Combining Two-Photon-Activated Fluorescence Resonance Energy Transfer and Near-Infrared Photothermal Effect of Unimolecular Micelles for Enhanced Photodynamic Therapy

Recent years have witnessed significant progress in the field of two-photon-activated photodynamic therapy (2P-PDT). However, the traditional photosensitizer (PS)-based 2P-PDT remains a critical challenge in clinics due to its low two-photon absorption (2PA) cross sections. Here, we propose that the therapeutic activity of current PSs can be enhanced through a combination of two-photon excited fluorescence resonance energy transfer (FRET) strategy and photothermal effect of near-infrared (NIR) light. A core-shell unimolecular micelle with a large two-photon-absorbing conjugated polymer core and thermoresponsive shell was constructed as a high two-photon light-harvesting material. After PSs were grafted onto the surface of a unimolecular micelle, the FRET process from the conjugated core to PSs could be readily switched "on" to kill cancer by the collapsed thermoresponsive shell due to the photothermal effect of NIR light. Such NIR-triggered FRET leads to an enhanced 2PA activity of the traditional PSs and, in turn, amplifies their cytotoxic singlet oxygen generation. Eventually, both in vitro and in vivo PDT efficiencies treated with the thermoresponsive micelles were dramatically enhanced under NIR light irradiation, as compared to pure PSs excited by traditional visible light. Such a facile and simple methodology for the enhancement of the photodynamic antitumor effect holds great promises for cancer therapy with further development.