Near Infrared‐Activatable Platinum‐Decorated Gold Nanostars for Synergistic Photothermal/Ferroptotic Therapy in Combating Cancer Drug Resistance

Abstract

Ferroptotic cell death results from glutathione peroxidase 4 (GPX4) inactivation and/or glutathione (GSH) depletion. Elevated GSH levels are often found in multidrug‐resistant (MDR) tumor cells, reducing their sensitivity to chemotherapeutic drugs and the efficacy of treatment. MDR cells also acquire a dependency on GPX4, reducing their oxidative stress and promoting their survival. Therefore, the depletion of GSH and inactivation of GPX4 has the potential to be a superior treatment strategy for MDR tumors. Platinum‐decorated gold nanostars (Pt‐AuNS) are presented as a novel metal nanoprodrug for ferroptotic therapy against MDR tumors. Under dark conditions, the synthesized Pt‐AuNS exhibit negligible levels of toxicity. Upon exposure of the Pt‐AuNS to near‐infrared (NIR) light, active metallic (Pt and Au) species are released, subsequently inducing cytotoxicity. The mechanism of action is attributed to GSH depletion and GPX4 inactivation, accumulating lipid hydroperoxides, which in turn leads to ferroptosis. In in vivo xenograft, the MDR cancer model confirmed the NIR light‐activation of Pt‐AuNS prodrugs, resulting in efficient ferroptotic therapeutic action against MDR tumors without long‐term side effects. The findings lay the groundwork for using Pt‐AuNS prodrugs responsive to NIR light as ferroptosis‐inducing agents in chemo‐resistant cancer cells and demonstrate their potential for use in future clinical applications.

Gold nanostar‐based complexes applied for cancer theranostics

“…83 Various AuNS-based nanohybrids have been developed for combination tumor therapy with formidable antitumor capabilities. 32,40,[84][85][86][87] For instance, Montoto et al 30 developed an NIR-stimulated F I G U R E 4 Schematic overview of the AuNS-based core-shell nanohybrids for dual-modal SERRS/MSOT imaging of GBM. Reproduced with permission, 80 Copyright 2018, Wiley-VCH AuNSs@mSiO 2 @DOX@paraffin nanohybrid for combination of PTT and chemotherapy of HeLa cells in vitro.…”

Recent Progress of Novel Nanotechnology Challenging the Multidrug Resistance of Cancer

“…At the same time, the influence of physiological properties of the tumor cell internal and external environment on MDR cannot be ignored. By enhancing the level of reactive oxygen species (ROS) or reducing the level of ATP by targeting mitochondria, NDDSs can effectively inhibit the expression of P-gp, reverse multidrug resistance, and significantly increase the concentration of intracellular chemotherapeutic drugs ( Liu Y. et al, 2019 ; Chang et al, 2020 ; Del Valle et al, 2020 ; Sui et al, 2020 ). For instance, Chang, N. et al engineered a pH/ROS programmed-responsive and self-accelerating drug release NDDS and utilized it for the treatment of multidrug-resistant human colon adenocarcinoma.…”

Multifunctional Nanomaterials for Ferroptotic Cancer Therapy

“…The salinomycin-AuNPs exhibited higher ability to induce ferroptosis via higher iron accumulation and GPX4 inactivation. Pt-decorated Au nanostars were presented as novel nanoprodrugs for FBT against MDR tumors ( Del Valle et al, 2020 ). Upon NIR light irradiation, Pt and Au were released, which resulted in GSH depletion, GPX4 inactivation, and accumulation of lipid hydroperoxides.…”