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 a-helical conformation) in overcoming the PSs' aggregation is systemically investigated based on the design of a-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 a-helical polypeptide backbones can significantly boost both fluorescence quantum yield and ROS by suppressing the p-p stacking interaction between TPP units. The enhanced in vitro and in vivo phototoxicity for helical polypeptides also revealed 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.

Automated summary

Aggregation caused quenching (ACQ) effect hinders the application of hydrophobic PSs with planar and rigid structures. Random-coiled polymers exacerbate the ACQ effect, thus a-helical polypeptides with tetraphenylporphyrin (TPP) side chains are designed to overcome PSs' aggregation. Molecular dynamics simulation, fluorescence quantum yield, and ROS generation yield demonstrate that a-helical polypeptide backbones significantly improve fluorescence quantum yield and ROS by suppressing p-p stacking interaction. Enhanced in vitro and in vivo phototoxicity and successful in vivo PDT in mice bearing H22 tumors show potential for clinical applications.