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Methods for producing drugs directly at the cancer site, particularly using bioorthogonal metal catalysts, are being explored to mitigate the side effects of therapy. Albumin‐based artificial metalloenzymes (ArMs) catalyze reactions in living mice while protecting the catalyst in the hydrophobic pocket. Here, we describe the in situ preparation and application of biocompatible tumor‐targeting ArMs using circulating albumin, which is abundant in the bloodstream. The ArM was formed using blood albumin through the intravenous injection of ruthenium conjugated with an albumin‐binding ligand; the tumor‐targeting unit was conjugated to the ArM using its catalytic activity, and the ArM was transported to the cancer site. The delivered ArM catalyzed a second tagging reaction of the proapoptotic peptide on the cancer surface, successfully suppressing cancer proliferation. This approach, which efficiently leveraged the persisting reactivity twice in vivo, holds promise for future in vivo metal‐catalyzed drug synthesis utilizing endogenous albumin. [ABSTRACT FROM AUTHOR]

Targeted α-particle therapy (TAT) is an attractive alternative to conventional therapy for cancer treatment. Among the available radionuclides considered for TAT, astatine-211 ( 211 At) attached to a cancer-targeting molecule appears very promising. Previously, we demonstrated that aryl azide derivatives could react selectively with the endogenous acrolein generated by cancer cells to give a diazo compound, which subsequently forms a covalent bond with the organelle of cancer cells in vivo . Herein, we synthesized 211 At-radiolabeled 2,6-diisopropylphenyl azide (ADIPA), an α-emitting molecule that can selectively target the acrolein of cancer cells, and investigated its antitumor effect. Our results demonstrate that a single intratumor or intravenous administration of this simple α-emitting molecule to the A549 (human lung cancer) cell-bearing xenograft mouse model, at a low dose (70 kBq), could suppress tumor growth without inducing adverse effects. Furthermore, because acrolein is generally overproduced by most cancer cells, we believe ADIPA is a simple TAT compound that deserves further investigation for application in animal models and humans with various cancer types and stages., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)