Double-activation of mitochondrial permeability transition pore opening via calcium overload and reactive oxygen species for cancer therapy

Background: Calcium ions (Ca2+) participates in various intracellular signal cascades and especially plays a key role in pathways relevant to cancer cells. Mitochondrial metabolism stimulated by calcium overload can trigger the opening of the mitochondrial permeability transition pore (MPTP), which leads to cancer cell death. Methods: Herein, a mitochondrial pathway for tumour growth inhibition was built via the double-activation of MPTP channel. Fe2+ doped covalent organic frameworks (COF) was synthesised and applied as template to grow CaCO3 shell. Then O-2 was storaged into Fe2+ doped COF, forming O-2-FeCOF@CaCO3 nanocomposite. After modification with folic acid (FA), O-2-FeCOF@CaCO3@FA (OFCCF) can target breast cancer cells and realize PDT/Ca2+ overload synergistic treatment. Results: COF can induce the production of O-1(2) under 650 nm irradiation for photodynamic therapy (PDT). Low pH and hypoxia in tumour microenvironment (TME) can activate the nanocomposite to release oxygen and Ca2+. The released O-2 can alleviate hypoxia in TME, thus enhancing the efficiency of COF-mediated PDT. Abundant Ca2+ were released and accumulated in cancer cells, resulting in Ca2+ overload. Notably, the reactive oxygen species (ROS) and Ca2+ overload ensure the sustained opening of MPTP, which leads to the change of mitochondria transmembrane potential, the release of cytochrome c (Cyt c) and the activation of caspases 3 for cancer cell apoptosis. Conclusion: This multifunctional nanosystem with TME responded abilities provided a novel strategy for innovative clinical cancer therapy.

Automated summary

In this study, a mitochondrial pathway was established to inhibit tumor growth through the double activation of the mitochondrial permeability transition pore (MPTP) channel. Fe2+ doped covalent organic frameworks (COF) were synthesized and used as templates to grow a CaCO3 shell, resulting in the formation of O-2-FeCOF@CaCO3 nanocomposite. After modification with folic acid (FA), the nanocomposite (OFCCF) could target breast cancer cells and achieve synergistic treatment through photodynamic therapy (PDT) and calcium overload. The multifunctional nanosystem with tumor microenvironment (TME) response abilities provided a novel strategy for clinical cancer therapy.