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

Abstract

Tumor reprogram pathway of mitochondrial metabolism is an emerging approach for malignant tumor treatment, such as triple-negative breast cancer. In this study, a tumor/mitochondria cascaded targeting, adenosine-triphosphate (ATP) responsive nanocarrier of zeolitic imidazolate framework-90 (ZIF-90) for breast cancer combination therapy is reported. Atovaquone (AVO) and hemin are loaded into ZIF-90, then a peptide iRGD with tumor-targeting ability is modified on the ZIF-90 nanoplatform. Hemin can specifically degrade BTB and CNC homology1 (BACH1), resulting in the changes of mitochondrial metabolism, and AVO acts as the inhibitor of the electron transport chain (ETC). The degradation of BACH1 using hemin can effectively improve the anti-tumor efficiency of mitochondrial metabolism inhibitor AVO, by increasing dependency on mitochondrial respiration. This nanoplatform displays both tumor-targeting and mitochondria-targeting capacity with high level of ATP responsive drug release behavior. The specific characteristic of mitochondria-targeting ability of this nanoplatform can increase the accumulation of AVO in the mitochondria, and in turn, can effectively improve the inhibition of the ETC. Both in vitro and in vivo results reveal that this composite nanocarrier has excellent tumor inhibition ability with limited side effects. Accordingly, this study provides an attractive strategy in the mitochondrial metabolism for cancer targeted therapy.

Coordinated regulation of BACH1 and mitochondrial metabolism through tumor-targeted self-assembled nanoparticles for effective triple negative breast cancer combination therapy

“…Recent studies identified novel functional roles of BACH1 in the regulation of metabolic pathways in cancer cells through transcriptional suppression of mitochondrial membrane genes. As a transcriptional factor, BACH1 supports aerobic glycolysis in breast cancer cells by increasing the expression of metabolic enzymes involved such as hexokinase 2 (HK2), lactate dehydrogenase A and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) 9 , 10 . Additionally, BACH1 promotes cancer cells metastasis by directly promoting the expression of E-cadherin, other epithelial-mesenchymal transition-related proteins and matrix metalloproteinases (MMPs), and suppressing the expression of tumor suppressor genes.…”

Multifunctional Mitochondria-Targeting Nanosystems for Enhanced Anticancer Efficacy

“…Due to the positive charges, ZIF-90 can actively target mitochondria. More importantly, ZIF-90 can be disassembled by mitochondrial ATP to liberate the loaded drugs because of the competitive coordination between ATP and Zn 2+ ( Lu et al, 2021 ). Secondly, they chose both 2-Methoxyestradiol (2-ME) and thioketal-linked camptothecin (TK-CPT, a prodrug) as the drugs.…”

Rational design of copper(i)-doped metal–organic frameworks as dual-functional nanocarriers for combined chemo–chemodynamic therapy

“…29,30 Zeolitic imidazole framework-90 (ZIF-90), consisting of imidazole-2-carboxaldehyde (2-ICA) and Zn 2+ , is widely studied in biomedical applications for its biocompatibility, and the properties of ATP/pH-responsive decomposition. [31][32][33][34] Especially, the aldehyde group of ZIF-90 provides a facile functional position for post-modification. For example, doxorubicin (DOX) can be covalently bound to ZIF-90.…”