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A Selective-Tumor-Penetrating Strategy via Unidirectional Direct Transfer for Intravesical Therapy of Bladder Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-03-18 , DOI: 10.1021/acs.jmedchem.4c00060 Xiaowen Qin 1 , Heng Wang 1 , Wentao Xu 2, 3 , Bin Zheng 1 , Haibao Zhang 4 , Qi Zhang 1 , Yang Liu 5 , Zhenghong Liu 1 , Li Sun 1 , Yixuan Mou 1 , Cenchao Yao 6 , Wei Zheng 1 , Yiyang Chen 1 , Chenkai Wang 1 , Xuanyi Zhou 1 , Youqing Shen 7 , Pu Zhang 1 , Dahong Zhang 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-03-18 , DOI: 10.1021/acs.jmedchem.4c00060 Xiaowen Qin 1 , Heng Wang 1 , Wentao Xu 2, 3 , Bin Zheng 1 , Haibao Zhang 4 , Qi Zhang 1 , Yang Liu 5 , Zhenghong Liu 1 , Li Sun 1 , Yixuan Mou 1 , Cenchao Yao 6 , Wei Zheng 1 , Yiyang Chen 1 , Chenkai Wang 1 , Xuanyi Zhou 1 , Youqing Shen 7 , Pu Zhang 1 , Dahong Zhang 1
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A selective tumor-penetrating strategy generally exploits tumor-targeted ligands to modify drugs so that the conjugate preferentially enters tumors and subsequently undergoes transcellular transport to penetrate tumors. However, this process shields ligands from their corresponding targets on the cell surface, possibly inducing an off-target effect during drug penetration at the tumor-normal interface. Herein, we first describe a selective tumor-penetrating drug (R11-phalloidin conjugates) for intravesical therapy of bladder cancer. The intravesical conjugates rapidly translocated across the mucus layer, specifically bound to tumors, and infiltrated throughout the tumor via direct intercellular transfer. Notably, direct transfer from normal cells to tumor cells was unidirectional because the pathways required for direct transfer, termed F-actin-rich tunneling nanotubes, were more unidirectionally extended from normal cells to tumor cells. Moreover, the intravesical conjugates displayed strong anticancer activity and well-tolerated biosafety in murine orthotopic bladder tumor models. Our study demonstrated the potential of a selective tumor-penetrating conjugate for effective intravesical anticancer therapy.
中文翻译：
通过单向直接转移的选择性肿瘤穿透策略用于膀胱癌膀胱内治疗
选择性肿瘤穿透策略通常利用肿瘤靶向配体来修饰药物，使结合物优先进入肿瘤，随后进行跨细胞转运以穿透肿瘤。然而，这个过程屏蔽了配体与细胞表面相应靶标的接触，可能在药物渗透到肿瘤-正常界面时引起脱靶效应。在此，我们首先描述了一种用于膀胱癌膀胱内治疗的选择性肿瘤穿透药物（R11-鬼笔环肽结合物）。膀胱内结合物快速转移穿过粘液层，特异性结合肿瘤，并通过直接细胞间转移渗透到整个肿瘤。值得注意的是，从正常细胞到肿瘤细胞的直接转移是单向的，因为直接转移所需的途径（称为富含 F-肌动蛋白的隧道纳米管）更单向地从正常细胞延伸到肿瘤细胞。此外，膀胱内结合物在小鼠原位膀胱肿瘤模型中表现出强大的抗癌活性和良好的耐受性生物安全性。我们的研究证明了选择性肿瘤穿透缀合物用于有效膀胱内抗癌治疗的潜力。
更新日期：2024-03-18
中文翻译：
通过单向直接转移的选择性肿瘤穿透策略用于膀胱癌膀胱内治疗
选择性肿瘤穿透策略通常利用肿瘤靶向配体来修饰药物，使结合物优先进入肿瘤，随后进行跨细胞转运以穿透肿瘤。然而，这个过程屏蔽了配体与细胞表面相应靶标的接触，可能在药物渗透到肿瘤-正常界面时引起脱靶效应。在此，我们首先描述了一种用于膀胱癌膀胱内治疗的选择性肿瘤穿透药物（R11-鬼笔环肽结合物）。膀胱内结合物快速转移穿过粘液层，特异性结合肿瘤，并通过直接细胞间转移渗透到整个肿瘤。值得注意的是，从正常细胞到肿瘤细胞的直接转移是单向的，因为直接转移所需的途径（称为富含 F-肌动蛋白的隧道纳米管）更单向地从正常细胞延伸到肿瘤细胞。此外，膀胱内结合物在小鼠原位膀胱肿瘤模型中表现出强大的抗癌活性和良好的耐受性生物安全性。我们的研究证明了选择性肿瘤穿透缀合物用于有效膀胱内抗癌治疗的潜力。
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