A DFX-based iron nanochelator for cancer therapy

Area of Science:

• Biomedical Engineering
• Cancer Biology
• Nanomedicine

Background:

• Iron is essential for cell viability, with cancer cells exhibiting higher dependency due to hyper-proliferation.
• Conventional iron chelators show anti-tumor activity but are limited by severe systemic toxicities.
• Polyaminoacids offer biocompatibility and serve as effective drug-delivery platforms and therapeutic agents.

Purpose of the Study:

• To develop a novel iron nanochelator, PL-DFX, by conjugating deferasirox (DFX) with hyperbranched polylysine.
• To evaluate the anti-tumor efficacy and mechanism of action of PL-DFX in cancer cells and clinical organoids.

Main Methods:

• Synthesis of the PL-DFX nanochelator.
• In vitro cytotoxicity assays, including Fe2+ reversal studies.
• Assessment of cancer cell migration, invasion, cell cycle, and mitochondrial membrane potential.
• Evaluation of anti-tumor potency using cancer-derived organoids.

Main Results:

• PL-DFX exhibited significantly higher cytotoxicity compared to deferasirox (DFX), with partial reversal by Fe2+.
• PL-DFX inhibited cancer cell migration and invasion, disrupted iron metabolism, induced G1/S phase arrest, and depolarized mitochondrial membrane potential.
• The anti-tumor efficacy of PL-DFX was validated in organoids derived from clinical cancer specimens.

Conclusions:

• The novel DFX-based iron nanochelator, PL-DFX, presents a promising strategy for cancer therapy.
• Targeting iron metabolism disruption via PL-DFX offers a prospective approach for enhanced anti-cancer treatment.
• PL-DFX demonstrates improved efficacy and a potentially better safety profile compared to conventional iron chelators.