biological responses can indirectly lead to cancer cell death without significantly harming surrounding tissue. As depicted in Figure B-I, we showed that individual HeLa cancer cells in living mice can be tagged in vivo with cyclic-Arg-Gly-Asp (cRGD) moieties for integrin-blocking, leading to disrupted cell adhesion and compromised successful seeding onto the extracellular matrix (ECM). The mice populations that received just one dosage of the SeCT labeling reagents via intrapenetrial injection showed a significant delay in tumor onset by 4 weeks (Figure B-II), resulting in an improvement in overall survival rates over a period of 81 days. Following the same concept of the SeCT therapy, we developed a cancer therapy based on targeted cell surface tagging with proapoptotic peptide 1 (Ac-GGKLFG-X; X = a benzyl fluoride moiety) that induce apoptosis when attached to the cell surface (Figure C-I)8). Using the Ru-catalyzed alkylation, the proapoptotic peptide 1 showed excellent therapeutic effects in vivo. In particular, co-treatment with the proapoptotic peptide and the cRGD-coated ArM-Ru-2 significantly and synergistically inhibited tumor growth and prolonged survival rate of tumor-bearing mice after only Referencesa single injection (Figure C-II). Except the above samples, we also successfully carried out cancer treatment through localized in vivo drug synthesis9-11). As depicted in Figure D, we investigated the design and optimization of synthetic prodrugs that can be robustly transformed in vivo to reach therapeutically relevant levels. To do this, retrosynthetic prodrug design led to the identification of combretastatin-based prodrugs, which form highly active cytostatic agents via sequential ring-closing metathesis and aromatization (Figure D-I)10). In vivo activation by intravenously administered the GArM-Ru-1 was also found to induce significant reduction of implanted tumour growth in mice (Figure D-II).Since our technology is targeting, non-invasive, without risk of immunogenicity, non-toxicity, and high efficiency of in vivo drug synthesis, we must point out that our technology could be the only possible method to apply to patients for disease treatment in a hospital. We anticipate that our technology will make a substantial contribution to biomedical fields in the future. 1) Fujiki K, Tanaka K. RIKEN click reagent for protein labeling, Encyclopedia of Reagents for Organic Synthesis (e-EROS): 2017 2) Latypova L, Sibgatullina R, Ogura A, Fujiki K, Khabibrakhmanova A, Tahara T, Nozaki S, Urano S, Tsubokura K, Onoe H, Watanabe Y, Kurbangalieva A, Tanaka K. Sequential double “clicks” toward structurally well-defined heterogeneous N-glycoclusters: the importance of cluster heterogeneity on pattern recognition in vivo, Adv. Sci. (4): 1600394, 2017 3) Smirnov I, Sibgatullina R, Urano S, Tahara T, Ahmadi P, Watanabe Y, Pradipta AR, Kurbangalieva A, Tanaka K. A Strategy for tumor targeting by high-order glycan pattern recognition: Synthesis and in vitro and in vivo properties of glycoalbumins conjugated with four different N-glycan molecules, Small, (16): 2004831, 2020 4) Eda S, Nasibullin I, Vong K, Kudo N, Yoshida M, Kurbangalieva A, Tanaka K. Biocompatibility and therapeutic potential of glycosilated albumin 5) Vong K, Eda S, Kadota Y, Nasibullin I, Wakatake T, Yokoshima S, Shirasu K, Tanaka K. An artificial metalloenzyme biosensor can detect ethylene gas in 6) Tsubokura, K. Vong, KKH, Pradipta, AR, Ogura A, Urano S, Tahara T, Nozaki S, Onoe H, Nakao Y, Sibgatullina R, Kurbangalieva A, Watanabe Y, 7) Vong K, Tahara T, Urano S, Nasibullin I, Tsubokura K, Nakao Y, Kurbangalieva A, Onoe H, Watanabe Y, Tanaka K. Disrupting tumor onset and growth 8) Ahmadi P, Muguruma K, Chang TC, Tamura S, Tsubokura K, Egawa Y, Suzuki T, Dohmae N, Nakao Y, Tanaka K. In vivo metal-catalyzed SeCT therapy 9) Chang TC, Vong K, Yamamoto T, Tanaka K. Prodrug activation by gold artificial metalloenzyme-catalyzed synthesis of phenanthridinium derivatives artificial metalloenzymes, Nature Catal. (2): 780-792, 2019fruits and arabidopsis leaves, Nature Commun. (10): 5746, 2019Tanaka K. In vivo gold complex catalysis within live mice, Angew. Chem. Int. Ed. (56): 3579-3584, 2017via selective cell tagging (SeCT) therapy, Sci. Adv. (7): eabg4038, 2021by a proapoptotic peptide, Chem. Sci. (12): 12266-12273, 2021via hydroamination, Angew. Chem. Int. Ed. (60): 2-11, 202110) Nasibullin I, Smirnov I, Ahmadi P, Vong K, Kurbangalieva A, Tanaka K. Synthetic prodrug design enables biocatalytic activation in mice to elicit tumor growth suppression, Nature Commun. (13): 39, 202211) Kurimoto M, Chang TC, Nishiyama Y, Suzuki T, Dohmae N, Tanaka K, Yokoshima S. Anticancer approach inspired by the hepatotoxic mechanism of pyrrolizidine alkaloids by glycosylated artificial metalloenzymes, Angew. Chem. Int. Ed., in press, 2022111
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