The acidic pH found in the extracellular fluid of many cancer tumors is an important difference from the slightly basic pH found in the corresponding benign cells. Contrary to common anti‐cancer drugs that have significant side effects in healthy cells, calcium sulfide (CaS) nanoclusters have shown to induce apoptosis selectively in human lung, skin, and breast cancer cell lines in vitro. We hypothesize that CaS nanostructures selectively dissociate in the characteristic acidic extracellular environments of cancer cells into free Ca2+ ions and sulfides such as H2S, HS‐ and S2‐, which can be proved via bench and computational experiments. Theoretical calculations at the DFT/B3LYP/DGVZVP level of theory of bare and protonated (CaS)n clusters (n = 1 to 4) were performed to address this hypothesis using the Gaussian 16W and GaussView 6.0.16 programs by varying the number of protons in a CaS cluster to assess cluster stability and reaction pathways in both acidic and neutral media. The total cluster energy decreases with the number of monomer units (n) in the (CaS)n clusters. The CaS monomer and dimer are more stable in water than in their corresponding standard state by about 336kJ/mol and 390kJ/mol, respectively. A single protonation of a sulfur atom in the solvated monomer results in an increase in the Ca‐S bond length from 2.55Å to 2.73Å, indicative of increasing drive to dissociate. It requires protonation of a sulfur atom by two hydrogen atoms to dissociate the cluster into free Ca2+ and H2S. Water facilitates the dissociation of the clusters when the sulfur atom is bonded by two protons. The products of the reaction of the solvated (CaSH2)2+ is more stable than the corresponding gas phase cluster ion by a significant 1479 kJ/mole. These results are consistent with the dissociation of CaS clusters to free Ca2+ and H2S in acidic media like the one found in the extracellular fluid of malignant tumors. Ca2+ ions are known to cause cell damage in cytosolic concentrations higher than 500nM. The biochemistry of H2S is still under study by several groups worldwide but it is generally accepted that it can be genotoxic and induce apoptosis. Therefore, CaS nanoclusters are promising drugs to selectively inhibit malignant tumor growth with little impact on benign tissue. The results are discussed in terms of the basic requirements of a (CaS)n‐based formulation for cancer treatment.

An acidic extracellular pH value (pHe) is characteristic of many cancers, in contrast to the physiologic pHe found in most benign cells. This difference in pH offers a unique opportunity to design and engineer chemicals that can be employed for pH-selective reactions in the extracellular fluid of cancer cells. The viability of human skin melanoma and corresponding fibroblasts exposed to CaS dispersions is reported. The viability of melanoma cells decreases with CaS dispersion concentration and reaches 57% at 3%, a value easily distinguishable from melanoma control experiments. In contrast, the viability of benign fibroblasts remains nearly constant within experimental error over the range of dispersion concentrations studied. The CaS dispersions facilitate vinculin delocalization in the cytoplasmic fluid, a result consistent with improved focal adhesion kinase (FAK) regulation in melanoma cells. Thermodynamic considerations are consistent with the formation of H2S from CaS in the presence of protons. The thermodynamic prediction is verified in independent experiments with solid CaS and acidic aqueous solutions. The amount of H2S formed decreases with pH. An activation energy for the process of (30 ± 10) kJ/mol in the temperature range of 280 to 330 K is estimated from initial rate measurements as a function of temperature. The total Gibbs energy minimization approach was employed to establish the distribution of sulfides—including H2S in the gas and aqueous phases—from the dissociation of CaS as a function of pH to mimic physiologically relevant pH values. Theoretical calculations suggest that partially protonated CaS in solution can be stable until the sulfur atom bonds to two hydrogen atoms, resulting in the formation of Ca2+ and H2S, which can be solvated and/or released to the gas phase. Our results are consistent with a model in which CaS is dissociated in the extracellular fluid of melanoma cells selectively. The results are discussed in the context of the potential biomedical applications of CaS dispersions in cancer therapies.

A common denominator of many cancer cells is that the extracellular pHe value is acidic (pHe<7) in contrast to the basic pHe values (>7) found in benign cells. The difference in the pHe values of cancer and benign cells has the potential to turn into a tool to develop chemical processes that will act against cancer cell proliferation selectively with a reduced impact in benign cells. We hypothesize that CaS nanostructures can selectively dissociate into Ca2+ ions and sulfides in the acidic extracellular fluid of cancer cells but not in the basic microenvironment of benign cells. We have studied the reactions of CaS as a function of pH to simulate the different extracellular environments of cancer and benign cells using the Gibbs minimization approach in the Python environment. We found that the CaS readily dissociated in the acidic pH values to Ca2+ ions and sulfides. The sulfides are distributed in pH sensitive species that include gaseous H2S, aqueous H2S, HS‐ and S2‐ ions. The results are consistent with experimental observations of H2S production from CaS as a function of pH performed in the laboratory bench. The results are discussed in the context of possible chemical process that take advantage of the acidic microenvironment in cancer tissues to selectively induce apoptosis in the cancer cells with no effect in the corresponding benign cells, reducing secondary effects associated with chemotherapies in the market today.