Rational design and generation of a bimodal bifunctional ligand for antibody-targeted radiation cancer therapy.
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.
Chemistry Division, Biological, Chemical, and Physical Sciences Department, Illinois Institute of Technology, Chicago, Illinois 60616, USA. chong@iit.edu
Hyun-Soon
HS
Chong
Xiang
X
Ma
Thien
T
Le
Baidoo
B
Kwamena
Diane E
DE
Milenic
Erik D
ED
Brady
Hyun A
HA
Song
Martin W
MW
Brechbiel
D000818:Animals; D000906:Antibodies; D001729:Bismuth; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D004355:Drug Stability; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007553:Isotope Labeling; D007700:Kinetics; D008024:Ligands; D008187:Lutetium; D051379:Mice; D008819:Mice, Nude; D016499:Radioimmunotherapy; D011868:Radioisotopes; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D044967:Serum; D013056:Spectrophotometry, Ultraviolet; D014018:Tissue Distribution
C526804:(4-(2-(bis(carboxymethyl)amino)-3-(4-nitrophenyl)propyl)-7-carboxymethyl(1,4,7)triazanonan-1-yl)acetic acid; D000906:Antibodies; D002614:Chelating Agents; D006573:Heterocyclic Compounds, 1-Ring; D008024:Ligands; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D008187:Lutetium; D005998:Glycine; D001729:Bismuth