Photodynamic Therapy Initiated Ferrotherapy of Self-Delivery Nanomedicine to Amplify Lipid Peroxidation via GPX4 Inactivation

Abstract

Lipid peroxide (LPO) is the hallmark of ferroptosis, which is a promising antitumor modality for its unique advantages. However, a cellular defense system would weaken the antitumor efficacy of ferrotherapy. Herein, a GPX4 inhibitor of ML162 and a photosensitizer of chlorine e6 (Ce6) are used to prepare the self-delivery nanomedicine (C-ML162) through hydrophobic and electrostatic interactions to enhance ferroptosis by photodynamic therapy (PDT). Specifically, carrier-free C-ML162 improves the solubility, stability, and cellular uptake of antitumor agents. Upon light irradiation, the internalized C-ML162 generates large amounts of reactive oxygen species (ROS) to oxidize cellular unsaturated lipid into LPO. More importantly, C-ML162 can directly inactivate GPX4 to enhance the accumulation of toxic LPO, inducing ferroptotic cell death. Additionally, C-ML162 is capable of accumulating at a tumor site for effective treatment. This self-delivery system to amplify lipid peroxidation via GPX4 inactivation for PDT initiated ferrotherapy might provide an appealing strategy against malignancies.

Nanoparticle-mediated synergistic anticancer effect of ferroptosis and photodynamic therapy: Novel insights and perspectives

“…Zhao et al. used a GPX4 inhibitor (ML162) and a PS (Ce6) to develop self-assembling NPs (C-ML162) via hydrophobic and electrostatic interactions to improve ferroptosis by PDT [157] . Carrier-free C-ML162 NPs enhanced antitumor drug stability, solubility, and cellular uptake.…”

“…Reprinted with permission from Ref. [157] Copyright ©2022 American Chemical Society. (D) Schematic illustration of SC NPs synthesis and potential mechanism of SC NPs for tumor therapy.…”

Advance Progress in Assembly Mechanisms of Carrier-Free Nanodrugs for Cancer Treatment

“…The electrostatic and hydrophobic interactions can efficiently facilitate the assembly of carrier-free nanodrugs in water solution. Zhou and coworkers prepared a carrier-free self-delivery photothermal converter (CypCel) comprised of the photothermal agent Cypate (Cyp) and the anti-inflammatory drug Celecoxib (Cel) [68]. The Cyp and Cel with nonpolar groups could aggregate in aqueous solutions via Hydrophobic interactions.…”

A GPX4-targeted photosensitizer to reverse hypoxia-induced inhibition of ferroptosis for non-small cell lung cancer therapy

“…17,18 However, among the ROS, 1 O 2 , produced by typical type II photosensitizers (e.g. Ce6 and porphyrin), [19][20][21][22][23][24][25][26][27][28][29][30][31] contributes little to LPO formation. Conversely, the radicals (e.g.…”