A Mitochondria‐Targeted Ferroptosis Inducer Activated by Glutathione‐Responsive Imaging and Depletion for Triple Negative Breast Cancer Theranostics

Abstract

Ferroptosis is a new type of iron‐dependent programmed cell death characterized by glutathione (GSH) depletion, selenoprotein glutathione peroxidase 4 (GPX4) inactivation, and lipid peroxides accumulation. Mitochondria, as the main source of intracellular energy supply and reactive oxygen species (ROS) generation, play a central role in oxidative phosphorylation and redox homeostasis. Therefore, targeting cancer‐cell mitochondria and attacking redox homeostasis is expected to induce robust ferroptosis‐mediated anticancer effects. In this work, a theranostic ferroptosis inducer (IR780‐SPhF), which can simultaneously achieve the imaging and therapy of triple‐negative breast cancer (TNBC) by targeting mitochondria is presented. It is developed from a mitochondria‐targeting small molecule (IR780) with cancer‐preferential accumulation, enabling it to react with GSH by nucleophilic substitution, resulting in mitochondrial GSH depletion and redox imbalance. More interestingly, IR780‐SPhF exhibits GSH‐responsive near‐infrared fluorescence emission and photoacoustic imaging characteristics, further facilitating diagnosis and treatment with real‐time monitoring of TNBC with a highly elevated GSH level. Both in vitro and in vivo results demonstrate that IR780‐SPhF exhibits potent anticancer effect, which is significantly stronger than cyclophosphamide, a classic drug commonly recommended for TNBC patients in clinic. Hence, the reported mitochondria‐targeted ferroptosis inducer may represent a promising candidate and a prospective strategy for efficient cancer treatment.

Multimodal optoacoustic imaging: methods and contrast materials

“…OA imaging can also visualize FL substances that thermalize part of the absorbed energy. 27 Small FL molecules, such as ICG 114 or other cyanine dyes 115,116 having absorption peaks in the NIR spectrum, are ideally suited for synergistically exploiting the advantages of dual-modality OA–FL imaging. The enhanced penetration of light in the NIR range enables tracking specifically-labeled biomolecules in small animals at the whole-body level.…”

“… 127 A synthesized IR780 derivative (IR780-SPhF) also induces ferroptosis-mediated cell death after accumulating in tumors with a highly elevated glutathione level. 116 The reduced light scattering in NIR-II facilitates imaging with deep-tissue. However, design and synthesis of organic probes emitting light in this range remains challenging.…”

Nutrient vitamins enabled metabolic regulation of ferroptosis via reactive oxygen species biology

“…It is a widely recognized fact that mitochondria serve as the primary organelles responsible for iron metabolism within cells. Consequently, the development of mitochondria-targeting ferroptosis platforms has demonstrated promising antitumor effects ( Gan et al, 2023 ). Nevertheless, recent studies have revealed that the rational design of lysosome-targeting systems capable of inducing ferroptosis may yield significant outcomes.…”