Title : Targeted upconverting nanoparticle that kills cancer by disrupting intracellular pH regulation
Short Description of what will be discussed during the presentation (about 250 - 500 words)
Cancer cells regulate intracellular pH more efficiently than non-cancerous cells to promote growth. Given the important role of pH buffering in tumor growth and development, proton pump inhibition and its subsequent effect on cellular pH regulation is a logical chemotherapeutic approach. While it has been established that disruption of intracellular pH in cancer cells can cause apoptosis and necrosis, it has been difficult to elicit decreases in pH in cancer cells only. The most effective blockers of the pH regulatory transporter sodium/hydrogen exchanger 1 (NHE1) have been amiloride-based chemotherapies, which lead to decreases in intracellular pH (pHi) and an increases inextracellular pH (pHe). Decreases in pHi sensitize the cell to apoptosis while slowing tumor cell glycolytic metabolism, whereas increases in pHe limit angiogenesis, cell mobility, and tumor metastases. Unfortunately, past attempts to kill cancer by disrupting NHE1 function have caused severe unwanted systemic side effects, as NHE1 is ubiquitously expressed in every tissue, including non-cancerous cells. For example, the NHE1 inhibitor cariporide, which has proven to inhibit the growth of breast cancer cells in vitro, showed an unacceptable level of stroke during a large Phase III trial which led to the cessation of further clinical development. Vitanova Biomedical (VNB) have previously proved that focal intracellular acidosis and concomitant cancer cell death can be achieved by uncaging protons from nitrobenzaldehyde in response to ultraviolet (UV) light activation. To improve the clinical application of light-activated intracellular acidosis’ ability to treat human cancers, VNB developed an upconverting nanoparticle (UCNP) specifically tuned to absorb deep-penetrating 980 nm light and emit the UV light necessary to release protons from the nitrobenzaldehyde conjugated to the nanoparticle surface. In addition to UV light emission, the UCNP produces 477 nm emission which may serve as a useful theranostic tool for clinicians. This construct has proven to: 1) absorb 980 nm light; 2) emit UV and 477 nm light; and 3) cause acidosis. To avoid disruption of pHi in healthy tissue, VNB targeted the UCNP to prostate cancer cells by conjugating prostate specific membrane antibody to the surface of the UCNP. This targeted UCNP shows binding to the prostate specific membrane antigen in a dose dependent manner and represents a novel tool to kill prostate cancer without causing damage to nearby healthy tissue.