Mitochondrial-Targeted Multifunctional Platinum-Based Nano "Terminal-Sensitive Projectile" for Enhanced Cancer...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Platinum-based chemotherapy faces resistance due to tumor cell repair mechanisms.
• Mitochondria play a crucial role in cancer progression and lack DNA repair pathways.
• Targeting mitochondrial DNA (mtDNA) presents a promising strategy to overcome drug resistance.

Purpose of the Study:

• To develop a novel platinum-based drug delivery system (TSB) for enhanced cancer therapy.
• To specifically target tumor cell mitochondria and induce cell death via mtDNA damage.
• To combine chemotherapy with photodynamic therapy for synergistic anti-cancer effects.

Main Methods:

• Development of a terminal-sensitive projectile (TSB) with a platinum prodrug, TPP, and Fenofibric acid (FFa).
• Encapsulation of TSB within IR780-coupled DSPE-PEG2K for targeted mitochondrial delivery (NTSB).
• Evaluation of NTSB's efficacy in vitro and in vivo, assessing mtDNA cross-linking, ETC disruption, and phototherapeutic effects.

Main Results:

• NTSB successfully targeted intertumoral mitochondria, releasing oxaliplatin (OXA) and FFa.
• OXA induced mtDNA cross-linking and mitochondrial dysfunction; FFa disrupted oxidative phosphorylation (OXPHOS).
• Near-infrared (NIR) irradiation enhanced ROS production and photothermal effects, increasing Pt cross-linking and depleting GSH.

Conclusions:

• The developed NTSB system effectively targets mitochondria and enhances platinum drug efficacy.
• Combined mitochondrial targeting, chemotherapy, and phototherapy significantly improve tumor cell sensitivity.
• This strategy offers a promising approach to overcome platinum resistance in cancer treatment.