Transferrin-Mediated Nanophotosensitizer to Enhance Phototherapy with Photoacoustic Imaging Under Hypoxia

Various obstacles [poor tissue penetration, hypoxic tumor microenvironment, and reactive oxygen species (ROS) production quenching due to aggregation] obstruct imaging-guided high-efficiency phototherapy targeting tumors. Herein, nanophthalocyanine (ZnPcN4-TF) is elaborately designed based on a synthetic phthalocyanine derivative (ZnPcN4) and nonimmunogenic transferrin (TF) through multiple noncovalent interactions for photoacoustic (PA) imaging-guided phototherapy. By conjugating electron-rich amino groups effectively suppressed fluorescence and ROS generation due to the strong photoinduced electron transfer effect, ZnPcN4 became an ideal photothermal and PA imaging agent. ZnPcN4-TF not only effectively targeted tumor sites and accumulated there, but also, surprisingly, facilitated the enhancement of ROS production via a type I process in an aggregate compared to ZnPcN4 itself, potentially due to accelerated electron transfer. Simultaneously, ZnPcN4-TF had a substantially more powerful photothermal effect than ZnPcN4 itself. Thus, this design effectively overcomes the obstacles to photodynamic therapy (aggregation-related ROS generation quenching in a hypoxic environment). Furthermore, PA imaging solves the tissue penetration challenge in optical imaging. This study provides a broader base for designing novel photosensitizers to improve phototherapy under hypoxia.(Formula