Prodrug Approaches to Target Tumor Acidosis and Counter Drug Resistance in Cancer Chemotherapy

November 4, 2016

Ming An

Many cancerous tumors have extracellular pH (pHe) in the range of 6.5-7.0, compared with that of 7.2-7.4 in healthy tissues. This small difference in pH presents an exciting opportunity, as well as a great challenge, for selective drug release to cancer cells. In addition, an under-appreciated mechanism of drug resistance is that tumor acidosis can directly reduce the potency of many amine drugs, such as anthracyclins, topotecan, vinka alkaloids and others, by simply decreasing their membrane permeability (because they are more protonated at tumor pHe). We aim to develop novel targeted chemotherapy based on selective prodrug activation in response to tumor acidosis. Two ultra acid-sensitive prodrug approaches will be discussed: (a) extracellular drug release via cleavable, disubstituted maleamic acid (DMA) linker, and (b) active intracellular drug translocation and release by pH-Low Insertion Peptide (pHLIP). To better understand the pH-sensing mechanism of pHLIP, through collaboration with the Wei Qiang lab, we used ssNMR to characterize the protonation-driven pHLIPmembrane interactions in unprecedented details. Our data revealed how pHLIP has a highly sophisticated, measured / graded response to acidity throughout the entire pH range of 6.8 to 5.5, which is accomplished by sequential protonations of D31 (pKa 6.5), D33 (pKa 6.3), D25 (pKa 6.1) and D14 (pKa 5.8) residues with gradual sinking and folding into the membrane. Such information will guide the
design of next generation pHLIP prodrugs.