Nuclear Medicine and Biology 2013-04-01

Synthesis and application of a novel cysteine-based DTPA-NCS for targeted radioimmunotherapy.

So-Young Lee, Young Don Hong, Hak-Sung Kim, Sun-Ju Choi

Index: Nucl. Med. Biol. 40(3) , 424-9, (2013)

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Abstract

For the development of safe and effective protein-based radiolabeled complexes such as radioimmunotherapy (RIT), the selection of the radionuclides and the chelating agents used for the radiolabeling of tumor-targeting molecules is a critical factor. We aim to synthesize a novel bifunctional chelating agent containing the isothiocyanate group for easy conjugation with antibodies having the characteristics of high stable chelation with therapeutic radionuclides.We have synthesized the DTPA analogue retaining L-cysteine as a core ligand of the thiol group. The chelating power of cysteine-based DTPA-NCS (cys-DTPA-NCS) was compared with that of commercial ρ-SCN-Bn-DTPA. In an application, the cetuximab was radioimmunoconjugated with (177)Lu using cys-DTPA-NCS. The affinity was tested in a cell line overexpressing EGFR. A therapy study was conducted in nude mice with subcutaneous HT-29 xenografts.The cys-DTPA-NCS presents an excellent ability to chelate as compared to the ρ-SCN-Bn-DTPA. For mean ratio chemical labeling yields of 95%, the result was 0.97. (177)Lu-cys-DTPA-NCS-cetuximab was prepared under ambient condition with a high radiolabeling yield and the radiochemical purity was sustained for at least 6days. The IC50 value of the (177)Lu-labeled cetuximab was 10nM (95% confidence). The stability and therapeutic efficacy of the candidate radiopharmaceutical were verified.The new DTPA derivative, cys-DTPA-NCS, is a good bifunctional chelating agent that can be used for protein-based radiopharmaceutical using lanthanides such as (177)Lu and (90)Y. The prepared (177)Lu-cys-DTPA-NCS-cetuximab can be used for the diagnosis and treatment of human colorectal tumor.Copyright © 2013 Elsevier Inc. All rights reserved.