State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, P. R. China.
Angew Chem Int Ed Engl. 2022 Nov 21;61(47):e202203243. doi: 10.1002/anie.202203243. Epub 2022 Oct 25.
Histone deacetylase (HDAC)-targeted probes and prodrugs are crucial for cancer theranostics. We developed a self-immolative design that enables in vivo activatable near-infrared fluorescence (NIRF) and photoacoustic (PA) imaging and prodrug release in response to HDAC. This design comprises a phenyl ester linker with tunable reactivity, facilitating efficient release of caged fluorophores/drugs upon deacetylation. We engineered a new fluorophore using a spirocyclic xanthene scaffold with ring-open property, affording NIRF/PA detection with high contrast. We showed that a nitro-substituted self-immolative linker allows sensitive NIRF/PA in vivo imaging of HDAC with minimal interference. A highly efficient prodrug system was further developed for targeted therapy in HDAC-overexpressed triple negative breast tumors in mice. Our study provides a valuable paradigm for HDAC-targeted NIRF/PA imaging and prodrug release in vivo, highlighting its potential for bioimaging and drug development.
组蛋白去乙酰化酶 (HDAC) 靶向探针和前药对于癌症治疗学至关重要。我们开发了一种自毁型设计，能够在体内激活近红外荧光 (NIRF) 和光声 (PA) 成像，并响应 HDAC 释放前药。该设计包含一个具有可调反应性的苯酯连接体，可促进在去乙酰化后有效释放被封闭的荧光团/药物。我们使用具有开环性质的螺环吖啶骨架设计了一种新型荧光团，提供了具有高对比度的 NIRF/PA 检测。我们表明，硝基取代的自毁型连接体允许使用最小干扰的灵敏 NIRF/PA 进行体内 HDAC 成像。还进一步开发了高效的前药系统，用于在荷有 HDAC 过表达的三阴性乳腺癌小鼠中进行靶向治疗。我们的研究为体内 HDAC 靶向 NIRF/PA 成像和前药释放提供了一个有价值的范例，突出了其在生物成像和药物开发方面的潜力。
