TY - JOUR
T1 - Novel Structural Modification Based on Evans Blue Dye to Improve Pharmacokinetics of a Somastostatin-Receptor-Based Theranostic Agent
AU - Bandara, Nilantha
AU - Jacobson, Orit
AU - Mpoy, Cedric
AU - Chen, Xiaoyuan
AU - Rogers, Buck E.
N1 - Funding Information:
We would like to acknowledge the Department of Radiation Oncology for the financial support for these studies. The authors would also like to thank the small-animal-imaging facility at Washington University School of Medicine for technical assistance. We would also like to acknowledge the University of Missouri Research Reactor (MURR) for production of 177Lu. We acknowledge Jalen Scott, Eric Tint, and Diana Tran for their assistance in the imaging and therapy studies. We are grateful to Dr. Marquiza C. Sablon (Research Scholar, Havana, Cuba)42 for her assistance in this work during her stay in the Rogers laboratory.
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/7/18
Y1 - 2018/7/18
N2 - The development of somastatin (SS) peptide analogues for the detection and treatment of neuroendocrine tumors has been successful with the recent FDA approval of 68Ga-DOTA-TATE and 177Lu-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 177Lu-DOTA-TATE to the modified 177Lu Evans Blue compound (177Lu-DMEB-TATE), in vitro and in vivo in mice bearing A427-7 xenografts. The tumor uptake of 177Lu-DMEB-TATE was significantly greater than the uptake of 177Lu-DOTA-TATE in the biodistribution and SPECT-imaging studies. The therapeutic effect of the 177Lu-DMEB-TATE construct was superior to the that of the 177Lu-DOTA-TATE construct at the doses evaluated.
AB - The development of somastatin (SS) peptide analogues for the detection and treatment of neuroendocrine tumors has been successful with the recent FDA approval of 68Ga-DOTA-TATE and 177Lu-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 177Lu-DOTA-TATE to the modified 177Lu Evans Blue compound (177Lu-DMEB-TATE), in vitro and in vivo in mice bearing A427-7 xenografts. The tumor uptake of 177Lu-DMEB-TATE was significantly greater than the uptake of 177Lu-DOTA-TATE in the biodistribution and SPECT-imaging studies. The therapeutic effect of the 177Lu-DMEB-TATE construct was superior to the that of the 177Lu-DOTA-TATE construct at the doses evaluated.
UR - http://www.scopus.com/inward/record.url?scp=85049242034&partnerID=8YFLogxK
U2 - 10.1021/acs.bioconjchem.8b00341
DO - 10.1021/acs.bioconjchem.8b00341
M3 - Article
C2 - 29927587
AN - SCOPUS:85049242034
SN - 1043-1802
VL - 29
SP - 2448
EP - 2454
JO - Bioconjugate Chemistry
JF - Bioconjugate Chemistry
IS - 7
ER -