Calcium Peroxide-Based Nanosystem with Cancer Microenvironment-Activated Capabilities for Imaging Guided Combination Therapy via Mitochondrial Ca²⁺ Overload and Chemotherapy

Abstract

Mitochondria are the "power plant" of the cell, providing a constant source of energy, and are involved in a variety of intracellular signaling pathways. Among these pathways, Ca 2+ homeostasis is closely related to the normal function of mitochondria. By destroying the Ca 2+ steady state of mitochondria and disrupting their multiple cellular activities, tumor cell killing can be achieved. In addition, the presence of an intracellular oxidative stress state triggers the closure of cellular calcium channels, which leads to intracellular Ca 2+ retention and enrichment. We designed a targeted and tumor microenvironment (TME)-responsive CaO 2 -based nanosystem that can selectively target cancer cells for pH-controlled degradation and drug release, alter cellular physiological mechanisms by disrupting Ca 2+ homeostasis in an artificial manner, and introduce mitochondrial Ca 2+ excess-mediated apoptosis. Meanwhile, the production of Ca(OH) 2 will raise the pH of the microenvironment and subsequently promote the oxidation process of glutathione by H 2 O 2 released from CaO 2 degradation, achieving the goal of remodeling TME. Moreover, calcium overload of tumor cells and calcification of tissues can both inhibit tumor growth and act as a contrast agent for computed tomography imaging.

Multistage‐Responsive Gene Editing to Sensitize Ion‐Interference Enhanced Carbon Monoxide Gas Therapy

“…The CaCO 3 layer of MG‐RNP@CaCO 3 degraded to release calcium ions under the acidic tumor microenvironment, which could disturb the calcium signals and result in calcium overload‐induced cell death. [ 58 ] The intracellular calcium level in A549 cancer cells was analyzed by Fluo‐4 AM. The PBS and MG@SiO 2 ‐RNP groups showed no green fluorescence, while the MG‐RNP@CaCO 3 group exhibited stronger intracellular green fluorescence due to the increase of exogenous free calcium ions (Figure S8, Supporting Information).…”

Nanoplatform-mediated calcium overload for cancer therapy

“…4). 47 After the internalization of this nanoplatform into cancer cells, the HA layer and the Zif-8 would be degraded by hyaluronidase and hydrogen ions, respectively, thereby resulting in the release of DOX, H 2 O 2 , and Ca 2+ . On the one hand, the generated H 2 O 2 rendered cells more vulnerable to getting into a homeostasis disequilibrium state.…”

Oncocyte Membrane-Camouflaged Multi-Stimuli-Responsive Nanohybrids for Synergistic Amplification of Tumor Oxidative Stresses and Photothermal Enhanced Cancer Therapy

“…However, it still has noteworthy potential for further improvements owing to the complications of TME, including irregular distribution of vascular networks, cell membrane (CM) barrier, etc. Recent studies have certified that overloading calcium ions (Ca 2+ ) by introducing calciferous nanoparticles (such as calcium phosphate, calcium carbonate, and calcium peroxide) could lead to the increase of ROS production via inducing the dysfunction of mitochondria and thus further enhance the oxidative stress to induce cancer cell death. − Among them, as a highly biocompatible metal peroxide, calcium peroxide (CaO 2 ) could react with water, followed by the simultaneous generation of O 2 and H 2 O 2 immediately, which are beneficial for relieving the hypoxia condition in TME and advancing the therapeutic efficiency of ROS-based therapy. − Hence, CaO 2 could be appreciated as an excellent candidate for the design of multifunctional nanosystems for promoting CDT and chemotherapy efficiency and meanwhile allowing cancer-localized Ca 2+ overloading, which has achieved synergistic amplification of intracellular oxidative stress for improving the tumor therapeutic effect ultimately.…”