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Synthesis and Evaluation of a Ruthenium-based Mitochondrial Calcium Uptake Inhibitor
Published on: October 26, 2017
Vacancy-Rich Bismuth-Based Nanosheets for Mitochondrial Destruction via CO Poisoning, Ca2+ Dyshomeostasis, and
Yinmin Zhao1, Xiaoqin Wang1, Mengting He1
1School of Materials and Energy, Southwest University, Chongqing, 400715, China.
Abstract:
Mitochondria are core regulators of tumor cell homeostasis, and their damage has become an arresting therapeutic modality against cancer. Despite the development of many mitochondrial-targeted pharmaceutical agents, the exploration of more powerful and multifunctional medications is still underway. Herein, oxygen vacancy-rich BiO2-x wrapped with CaCO3 (named BiO2-x@CaCO3/PEG, BCP) is developed for full-fledged attack on mitochondrial function. After endocytosis of BCP by tumor cells, the CaCO3 shell can be decomposed in the acidic lysosomal compartment, leading to immediate Ca2+ release and CO2 production in the cytoplasm. Near-infrared irradiation enhances the adsorption of CO2 onto BiO2-x defects, which enables highly efficient photocatalysis of CO2-to-CO. Meanwhile, such BiO2-x nanosheets possess catalase-, peroxidase- and oxidase-like catalytic activities under acidic pH conditions, allowing hypoxia relief and the accumulation of diverse reactive oxygen species (ROS) in the tumor microenvironment. Ca2+ overload-induced ion dyshomeostasis, CO-mediated respiratory chain poisoning, ROS-triggered oxidative stress aggravation, and cytosolic hyperoxia can cause severe mitochondrial disorders, which further lead to type I cell death in carcinoma. Not only does BCP cause irreversible apoptosis, but immunogenic cell death is simultaneously triggered to activate antitumor immunity for metastasis inhibition. Collectively, this platform promises high benefits in malignant tumor therapy and may expand the medical applications of bismuth-based nanoagents.
Insights
A novel bismuth-based nanoagent (BCP) effectively targets cancer cell mitochondria. This agent induces cell death and triggers antitumor immunity, offering a promising new strategy for cancer therapy.
Area of Science:
- Nanotechnology
- Biomedical Engineering
- Oncology
Background:
- Mitochondria play a crucial role in cancer cell survival and are a key therapeutic target.
- Existing mitochondrial-targeting drugs require further development for enhanced efficacy and multifunctionality.
Purpose of the Study:
- To develop a novel multifunctional nanoagent for comprehensive attack on mitochondrial function in cancer cells.
- To investigate the therapeutic potential of oxygen vacancy-rich bismuth oxide nanosheets coated with calcium carbonate (BiO2-x@CaCO3/PEG, BCP) against malignant tumors.
Main Methods:
- Synthesis and characterization of BiO2-x@CaCO3/PEG (BCP) nanoagent.
- Investigation of BCP's intracellular behavior, including CaCO3 shell decomposition, Ca2+ and CO2 release, and CO generation under near-infrared irradiation.
- Evaluation of BCP's catalytic activities (catalase, peroxidase, oxidase-like) in the tumor microenvironment.
- Assessment of BCP-induced mitochondrial dysfunction, cell death (apoptosis, immunogenic cell death), and antitumor immune response.
Main Results:
- BCP nanoagents were successfully synthesized and demonstrated effective endocytosis by tumor cells.
- CaCO3 shell decomposition released Ca2+ and CO2, with near-infrared irradiation promoting CO generation via photocatalysis.
- BiO2-x nanosheets exhibited multi-enzyme-like activities, leading to ROS accumulation and hypoxia relief.
- Combined effects of Ca2+ overload, CO poisoning, ROS stress, and hyperoxia induced severe mitochondrial damage and type I cell death.
- BCP triggered both apoptosis and immunogenic cell death, activating antitumor immunity and inhibiting metastasis.
Conclusions:
- The developed BCP nanoagent provides a multifunctional platform for attacking cancer cell mitochondria through various mechanisms.
- BCP induces significant tumor cell death and simultaneously activates antitumor immunity, demonstrating potential for effective cancer therapy.
- This bismuth-based nanoagent platform shows promise for expanding medical applications in malignant tumor treatment.
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