Tumor-Directed Disulfidptosis via Spatiotemporally Controlled Copper Bioorthogonal Activation

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Therapy

Background:

• Disulfidptosis is a programmed cell death pathway with therapeutic potential against tumors.
• SLC7A11 overexpression in tumors presents a challenge for selective disulfidptosis induction.
• Targeted cancer therapies are crucial for improving treatment efficacy and minimizing side effects.

Purpose of the Study:

• To develop a method for selectively inducing disulfidptosis in tumor cells using a bioorthogonal reaction.
• To investigate the mechanism by which the generated agents trigger cell death.
• To evaluate the in vivo therapeutic efficacy of this novel strategy.

Main Methods:

• Encapsulation of rhein-alkyne in ferritin as a copper complex (Cu/rhein) for tumor targeting.
• Utilizing a copper-triggered bioorthogonal reaction (Cu(I)-catalyzed azide-alkyne cycloaddition) with azido-Ru-arene (Ru-N₃).
• Assessing the generation of cytotoxic Ru-rhein and its effects on glucose transporter 1 (GLUT1), glucose, NADPH, and disulfide bond accumulation.

Main Results:

• The bioorthogonal reaction successfully generated cytotoxic Ru-rhein specifically within tumor cells.
• Ru-rhein induced disulfidptosis by downregulating GLUT1, leading to decreased glucose and NADPH levels and disulfide bond accumulation.
• Copper ion accumulation promoted cuproptosis, enhancing the overall cell death effect.
• Significant in vivo therapeutic effects were observed in tumor-bearing mice.

Conclusions:

• Copper-triggered bioorthogonal reactions can selectively induce disulfidptosis and cuproptosis in tumors.
• This approach offers a promising strategy for cancer therapy by targeting key metabolic pathways and inducing multiple cell death mechanisms.
• The study demonstrates the potential of ferritin-based drug delivery and bioorthogonal chemistry in cancer treatment.