Superoxide Radical Photogenerator with Amplification Effect: Surmounting the Achilles' Heels of Photodynamic Oncotherapy

Strong oxygen dependence, poor tumor targeting, and limited treatment depth have been considered as the Achilles' heels facing the clinical usage of photodynamic therapy (PDT). Different from common approaches, here, we propose an innovative tactic by using photon-initiated dyad cationic superoxide radical (O-2(-center dot)) generator (ENBOS) featuring 0 + 1 > 1 amplification effect to simultaneously overcome these drawbacks. In particular, by taking advantage of the Forster resonance energy transfer theory, the energy donor successfully endows ENBOS with significantly enhanced NIR absorbance and photon utility, which in turn lead to ENBOS more easily activated and generating more O-2(-center dot) in deep tissues, that thus dramatically intensifies the type I PDT against hypoxic deep tumors. Moreover, benefiting from the dyad cationic feature, ENBOS achieves superior structure-inherent targeting abilities with the signal-to-background ratio as high as 25.2 at 48 h post intravenous injection, offering opportunities for accurate imaging-guided tumor treatment. Meanwhile, the intratumoral accumulation and retention performance are also markedly improved (>120 h). On the basis of these unique merits, ENBOS selectively inhibits the deep-seated hypoxic tumor proliferation at a low light-dose irradiation. Therefore, this delicate design may open new horizons and cause a paradigm change for PDT in future cancer therapy.