Secondary Structure in Overcoming Photosensitizers’ Aggregation: α‐Helical Polypeptides for Enhanced Photodynamic Therapy

Aggregation caused quenching (ACQ) effect can severely inhibit the application of hydrophobic photosensitizers (PSs) bearing planar and rigid structures. Most of the reported cases utilized random‐coiled polymers for the in vivo delivery of PSs, which would inevitably aggravate ACQ effect due to the flexible chains. In this work, the role of polymers’ secondary structures (especially α‐helical conformation) in overcoming the PSs’ aggregation is systemically investigated based on the design of α‐helical polypeptides bearing tetraphenylporphyrin (TPP) side chains. Atomistic molecular dynamics simulation, fluorescence quantum yield, and reactive oxygen species (ROS) generation yield are evaluated to demonstrate that α‐helical polypeptide backbones can significantly boost both fluorescence quantum yield and ROS by suppressing the π‐π stacking interaction between TPP units. The enhanced in vitro and in vivo phototoxicity for helical polypeptides also reveal functions of secondary structures in inhibiting ACQ and improving the membrane activity. Successful in vivo photodynamic therapy (PDT) results in mice bearing H22 tumors showed great potentials for further clinical applications. α‐Helical backbones significantly boost both fluorescence quantum yield and reactive oxygen species (ROS) by suppressing the π–π stacking interaction. As a typical cell penetrating material, α‐helical polypeptides can also contribute to the intracellular delivery synergistically. The in vitro and in vivo phototoxicity of PSs located on helical backbones are also enhanced in mice bearing H22 tumors.