Design and delivery of selective inhibitors of tumor overexpressed isozymes of carbonic anhydrase- towards new theranostic systems for cancer detection and treatment

Abstract

Cancer is the second most common cause of death and a major cause of mortality in the world. The high mortality associated with cancer is due to the fact that usually it is discovered too late, when it is metastasized to different organs and is very hard to cure. Finding more efficient, convenient and selective ways for early diagnosis and eradication of pre-malignant or malignant tumors of small dimensions is a task of utmost importance. The development of many malignant tumors was associated with hypoxia and the over-expression of specific membrane-bound carbonic anhydrase (CA) isozymes CA IX and CA XII. Malignant tissue of relatively small dimensions can grow fast and can invade the surrounding tissues by reverting to anaerobic metabolism and by acidifying the extracellular milieu around the tumor, increasing its invasiveness. Our goal is to detect and treat malignant hypoxic tumors using selective inhibitors of CA IX and CA XII and the objective of this thesis was to develop selective and efficient carbonic anhydrase inhibitors (CAIs) for the tumoral CA IX and CA XII that will leave unaltered the normal tissues. Two new sets of membrane-impermeant carbonic anhydrase inhibitors are proposed to be developed based on pyridinium positively-charged moieties attached to know CAI pharmacophores. Our guiding hypothesis was that modulation of carbonic anhydrase potency and tissue penetrability is possible to be achieved via fine tuning of pyridinium substitution. The use of appropriate substitutents on the pyridinium ring allowed the creation of CAI with special optical properties (e.g. fluorescence). The rationale for the research summarized in this thesis was that a CAI selective for membrane isozymes CA IX and CA XII over-expressed in cancer with controlled tissue penetrability can open new avenues in cancer early detection and treatment that will complement and/or potentiate present technologies and therapies.