Chem
Volume 7, Issue 2, 11 February 2021, Pages 480-494
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Article
Synergistic Combination of Calcium and Citrate in Mesoporous Nanoparticles Targets Pleural Tumors

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Highlights

  • Synthesis of mesoporous, amorphous calcium-phosphate citrate nanoparticles

  • Induction of apoptosis selectively in cancer cells

  • Excellent growth inhibition of pleural tumors with minimal adverse effects

The Bigger Picture

Pleural tumors are often highly aggressive and rapidly growing. Their proximity to the lung requires highly selective anticancer agents to avoid adverse effects. Such a selective anticancer agent is an urgent, yet unmet clinical need. A promising strategy to realize this selectivity may be based on a material that degrades selectively in cancer cells and releases high amounts of ions into these cells. Calcium and citrate are ions that are generally nontoxic, but they can induce cell death when released into a cell at high concentrations. However, triggering their efficient release selectively in cancer cells has not been achieved yet. Here, we developed mesoporous, amorphous calcium-phosphate citrate nanoparticles. These features are key to their intracellular degradation, allowing for ion release and selective toxicity toward cancer cells. Successful mouse experiments show their potential to meet the clinical need for a therapeutic against pleural tumors.

Summary

Conventional chemotherapy leads to severe adverse effects since it involves systemic administration of toxic drugs at high dosage. Unlike traditional chemotherapeutics, calcium phosphate and citrate have both been discussed as very promising anticancer agents and are not inherently toxic. Yet, their breakthrough has been hampered by the lack of an administration approach that overcomes the strict regulatory mechanisms of the cell. Here, we present a combinatorial administration of calcium, phosphate, and citrate as colloidal, amorphous nanoparticles (CPCs) that selectively kill cancer cells without involvement of inherently toxic drugs. The particles are toxic neither before endosomal release nor after their degradation. This highly selective toxicity allowed us to successfully treat two different aggressive pleural tumors in mice, reducing their size by about 40% and 70% after only two local applications. Safety assessment studies over 2 months show no signs of adverse effects except for slightly enhanced pleural thickening after eight applications.

UN Sustainable Development Goals

SDG3: Good health and well-being

Keywords

calcium phosphate
citrate
mesoporous nanoparticles
pleural tumor
ion release
selective toxicity
anticancer agent

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Present address: Faculty of Pharmacy, Universitas Gadjah Mada, Indonesia

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