Zhu Jiawei, Jiao Aihong, Li Qinzhe, Lv Xinyi, Wang Xiaorui, Song Xuejiao, Li Buhong, Zhang Yewei, Dong Xiaochen
Key Laboratory of Flexible Electronics (KLOFE) and Institute of Advanced Materials (IAM), School of Physical and Mathematical Sciences, Nanjing Tech University (NanjingTech), Nanjing 211816, China.
Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, China.
Acta Biomater. 2022 Jan 1;137:252-261. doi: 10.1016/j.actbio.2021.10.016. Epub 2021 Oct 13.
The Ca 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 CaCO-based tumor microenvironment (TME) responsive nanoplatform (CaNP@Ce6-PEG) was designed for oxygen/GSH depletion-boosted photodynamic therapy (PDT) and mitochondrial Ca-overloading synergistic therapy. In acidic TME, CaCO decomposed and released the cargos (catalase (CAT), buthionine sulfoximine (BSO), chlorin e6 (Ce6), and Ca). The tumor hypoxia and reductive microenvironment could be significantly reversed by CAT and BSO, which greatly enhanced the PDT efficacy. The generated O during PDT process not only directly killed cancer cells but also destroyed the Ca buffering capacity, leading to the mitochondrial Ca-overloading. The increased Ca 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 Ca-overloading, the CaNP@Ce6-PEG NPs showed remarkable synergistic effects in tumor inhibition without any side effects. STATEMENT OF SIGNIFICANCE: In the manuscript, a CaCO-based nano-platform for tumor microenvironment response was designed. With the decomposition of CaNP@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 Ca buffering capacity was destroyed which led to the mitochondrial Ca-overloading. The synergistic effect of enhanced PDT and mitochondrial Ca-overloading made the CaNP@Ce6-PEG NPs present remarkable antitumor performance.
线粒体的钙缓冲能力维持着细胞生理活动的平衡。外源性活性氧（ROS）可用于打破这种平衡，导致线粒体功能障碍和不可逆的细胞凋亡。在此，设计了基于碳酸钙的肿瘤微环境（TME）响应纳米平台（CaNP@Ce6-PEG），用于氧/谷胱甘肽消耗增强的光动力疗法（PDT）和线粒体钙超载协同治疗。在酸性肿瘤微环境中，碳酸钙分解并释放所载物质（过氧化氢酶（CAT）、丁硫氨酸亚砜胺（BSO）、二氢卟吩e6（Ce6）和钙）。CAT和BSO可显著逆转肿瘤缺氧和还原性微环境，极大地增强了PDT疗效。PDT过程中产生的氧不仅直接杀死癌细胞，还破坏了钙缓冲能力，导致线粒体钙超载。钙浓度的增加促进了氧化磷酸化过程，抑制了三磷酸腺苷（ATP）的产生，导致细胞死亡加速。在增强的PDT和线粒体钙超载的联合作用下，CaNP@Ce6-PEG纳米颗粒在肿瘤抑制方面显示出显著的协同效应，且无任何副作用。
在本论文中，设计了一种基于碳酸钙的肿瘤微环境响应纳米平台。随着CaNP@Ce6-PEG纳米颗粒在酸性肿瘤微环境中的分解，释放的过氧化氢酶（CAT）和丁硫氨酸亚砜胺（BSO）可缓解肿瘤缺氧并抑制谷胱甘肽的产生。在660 nm激光照射下，光动力效应增强并导致细胞凋亡。同时，钙缓冲能力被破坏，导致线粒体钙超载。增强的PDT和线粒体钙超载的协同作用使CaNP@Ce6-PEG纳米颗粒呈现出显著的抗肿瘤性能。
