Recent Advances in Calcium‐Based Anticancer Nanomaterials Exploiting Calcium Overload to Trigger Cell Apoptosis

Abstract

Calcium ion is vital for the regulation of many cellular functions and serves as a second messenger in the signal transduction pathways. Once the intracellular Ca 2+ level exceeds the tolerance of cells (called Ca 2+ overload), oxidative stress, mitochondrial damage, and cell/mitochondria apoptosis happen. Therefore, Ca 2+ overload has started to be deeply exploited as a new strategy for cancer therapy due to its high efficiency and satisfactory safety. This review aims to highlight the recent development of Ca 2+ -based nanomaterials (such as Ca 3 (PO 4 ) 2 , CaCO 3 , CaO 2 , CaH 2 , CaS, and others) able to trigger intracellular Ca 2+ overload and apoptosis in cancer therapy. The intracellular mechanisms of varied Ca 2+ -based nanomaterials and the different types of strategies to enhance Ca 2+ overload are discussed in detail. Moreover, the design of more efficient Ca 2+ overload-mediated cancer therapies is prospected mainly based on 1) the enhanced cellular uptake by surface modification and morphology optimization of nanomaterials, 2) the accelerated Ca 2+ release from nanomaterials by increasing the intracellular H + level and by photothermal effect, and 3) the overload maintenance by Ca 2+ efflux inhibition, Ca 2+ influx promotion, or promoting Ca 2+ release from the endoplasmic reticulum.

Organic Nanoparticle–Carbon Dots Conjugate for Multimodal Cancer Therapy

“…This approach aims to integrate Ca 2+ overload with other therapeutic methods within nanoplatforms, offering an innovative avenue in cancer treatment. 27,28,33 Ca 2+ -doped CDs can serve a dual purpose both as a pro-drug activator and a diagnostic probe. In tumor cells, oxidative stress can desensitize calcium-related channels due to low catalase (CAT) levels, resulting in uncontrollable Ca 2+ accumulation and thereby cell death.…”

“…Calcium (Ca 2+ ) is a critical second messenger involved in various physiological processes and cancer-related events. ,,, Overload of Ca 2+ within cells through voltage-dependent calcium channels (VDCCs) leads to harmful intracellular effects like oxidative stress, mitochondrial dysfunction, and cell death (calcicoptosis). , In this context, a CD based nanoplatform was developed with overloaded Ca 2+ as a pro-drug stimulator. This approach aims to integrate Ca 2+ overload with other therapeutic methods within nanoplatforms, offering an innovative avenue in cancer treatment. ,, Ca 2+ -doped CDs can serve a dual purpose both as a pro-drug activator and a diagnostic probe. In tumor cells, oxidative stress can desensitize calcium-related channels due to low catalase (CAT) levels, resulting in uncontrollable Ca 2+ accumulation and thereby cell death.…”

“…Pro-drugs, inert biomolecules activated in vivo through chemical or enzymatic reactions, serve various purposes: (i) enhancing solubility in water or lipid membranes, (ii) mitigating side effects, and (iii) augmenting cellular uptake. − Ca 2+ overload is a widespread, safe therapeutic approach in cancer treatment, activating mitochondrial apoptosis for effective suppression of cancer proliferation. − We aim to use Ca 2+ overload by means of Ca 2+ -doped CDs (CaCDs) as a pro-drug in multimodal therapy. Importantly, the selected components (pro-drug or free drug) should operate through distinct mechanisms.…”

A calcium hydroxide/oleic acid/phospholipid nanoparticle induced cancer cell apoptosis by the combination of intracellular calcium overload and lactic acidosis elimination

“…Although cancer therapy has made great progress in chemotherapy, 1 radiotherapy, 2 immunotherapy, 3 etc., the development of an alternative therapy with non-toxicity or hypotoxicity is still challenging but necessary. Intracellular calcium ions (Ca 2+ ) as secondary messengers mediate the proliferation-apoptosis balance of cells, 4,5 and mitochondria usually act as a significant checkpoint in apoptotic processes due to the release of caspase cofactors. 6 Once the intracellular Ca 2+ concentration maintains a long-term rise, intracellular calcium overload may occur, leading to the release of mitochondrial cytochrome c and the activation of caspase 3 and caspase 9, inducing cell mitochondrial-dependent apoptosis.…”

“…Current studies in intracellular calcium overload focus mainly on calcium carbonate nanoparticles (CaCO 3 NPs), [15][16][17][18] calcium phosphate nanoparticles [Ca 3 (PO 4 ) 2 NPs], 19 and calcium sulfide nanoparticles (CaS NPs), 4 etc. However, these calciumbased nanoparticles present slow intracellular Ca 2+ delivery, and meanwhile tumor lactic acidosis cannot be efficiently eliminated as well.…”