Mitochondria-Targeted Multifunctional Nanoprodrugs by Inhibiting Metabolic Reprogramming for Combating...

Area of Science:

• Biomedical Engineering
• Cancer Research
• Drug Delivery Systems

Background:

• Cisplatin resistance is a major clinical challenge in cancer therapy.
• Tumor cells exhibit metabolic plasticity, switching between glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) to develop resistance.
• Mitochondrial DNA (mtDNA) is vulnerable to damage and can be targeted by platinum-based drugs.

Purpose of the Study:

• To develop a targeted drug delivery system to overcome cisplatin resistance in lung cancer.
• To investigate the synergistic effects of targeting both mtDNA and glycolysis in cisplatin-resistant cells.

Main Methods:

• Construction of a self-assembled, mitochondria-targeted nanoparticle system (LND-SS-Pt-TPP/HA-CD).
• The system encapsulates lonidamine (LND) and a cisplatin prodrug (Pt(IV)) and targets CD44 receptors.
• Mitochondrial delivery is facilitated by a triphenylphosphine (TPP+) group, with disulfide bonds releasing drugs upon glutathione (GSH) degradation.

Main Results:

• The nanoparticles effectively delivered LND and Pt(IV) to mitochondria, where Pt(IV) was reduced to cisplatin (Pt(II)).
• Cisplatin induced mtDNA damage, mitochondrial dysfunction, and mitophagy, impacting OXPHOS.
• LND reduced hexokinase II (HK II) levels, inhibited glycolysis, and disrupted mitochondrial function.

Conclusions:

• The developed nano-drug delivery system synergistically kills cisplatin-resistant lung cancer cells.
• This approach offers a potential strategy to overcome cisplatin resistance by disrupting mitochondrial function and energy metabolism.