A novel drug therapeutic treatment: hydrogen uncaging using flash photolysis for fast and focal intracellular acidification as a cancer therapeutic system

Current therapies for many types of cancers involve the disruption of the cancer cells' ability to alter intracellular pH (pH i). Virtually all mammalian cells, including cancerous cells, ubiquitously express the transmembrane sodium-hydrogen exchanger (NHE1), which is used to regulate pHi, salt concentrations and cell volume. Cancer cells use NHE1 to their advantage by upregulating the expression of the NHE1 protein and continually activating NHE1 to achieve cytosolic alkalization as well as extracellular acidification for increased local vascularization. Many chemotherapeutic approaches to cancer treatment involve the use of proton pump inhibitors (PPI's) to block NHE1 in order to cause a decrease in pH i and disrupt cell functions and tumor progression. However, PPI's are systemically delivered and often cause devastating side effects to normal cells. Our lab developed a novel technique using the photolytic compound 2-nitrobenzaldehyde (NBA) to induce fast and focal intracellular acidification by releasing hydrogen ions in the presence of ultraviolet (UV) light in healthy rat pheochromocytoma (PC12) cells and MCF-7 breast cancer cells. The cancer cells were also treated with NBA-conjugated upconversion nanoparticles to absorb near infrared light and emit UV light for non-invasive remote activation of NBA. This hydrogen uncaging technique has shown exceedingly high cell death through the activation of a previously undiscovered positive feedback loop seen in in MCF-7 cancer cells but not in healthy PC12 cells. The use of NBA and NBA-conjugated nanoparticles also showed minimal cytotoxic effects in the absence of UV activation. These results support our hypothesis that focal intracellular acidification would be an excellent candidate for future cancer therapeutics.