To develop a next-generation metal agent and dual-agent multitargeted combination therapy, we developed a copper (Cu) compound based on the properties of the human serum albumin (HSA)–indomethacin (IND) complex to remodel the tumor microenvironment (TME). We optimized a series of Cu(II) isopropyl 2-pyridyl ketone thiosemicarbazone compounds to obtain a Cu(II) compound (C4) with significant cytotoxicity and then constructed an HSA–IND–C4 complex (HSA–IND–C4) delivery system. IND and C4 bind to the hydrophobic cavities of the IB and IIA domains of HSA, respectively. In vivo, the HSA–IND–C4 not only showed enhanced antitumor efficacy relative to C4 and C4 + IND but also improved their targeting ability and decreased their side effects. The antitumor mechanism of C4 + IND involved acting on the different components of the TME. IND inhibited tumor-related inflammation, while C4 not only induced apoptosis and autophagy of cancer cells but also inhibited tumor angiogenesis.

中文翻译：

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基于人血清白蛋白-吲哚美辛复合物的IB子结构域开发铜(II)异丙基2-吡啶酮缩氨基硫脲化合物：通过重塑肿瘤微环境抑制肿瘤生长

为了开发下一代金属制剂和双制剂多靶点联合疗法，我们基于人血清白蛋白（HSA）-吲哚美辛（IND）复合物的特性开发了一种铜（Cu）化合物，以重塑肿瘤微环境（TME） 。我们优化了一系列Cu(II)异丙基2-吡啶酮缩氨基硫脲化合物，得到具有显着细胞毒性的Cu(II)化合物(C4)，然后构建了HSA-IND-C4复合物(HSA-IND-C4)递送系统。 IND 和 C4 分别与 HSA IB 和 IIA 结构域的疏水空腔结合。在体内，HSA-IND-C4不仅表现出相对于C4和C4+IND增强的抗肿瘤功效，而且还提高了它们的靶向能力并降低了它们的副作用。 C4 + IND 的抗肿瘤机制涉及作用于 TME 的不同成分。 IND抑制肿瘤相关炎症，而C4不仅诱导癌细胞凋亡和自噬，还抑制肿瘤血管生成。