An NIR-Fluorophore-Based Therapeutic Endoplasmic Reticulum Stress Inducer

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are implicated in numerous human diseases, including cancer.
• Targeting ER stress for cancer therapy is a promising strategy, but current agents have limitations in efficacy and specificity.
• Existing ER-stress inducers often target UPR components or proteasomes, leading to off-target effects and poor tumor distribution.

Purpose of the Study:

• To synthesize and characterize a novel near-infrared (NIR) fluorophore, IR-34, for targeted cancer therapy.
• To investigate IR-34's ability to selectively induce tumoricidal endoplasmic reticulum stress.
• To evaluate IR-34 as a theranostic agent for cancer imaging and treatment.

Main Methods:

• Synthesis and identification of the novel NIR fluorophore IR-34.
• Demonstration of IR-34's selective accumulation in cancer cells.
• Assessment of IR-34's ability to induce ER stress and inhibit tumor growth in vivo.
• Evaluation of IR-34 for NIR tumor imaging.

Main Results:

• IR-34 selectively and efficiently triggers tumoricidal ER stress by targeting the mitochondrial protein NDUFS1.
• IR-34 specifically accumulates in living cancer cells, enabling effective tumor NIR imaging.
• IR-34 drastically inhibits tumor growth and recurrence with no apparent toxicity.
• The study demonstrates the potential of mitochondria as a therapeutic target for ER stress in cancer.

Conclusions:

• The multifunctional NIR fluorophore IR-34 represents a novel theranostic agent for tumor imaging-guided cancer treatment.
• Targeting mitochondrial protein NDUFS1 offers a selective approach to inducing therapeutic ER stress in cancer cells.
• IR-34 shows significant promise for enhancing cancer therapy through targeted imaging and treatment.