Rational Design and Generation of a Bimodal Bifunctional Ligand for Antibody-Targeted Radiation Cancer Therapy
| Autor: | Diane E. Milenic, Hyun-Soon Chong, Baidoo Kwamena, Hyun A. Song, Thien Le, Erik D. Brady, Martin W. Brechbiel, Xiang Ma |
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| Rok vydání: | 2007 |
| Předmět: |
Serum
Biodistribution Stereochemistry medicine.medical_treatment Glycine Mice Nude Lutetium Ligands Antibodies Article Heterocyclic Compounds 1-Ring Mice chemistry.chemical_compound Drug Stability In vivo Drug Discovery medicine Animals Humans Moiety Tissue Distribution Chelation Bifunctional Chelating Agents Radioisotopes Chemistry Ligand Rational design Radioimmunotherapy Kinetics Drug Design Isotope Labeling Molecular Medicine Female Spectrophotometry Ultraviolet Radiopharmaceuticals Bismuth |
| Zdroj: | Journal of Medicinal Chemistry. 51:118-125 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | An antibody-targeted radiation therapy (radioimmunotherapy, RIT) employs a bifunctional ligand that can effectively hold a cytotoxic metal with clinically acceptable complexation kinetics and stability while being attached to a tumor-specific antibody. Clinical exploration of the therapeutic potential of RIT has been challenged by the absence of adequate ligand, a critical component for enhancing the efficacy of the cancer therapy. To address this deficiency, the bifunctional ligand C-NETA in a unique structural class possessing both a macrocyclic cavity and a flexible acyclic moiety was designed. The practical, reproducible, and readily scalable synthetic route to C-NETA was developed, and its potential as the chelator of (212)Bi, (213)Bi, and (177)Lu for RIT was evaluated in vitro and in vivo. C-NETA rapidly binds both Lu(III) and Bi(III), and the respective metal complexes remain extremely stable in serum for 14 days. (177)Lu -C-NETA and (205/6)Bi -C-NETA possess an excellent or acceptable in vivo biodistribution profile. |
| Databáze: | OpenAIRE |
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