Mitochondrial Ca2+-overloading by oxygen/glutathione depletion-boosted photodynamic therapy based on a CaCO3 nanoplatform for tumor synergistic therapy

• Published in: Acta biomaterialia 2022-01, Vol.137, p.252-261
• Main Authors: Zhu, Jiawei, Jiao, Aihong, Li, Qinzhe, Lv, Xinyi, Wang, Xiaorui, Song, Xuejiao, Li, Buhong, Zhang, Yewei, Dong, Xiaochen
• Format: Article
• Language: English
• Subjects: Adenosine triphosphate; Apoptosis; ATP; Buffers; Buthionine sulfoximine; Ca2+-buffering capacity; Ca2+-overloading; Calcium (mitochondrial); Calcium buffering; Calcium carbonate; Calcium ions; Catalase; Cell death; Depletion; Glutathione; Hypoxia; Mitochondria; Mitochondrial dysfunction; Overloading; Oxidative phosphorylation; Oxygen; Oxygen/GSH depletion; Phosphorylation; Photodynamic therapy; Reactive oxygen species; Side effects; Synergistic effect; Tumor microenvironment; Tumors
• ISSN: 1742-7061; 1878-7568
• DOI: 10.1016/j.actbio.2021.10.016

The Ca2+ buffering capacity of mitochondria maintains the balance of cell physiological activities. The exogenous reactive oxygen species (ROS) can be used to break the balance, resulting in mitochondrial dysfunction and irreversible cell apoptosis. Herein, the CaCO3-based tumor microenvironment (TME) responsive nanoplatform (CaNPCAT+BSO@Ce6-PEG) was designed for oxygen/GSH depletion-boosted photodynamic therapy (PDT) and mitochondrial Ca2+-overloading synergistic therapy. In acidic TME, CaCO3 decomposed and released the cargos (catalase (CAT), buthionine sulfoximine (BSO), chlorin e6 (Ce6), and Ca2+). The tumor hypoxia and reductive microenvironment could be significantly reversed by CAT and BSO, which greatly enhanced the PDT efficacy. The generated 1O2 during PDT process not only directly killed cancer cells but also destroyed the Ca2+ buffering capacity, leading to the mitochondrial Ca2+-overloading. The increased Ca2+ concentration promoted the process of oxidative phosphorylation and inhibited the production of adenosine triphosphate (ATP), resulting in the acceleration of cell death. Under the joint action of enhanced PDT and mitochondrial Ca2+-overloading, the CaNPCAT+BSO@Ce6-PEG NPs showed remarkable synergistic effects in tumor inhibition without any side effects. In the manuscript, a CaCO3-based nano-platform for tumor microenvironment response was designed. With the decomposition of CaNPCAT+BSO@Ce6-PEG NPs in the acidic tumor microenvironment, the released catalase (CAT) and buthionine sulfoximine (BSO) could relieve the tumor hypoxia and inhibit GSH production. Under 660 nm laser irradiation, the photodynamic effect was enhanced and caused apoptosis. Meanwhile, the Ca2+ buffering capacity was destroyed which led to the mitochondrial Ca2+-overloading. The synergistic effect of enhanced PDT and mitochondrial Ca2+-overloading made the CaNPCAT+BSO@Ce6-PEG NPs present remarkable antitumor performance. [Display omitted]