Lai Xixi, Lu Tianxiao, Zhang Fusheng, Khan Arshad, Zhao Yili, Li Xin, Xiang Shuo, Lin Kuailu
Department of Respiratory and Critical Care Medicine, Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China.
Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China; First Clinical Medical College, Wenzhou Medical University, Wenzhou 325035, China.
J Inorg Biochem. 2025 Nov;272:113015. doi: 10.1016/j.jinorgbio.2025.113015. Epub 2025 Jul 23.
The development of lysosome-targeted theranostic platforms stands at the forefront of precision oncology. However, significant challenges persist in synchronizing real-time diagnostic imaging with spatiotemporal controlled therapeutic delivery. Current systems commonly encounter issues such as suboptimal quantum yields, pH-insensitive release kinetics, and spectral interference between imaging and drug-tracking modes. To address these limitations, we rationally designed a novel series of Zn(II)-Schiff base complexes through coordination chemistry to achieve lysosomal targeting, enhanced optical properties, and microenvironment-responsive drug release. Optical characterization revealed significant red shifts in the absorption and emission spectra after Zn(II) coordination, which can be attributed to the reduction in energy bandgap. Among these complexes, Zn-((2,5-diamino-1,4-benzenedithiol dihydrochloride)-(2,4-Dihydroxybenzaldehyde)) (Zn-MTDH) exhibited the highest quantum yield (63.7 %) and enabled high-contrast lysosomal imaging in 4 T1 breast cancer cells, positioning it as a promising candidate for biological applications. When loaded with camptothecin (CPT), CPT@Zn-MTDH displayed pH-dependent drug release kinetics (81 % cumulative release at pH 5.6 vs. 51 % at pH 7.4 over 36 h). Cellular assays demonstrated that Zn-MTDH exhibits low cytotoxicity and excellent biocompatibility. In contrast, CPT@Zn-MTDH exhibited enhanced cytotoxicity compared to free CPT, highlighting the potential of these complexes for lysosome-targeted cancer therapy. This study establishes Zn(II)-Schiff base complexes as a versatile "track-and-treat" theranostic platform, thereby bridging diagnostic precision with therapeutic efficacy.
溶酶体靶向诊疗平台的发展处于精准肿瘤学的前沿。然而，在将实时诊断成像与时空可控的治疗递送同步方面，仍存在重大挑战。当前系统普遍存在量子产率欠佳、pH不敏感的释放动力学以及成像与药物追踪模式之间的光谱干扰等问题。为解决这些局限性，我们通过配位化学合理设计了一系列新型的Zn(II)-席夫碱配合物，以实现溶酶体靶向、增强光学性质以及微环境响应性药物释放。光学表征显示，Zn(II)配位后吸收和发射光谱发生显著红移，这可归因于能带隙的减小。在这些配合物中，Zn-((2,5-二氨基-1,4-苯二硫醇二盐酸盐)-(2,4-二羟基苯甲醛))（Zn-MTDH）表现出最高的量子产率（63.7%），并能在4T1乳腺癌细胞中实现高对比度的溶酶体成像，使其成为生物应用的有前景候选物。负载喜树碱（CPT）时，CPT@Zn-MTDH表现出pH依赖性的药物释放动力学（在pH 5.6时36小时内累积释放81%，而在pH 7.4时为51%）。细胞实验表明，Zn-MTDH具有低细胞毒性和优异的生物相容性。相比之下，CPT@Zn-MTDH与游离CPT相比表现出增强的细胞毒性，突出了这些配合物在溶酶体靶向癌症治疗中的潜力。本研究将Zn(II)-席夫碱配合物确立为一种多功能的“追踪-治疗”诊疗平台，从而将诊断精度与治疗效果联系起来。
