Identification of side arm-modified DOTA scaffolds as multi-site binding ligands for cancer cells over normal cells

Abstract The metal-chelated 1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid-tetraamide (DOTA) scaffold has been widely used as a contrast agent for diagnostic purposes in positron emission tomography (PET) and magnetic resonance imaging (MRI), but not as a biomarker targetable ligand. While the oxygen atoms at the stem of the four arms of the DOTA scaffold are needed for metal chelation, we previously introduced various physiochemical properties to extend these arms in a chemical library fashion to enhance the imaging contrast mechanism. We developed two such on-bead libraries, with 80 and 76 DOTA derivatives, where one arm was used to attach the DOTA scaffold onto resin beads and the other three arms were chemically modified. We now hypothesized that the chemical moieties used to modify these three arms can also recognize biomarkers on a cell surface. Therefore in this current study, we used such 76 derivatives of DOTA library to screen against HeLa cervical cancer cells. We found that two of the four ‘hits’ identified displayed higher binding towards HeLa cells than the unmodified parent DOTA. Furthermore, one of those ‘hits’ displayed better binding towards cervical and prostate cancer cells than lung and breast cancer cells and normal HBEC-3KT and RWPE1 cells. This indicates that this derivative can recognize a biomarker specific for certain types of cancer cells. If the compounds has intrinsic activity, this can be used as a theranostic agent for real time therapy monitoring applications in the future. We believe that our DOTA derivative-based library approach can be applied to other types of cell and protein screens on various disease types in the future.