Novel Structural Modification Based on Evans Blue Dye to Improve Pharmacokinetics of a Somastostatin-Receptor-Based Theranostic Agent

The development of somastatin (SS) peptide analogues for the detection and treatment of neuroendocrine tumors has been successful with the recent FDA approval of Ga-68-DOTA-TATE and Lu-177-DOTA-TATE. The structure of these peptide constructs contains the peptide binding motif that binds to the receptor with high affinity, a chelator to complex the radioactive metal, and a linker between the peptide and chelator. However, these constructs suffer from rapid blood clearance, which limits their tumor uptake. In this study, this design has been further improved by incorporating a modification to control the in vivo pharmacokinetics. Adding a truncated Evans Blue (EB) dye molecule into the construct provides a prolonged half-life in blood as a result of its low micromolar affinity to albumin. We compared Lu-177-DOTA-TATE to the modified Lu-177 Evans Blue compound (Lu-177-DMEB-TATE), in vitro and in vivo in mice bearing A427-7 xenografts. The tumor uptake of Lu-177-DMEB-TATE was significantly greater than the uptake of Lu-177-DOTA-TATE in the biodistribution and SPECT-imaging studies. The therapeutic effect of the Lu-177-DMEB-TATE construct was superior to the that of the Lu-177-DOTA-TATE construct at the doses evaluated.