumor-targetable PS is developed, and its abilities in killing cancer cells and in ablating tumors without damage to normal cells/tissues under NIR light irradiation are verified and . The study expands the design scope of PSs by introducing the -PeT conception, thus being highly valuable for achieving novel PSs in the realm of tumor PDT.