Boosting O₂^•− Photogeneration via Promoting Intersystem-Crossing and Electron-Donating Efficiency of Aza-BODIPY-Based Nanoplatforms for Hypoxic-Tumor Photodynamic Therapy

Tumor hypoxia severely impedes the therapeutic efficacy of type II photodynamic therapy (PDT) depending on singlet oxygen (¹O₂) generation. To combat hypoxic tumors, herein, a new approach is devised to boost superoxide radical (O₂^•−) photogeneration for type I PDT. Heavy atoms are introduced onto aza-BODIPY molecules (iodine substituted butoxy-aza-BODIPY, IBAB) to promote their intersystem-crossing (ISC) ability. Meanwhile, methoxy-poly(ethylene glycol)-b-poly(2-(diisopropylamino) ethyl methacrylate) (mPEG-PPDA) with enhanced electron-donating efficiency is employed as a coating matrix to encapsulate IBAB, thereby obtaining amphiphilic aza-BODIPY nanoplatforms (PPIAB NPs). Under irradiation, triplet-state IBAB in PPIAB NPs is efficiently generated from singlet state favored by the elevated ISC ability. The electron-rich environment provided by mPEG-PPDA can donate triplet-state IBAB with one electron to form charge-separated-state IBAB, which in turn transfers electron to O₂ for O₂^•− production. Significantly, owing to recyclable O₂ generated by disproportionation or Harber–Weiss/Fenton reaction, prominent O₂^•− is generated by PPIAB NPs even in a severe hypoxic environment (2% O₂), enabling superior therapeutic efficacy (96.2% tumor-inhibition rate) over NPs not following this strategy. Thus, the proof-of-concept design of ISC-enhanced and electron-rich polymer encapsulating PPIAB NPs illuminates the path to preparing O₂^•− photogenerator for hypoxic cancer treatment.