Malignant melanoma is a very aggressive form of skin cancer, with a low long-term survival rate. Developing multifunctional theranostic agents to simultaneously track and inhibit the activity of tumor targets is a potential strategy for combating melanoma metastasis. S100B expression is directly correlated with the degree of malignant metastatic melanoma and is overexpressed in the majority of malignant melanoma patients. Herein, the Ir(III) complex 7 was identified as a potent theranostic agent with nanomolar potency against S100B and selectivity over related substrates. Complex 7 exhibited desirable photophysical properties including a large Stokes shift and high photostability, while its long emission lifetime enabled its luminescence signal to be discriminated from a highly autofluorescent background by use of time-resolved emission spectroscopy. Importantly, complex 7 showed strong colocalization with S100B protein in melanoma cells with a stable signal up to at least 12 h, revealing its potential as a cellular probe for S100B. Moreover, complex 7 impeded the interaction between S100B and the C-terminus of p53 in the cytoplasm, thereby restoring the binding of p53 to its target promoters. Finally, complex 7 suppressed tumor growth and restrained lung metastases in vivo in two separate melanoma mouse models. To our knowledge, complex 7 is the first reported theranostic agent for simultaneously monitoring S100B and suppressing malignant melanoma metastasis in vivo via targeting S100B protein.

中文翻译：

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脂肪族束缚铱复合物作为治疗恶性黑色素瘤转移的治疗剂

恶性黑色素瘤是一种侵袭性很强的皮肤癌，长期存活率低。开发多功能治疗诊断剂以同时跟踪和抑制肿瘤靶点的活性是对抗黑色素瘤转移的潜在策略。S100B 表达与恶性转移性黑色素瘤的程度直接相关，并且在大多数恶性黑色素瘤患者中过度表达。在此，Ir(III) 配合物7被鉴定为一种有效的治疗诊断剂，具有针对 S100B 的纳摩尔效力和对相关底物的选择性。复杂7表现出理想的光物理特性，包括大斯托克斯位移和高光稳定性，而其长发射寿命使其能够通过使用时间分辨发射光谱将其发光信号与高度自发荧光背景区分开来。重要的是，复合物7在黑素瘤细胞中显示出与 S100B 蛋白的强共定位，并且在至少 12 小时内具有稳定的信号，揭示了其作为 S100B 细胞探针的潜力。此外，复合物7阻碍了 S100B 与细胞质中 p53 的 C 端之间的相互作用，从而恢复了 p53 与其靶启动子的结合。最后，复合物7在体内抑制肿瘤生长并抑制肺转移在两个单独的黑色素瘤小鼠模型中。据我们所知，复合物7是第一个报道的通过靶向 S100B 蛋白同时监测 S100B 和抑制体内恶性黑色素瘤转移的治疗诊断剂。