Mitochondrial Metabolism Targeted Nanoplatform for Efficient Triple-Negative Breast Cancer Combination Therapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Malignant tumors can reprogram mitochondrial metabolism pathways.
• Targeting mitochondrial metabolism is a promising cancer treatment strategy, especially for triple-negative breast cancer.

Purpose of the Study:

• To develop a tumor/mitochondria dual-targeting, adenosine-triphosphate (ATP)-responsive nanocarrier (zeolitic imidazolate framework-90, ZIF-90) for combination therapy in breast cancer.
• To investigate the synergistic anti-tumor effects of atovaquone (AVO) and hemin loaded onto the ZIF-90 nanoplatform.

Main Methods:

• Zeolitic imidazolate framework-90 (ZIF-90) nanoparticles were synthesized and loaded with atovaquone (AVO) and hemin.
• The nanoplatform was modified with iRGD peptide for tumor targeting.
• The nanocarrier's ability to target mitochondria and release drugs in response to ATP was evaluated.
• In vitro and in vivo studies were conducted to assess anti-tumor efficacy and side effects.

Main Results:

• The nanoplatform demonstrated tumor-targeting and mitochondria-targeting capabilities with ATP-responsive drug release.
• Hemin degraded BTB and CNC homology1 (BACH1), enhancing mitochondrial metabolism and increasing dependency on mitochondrial respiration.
• AVO inhibited the electron transport chain (ETC), and its mitochondrial accumulation was improved by the nanocarrier.
• The composite nanocarrier showed significant tumor inhibition in vitro and in vivo with limited side effects.

Conclusions:

• The developed nanocarrier provides a dual-targeting strategy for breast cancer therapy.
• This approach enhances the anti-tumor efficiency of mitochondrial metabolism inhibitors by improving drug accumulation and targeting.
• The study presents a promising strategy for cancer-targeted therapy by modulating mitochondrial metabolism.