Shuttle-like nanoassemblies by isomeric photosensitizers to enhance ROS generation and tumor penetration for photodynamic therapy

Photosensitizers with high reactive oxygen species (ROS) generation and good tumor targeting and penetration are urgently needed for photodynamic therapy (PDT), but it is still challenging when preparing organic aggregates to achieve all these goals simultaneously. In particular, nanoaggregates assembled by isomeric photosensitizers but in different shapes have not been reported yet. Therefore, isomeric photosensitizers of DTPA-2,5-BT-P and DTPA-5,2-BT-P are developed, where an efficient intermolecular interaction can be obtained in DTPA-2,5-BT-P but an intramolecular interaction occurs in DTPA-5,2-BT-P. This results in the formation of crystalline nanoshuttles (NSs) for DTPA-2,5-BT-P but amorphous nanospheres (NPs) for DTPA-5,2-BT-P. Notably, higher ROS generation occurs in DTPA-2,5-BT-P NSs than in DTPA-5,2-BT-P NPs. Moreover, faster cellular internalization and better tumor targeting and penetration can be achieved in DTPA-2,5-BT-P NSs, leading to efficient PDT in vivo with an inhibition rate of 81%. This demonstrates that closely packed DTPA-2,5-BT-P NSs can be promising photosensitizers for high-performance PDT in cancer therapy.