Dually fluorinated unimolecular micelles for stable oxygen-carrying and enhanced photosensitive efficiency to boost photodynamic therapy against hypoxic tumors.

Tumor hypoxia is one of key challenges in deep tumor photodynamic therapy (PDT), and how to fix this issue is attracting ongoing concerns worldwide. This work demonstrates dually fluorinated unimolecular micelles with desirable and stable oxygen-carrying capacity, high cellular penetration, and integrative type I & II PDT for deep hypoxic tumors. Dually fluorinated star copolymers with fluorinated phthalocyanines as the core are prepared through photoinitiated electron/energy transfer-reversible addition-fragmentation chain transfer (PET-RAFT) polymerization under irradiation with NIR LED light at room temperature, followed by assembly into unimolecular micelles. Perfluorocarbons (PFCs) are also introduced into the star polymers during the polymerization to further enhance and stabilize oxygen-carrying capacity, which is slightly affected by concentration-induced size transformation. PFCs assist unimolecular micelles with repelling mucin adsorption, which results in superior cellular uptake within 1 h and high effective accumulation rates in tumors of CT26 tumor-bearing mice within 24 h after systemic administration, and showing effective anti-tumor effects under the irradiation of NIR LED light. This work provides a new type of nano-photosensitizers for highly efficient hypoxic PDT. STATEMENT OF SIGNIFICANCE: One of the major challenges in improving the efficiency of photodynamic therapy (PDT) for deep tumors is how to address tumor hypoxia, which is receiving continued attention worldwide. However, most of the reported oxygen carriers combine with photosensitizers by physical means and the carriers have the risk of dissociating easily, which is not conducive to long-term and efficient PDT, resulting in poor therapeutic effect. This work demonstrates dually fluorinated unimolecular micelles with desirable and stable oxygen-carrying capacity, high cellular penetration, and integrative type I & II PDT for enhanced deep hypoxic tumors, overcoming the key challenges of tumor hypoxia and low photosensitizer efficiency.