Near Infrared-Activatable Methylene Blue Polypeptide Codelivery of the NO Prodrug via π-π Stacking for Cascade Reactive Oxygen Species Amplification-Mediated Photodynamic Therapy

The application of photodynamic therapy (PDT) has attracted remarkable interest in cancer treatment because of the advantages of noninvasiveness and spatiotemporal selectivity. However, the PDT efficiency is considerably limited by photosensitizer (PS) quenching and severe hypoxia in solid tumors. Herein, a kind of near infrared (NIR)-activatable methylene blue (MB) peptide nanocarrier was developed for codelivery of nitric oxide (NO) prodrug JSK, expecting a cascade of reactive oxygen species (ROS) amplification-mediated antitumor PDT. In detail, MB was conjugated to water-soluble polyethylene glycol-polylysine (PEG-PLL) through NIR-photocleavable 10-N-carbamoyl bonds, and the subsequent amphiphilic conjugates (mPEG-PLL-MB) selfassembled into nanoparticles (NPs), which allowed JSK codelivery via pi-pi stacking interactions. MB in quenched state in mPEG-PLL-MB/JSK NPs could be photoactivated by NIR light locoregionally in a controlled manner due to the photocleavage of carbamoyl bonds. Apart from ROS production, assembly disturbance and even disintegration of mPEG-PLL-MB/JSK occurred along with MB activation that subsequently freed JSK, which was further triggered by intracellularly overexpressed glutathione (GSH) and glutathione S-transferase (GST) to sustain the release of NO. NO then served as a hypoxia relief agent through inhibition of cellular respiration to economize O-2, cooperating with MB activation and GSH depletion, which synergistically enabled a cascade of ROS amplification to augment PDT for mitochondrial apoptosis-mediated tumor inhibition in vitro and in vivo. Therefore, this pioneering strategy of cascade amplification of ROS addressed the key issues of PS inactivation, hypoxia resistance, and ROS neutralization in a three-pronged approach, which hold great promise in efficient antitumor PDT.

Automated summary

This study developed a near-infrared-activated methylene blue peptide nanocarrier for the co-delivery of JSK, a nitric oxide prodrug, aiming to achieve a cascade of reactive oxygen species amplification-mediated antitumor photodynamic therapy. The nanocarrier self-assembled into nanoparticles and could be photoactivated by NIR light, releasing both methylene blue and nitric oxide. The cascade amplification of reactive oxygen species addressed the key issues of photosensitizer inactivation, hypoxia resistance, and reactive oxygen species neutralization, demonstrating promising potential in efficient antitumor photodynamic therapy.