Calcium-Orchestrated Vascular Collapse in Cancer Therapy: Mechanisms, Nanotherapeutic Platforms, and Translational...

Cancer therapy is increasingly focused on manipulating the tumor microenvironment rather than directly eradicating malignant cells. Vascular-targeting strategies are emerging, and calcium-mediated vascular disruption is an exciting approach through which rapid and irreversible blood flow shutdown can be achieved. Here, we overview the molecular and physiological basis of calcium signaling in vascular homeostasis and outline how unregulated calcium dysfunctions in endothelial cells compromise their functionality and represent therapeutic opportunities. Elevation of intracellular calcium concentrations in endothelial cells promotes their dysfunction, coagulation, mitochondrial collapse, oxidative stress, and ultimately apoptosis, resulting in catastrophic vascular depletion and secondary necrosis that follows such collapse. A promising area of calcium-mediated attack is the emergence of exciting nanotechnologies that result in the development of calcium phosphate, calcium carbonate, and calcium peroxide nanoparticles, exploiting the enhanced permeability and retention effect of nanoparticle therapeutics to achieve selective tumor accumulation and controlled calcium release. Indeed, hybrid therapeutic platforms that couple calcium dysregulation with chemotherapy, photodynamic therapy, sonodynamic therapy, immunotherapy, or thermal ablation can exhibit pronounced antitumor effects through synergistic means. There is good preclinical evidence for the feasibility of vascular collapse mediated via calcium dysregulation. The transition of calcium to the clinic faces hurdles in relation to biosafety, how to achieve precise delivery, pharmacokinetics, and regulatory harmonization. Compared to traditional vascular disrupting agents and anti-angiogenic therapies, calcium modalities can provide rapid occlusion of vessels, are less prone to resistance development, and potentially have less systemic toxicity. Overall, calcium-mediated vascular collapse is thus an exciting next-generation technology for the vascular-targeted treatment of cancer, and likely to play an important role in precision oncology therapeutics.