Carbonic Anhydrase IX-Targeted α-Radionuclide Therapy with 225Ac Inhibits Tumor Growth in a Renal Cell Carcinoma Model

In this study, we compared the tumor-targeting properties, therapeutic efficacy, and tolerability of the humanized anti-CAIX antibody (hG250) labeled with either the α-emitter actinium-225 (225Ac) or the β--emitter lutetium-177 (177Lu) in mice. BALB/c nude mice were grafted with human renal cell carcinoma SK-RC-52 cells and intravenously injected with 30 µg [225Ac] Ac-DOTA-hG250 (225Ac-hG250) or 30 µg [177Lu] Lu-DOTA-hG250 (177Lu-hG250), followed by ex vivo biodistribution studies. Therapeutic efficacy was evaluated in mice receiving 5, 15, and 25 kBq of 225Ac-hG250; 13 MBq of 177Lu-hG250; or no treatment. Tolerability was evaluated in non-tumor-bearing animals. High tumor uptake of both radioimmunoconjugates was observed and increased up to day 7 (212.8 ± 50.2 %IA/g vs. 101.0 ± 18.4 %IA/g for 225Ac-hG250 and 177Lu-hG250, respectively). Survival was significantly prolonged in mice treated with 15 kBq 225Ac-hG250, 25 kBq 225Ac-hG250, and 13 MBq 177Lu-hG250 compared to untreated control (p < 0.05). Non-tumor-bearing mice that received single-dose treatment with 15 or 25 kBq 225Ac-hG250 showed weight loss at the end of the experiment (day 126), and immunohistochemical analysis suggested radiation-induced nephrotoxicity. These results demonstrate the therapeutic potential of CAIX-targeted α-therapy in renal cell carcinoma. Future studies are required to find an optimal balance between therapeutic efficacy and toxicity

2-Phenoxypyridyl Dinucleating Ligands for Assembly of Diiron(II) Complexes: Efficient Reactivity with O[subscript 2] to Form (μ-Oxo)diiron(III) Units

A series of 2-phenoxypyridyl and 2-phenoxyimino ligands, H[subscript 2]L[superscript R,R′] [2,2′-(5,5′-(1,2-phenylenebis(ethyne-2,1-diyl))bis(pyridine-5,2-diyl))diphenol, where R = H, Me, or t-Bu, and R′ = H or Ph] and H[subscript 2]BIPS[superscript Me,Ph] [(3,3′-(1E,1′E)-(3,3′-sulfonylbis(3,1-phenylene)bis(azan-1-yl-1-ylidene))bis(methan-1-yl-1-ylidene)bis(5-methylbiphenyl-2-ol)], were synthesized as platforms for nonheme diiron(II) protein model complexes. UV−vis spectrophotometric studies and preparative-scale reactions of L[superscript R,R′] or BIPS[superscript Me,Ph], where L[superscript R,R′] and BIPS[superscript Me,Ph] are the deprotonated forms of H[subscript 2]L[superscript R,R′] and H[subscript 2]BIPS[superscript Me,Ph], respectively, with iron(II) revealed that the presence of sterically protective o-phenol substituents is necessary to obtain discrete dinuclear species. The reaction of L[superscript Me,Ph] with iron(II) in tetrahydrofuran (THF) afforded the doubly bridged compound [Fe[subscript 2](L[superscript Me,Ph])[subscript 2](THF)[subscript 3]] (1), which was characterized in the solid state by X-ray crystallography. A large internal cavity in this complex facilitates its rapid reaction with dioxygen, even at −50 °C, to produce the thermodynamically stable [Fe[subscript 2](μ-O)(L[superscript Me,Ph])[subscript 2]] (2) species. Reaction of [superscript 18]O[subscript 2] instead of [superscript 16]O[subscript 2] with 1 led to a shift in the Fe−O−Fe vibrational frequency from 833 to 798 cm[superscript −1], confirming the presence of the (μ-oxo)diiron(III) core and molecular oxygen as the source of the bridging oxo group. The L[superscript Me,Ph] ligand is robust toward oxidative decomposition and does not display any reversible redox activity.National Institute of General Medical Sciences (U.S.) (Grant GM032134