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Nasibullin, I. Smirnov, P. Ahmadi, K. Vong, A. Kurbangalieva, K. Tanaka, Nature Commun. DOI : 10.1038/s41467-021-27804-5. 5B).39 The concept of SeCT therapy is based on a strategy of preferentially tagging specific cellswith a biological small molecule. In contrast to traditional chemotherapy that directly eliminates cancer cells using highly cytotoxic drugs, the principal benefit of SeCT therapy allows cancer cells to be tagged using non-toxic chemical moieties that can either disrupt cellular function (ex/ inhibitors of adhesion) or elicit immunological responses (ex/ antigens). Subsequent functional impairment or related biological responses can indirectly lead to cancer cell death without significantly harming surrounding tissue. As depicted in Figure 5B-I, it showed that individual HeLa cancer cells in living mice can be tagged in vivo with cyclic-Arg-GlyAsp (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 (Fig. 5B-II), resulting in an improvement in overall survival rates over a period of 81 days. Following the same concept of the SeCT therapy, we report 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 (Fig. 5C-I).40 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 a single injection (Fig. 5C-II). This is the first report of Ru catalyst application in vivo. Except of the above samples of therapeutic in vivo synthetic chemistry, we also successfully carried out cancer treatment through localized in vivo drug synthesis. As depicted in Figure 5D, 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 naphthylcombretastatin-based prodrugs, which form highly active cytostatic agents via sequential ring-closing metathesis and aromatization (Fig. 5D-I). Structural adjustments were then made to improve aspects related to catalytic reactivity, intrinsic bioactivity, and hydrolytic stability. Furthermore, in vivo activation by intravenously administered the GArM-Ru-1 was also found to induce significant reduction of implanted tumour growth in mice (Fig. 5D-II). Conclusions In an ideal world, one could simply perform reactions developed in a lab setting directly in a living system without any significant loss of reactivity. Unfortunately, for most transition metal catalyzed reactions, the key issues pertaining to biocompatibility are the ease of metal quenching and the intrinsic toxicities of metals. To the credit of many former and current researchers worldwide, numerous ways have been elegantly devised to successfully perform metal-catalyzed reactions in biological settings. Following the success of our works, our group is continuing to research how we can adapt GArMs for biomedical research, as well as to find ways to address the challenges needed for their improvement. Our final ambition is to cure diseases, especially cancer, without any side effects using our technology. 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, compared to other methods, 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. ◆
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