Abstract
Cancer is the second leading cause of death in the United States after heart disease. Because the frequency of cancer diagnoses is correlated with life expectancy, we can expect the rate of cancer diagnosis to increase with the increase of life expectancy. Additionally, cancer treatments are notoriously costly and challenging due to the heterogeneity of the cancer cell population. For these reasons, devising methods to study the characteristics, efficiently diagnose and treat cancer is extremely important. Warburg effect has been considered as the most unique mechanism that differ cancer cells from normal cells. Normally, most of the healthy cells predominantly produce energy by a low rate of glycolysis and oxidation of pyruvate in mitochondria, called oxidative phosphorylation. In the 1920s, Otto Warburg observed that tumors uptake a massive amount of glucose compared to its surrounding healthy tissues. Additionally, glycolysis was continued even in the presence of oxygen, called aerobic glycolysis. Cancer cells trend to metabolize excessive uptake of glucose and ferment to lactate unlike normal cells, even in the presence of oxygen and fully functioning mitochondria. This high rate of aerobic glycolysis in cancer cells is known as Warburg effect, which has been studied extensively especially after 2000s. Cancer cells have an unusually high rate of glycolysis and subsequently lactic acid fermentation to produce energy for cell activities, even under aerobic conditions, a seemingly inefficient way of producing energy. It is recognized that cancer tumors undergo acidification due to the Warburg effect and the overexpression of carbonic anhydrase enzymes at the surfaces of cancer cells, making acidity a universal tumor characteristic, and following the micro calories exchange during glycolytic fermentation. The more invasive the cancer is, the greater the extra-cellular acidosis and heat production. The pH (Low) Insertion Peptides comprise a novel class of pH-sensitive targeting agents that spontaneously insert into cell membranes under acidic conditions. Therefore, the applicability of pHLIP® peptides to tumor-targeting applications is an obvious choice for investigation, it could be reconstructed with many different types of imaging and therapeutic agents. The membrane associated folding mechanism of action of pHLIP is triggered by low pH. The high concentration of proton in the low pH environment increase the protonation of the protonatable residues in pHLIP, which increase the overall hydrophobicity and drives the peptide into the hydrophobic core of the membrane, where it forms transmembrane helix. The two terminus of the peptide, one stays in the extracellular space
Highlights
Otto Warburg discovered that cancer cells predominately use glycolysis for ATP production even when oxygen supply is sufficient, and he found that tumor microenvironment is more acidic than that in normal tissues [1]
We demonstrated using quenching of SNARF fluorescence by membrane impermeable Trypan Blue that SNARF pH Low Insertion Peptide (pHLIP) is not taken by endocytosis, and SNARF is located in the extracellular space and reports about cell surface pH [9]
After development of magnetic resonance spectroscopy (MRS) methods it was found that pHi in cancer cells is similar to or slightly more basic than that in normal cells, while pHe in tumors was more acidic than pHe in healthy tissues [3, 5]
Summary
Otto Warburg discovered that cancer cells predominately use glycolysis for ATP production even when oxygen supply is sufficient, and he found that tumor microenvironment is more acidic than that in normal tissues [1]. The metabolic chemical reactions and the various kinds of ions directional flows in living cells driven by electrochemical potentials and energy-consuming pumping processes is hypothesized to result in the heat production [3, 4]. With the development of new methods and technologies, there are appeared some recent studies on thermogenesis at single-cell level. In this part, I will introduce the methods that we developed for single cell heat production measurements, progresses and some results. Nanocarriers decorated with pHLIPs are biocompatible, can target tumor and demonstrate enhanced cellular uptake by cancer cells (Du et al, 2014, Wijesinghe et al, 2013, Yao et al, 2013b, Arachchige et al, 2015, Yao et al, 2013a). In addition to pHLIP-coated nanoparticles, nanocarriers containing pHsensitive polymers and lipids were known for decades (Chu et al, 1990, Subbarao et al, 1987, Karanth and Murthy, 2007, Lee et al, 1998)
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