A Small-Molecule Platform Demonstrates Light-Activated Synergy Between Cuproptosis and Photodynamic Tumor Therapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Cuproptosis is a promising strategy against chemotherapy resistance but lacks tumor selectivity.
• Glutathione (GSH), abundant in tumors, paradoxically inhibits cuproptosis by binding copper ions.
• Existing nanoplatforms combining photodynamic therapy (PDT) and cuproptosis are complex and raise safety concerns.

Purpose of the Study:

• To develop a novel small-molecule platform that synergizes PDT and cuproptosis for selective cancer therapy.
• To investigate the mechanism by which PDT can trigger cuproptosis, overcoming GSH inhibition.
• To evaluate the efficacy and biosafety of the developed platform in preclinical tumor models.

Main Methods:

• Synthesis of a copper(II) complex (NC) by linking 8-hydroxyquinoline to Nile Blue.
• Utilizing near-infrared irradiation to activate NC, generating superoxide anions.
• Assessing the reduction of GSH's copper-binding capacity and subsequent induction of cuproptosis.
• Evaluating tumor suppression and biosafety in murine tumor models.

Main Results:

• The NC complex successfully synergized PDT and cuproptosis as a small-molecule platform.
• Near-infrared irradiation of NC generated superoxide anions, liberating copper ions by reducing GSH binding.
• NC demonstrated high biosafety and superior tumor suppression compared to PDT alone in murine models.
• Complete tumor inhibition was achieved over 14 days in treated mice.

Conclusions:

• The developed NC platform establishes PDT as a controllable inducer of cuproptosis.
• This approach effectively converts GSH from a cuproptosis inhibitor to a therapeutic trigger.
• The findings expand the therapeutic potential of both PDT and cuproptosis for cancer treatment.