School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, China.
Org Biomol Chem. 2020 May 13;18(18):3512-3521. doi: 10.1039/d0ob00690d.
Early evaluation of the therapy efficiency can promote the development of anti-tumor drugs and optimization of the treatment method. Caspase-3 is a key biomarker for early apoptosis. Detection of caspase-3 activity is essential for quick assessment of the curative effect. We have reported a PET probe that could image drug-induced tumor apoptosis in vivo. However, high liver uptake limits its application. In order to optimize the pharmacokinetics of the previous probe, we introduced a hydrophilic peptide sequence to minimize liver uptake. The structure of the new probe was confirmed by mass spectrometry and nuclear magnetic resonance. This probe was able to cross the cell membrane freely and could be converted into a dimer through the condensation reaction of 2-cyano-6-aminobenzothiazole (CBT) and cysteine in response to intracellular activated caspase-3 and glutathione (GSH). The hydrophobic dimers further self-assembled into nanoparticles, which could enhance the probe aggregation in apoptotic tumor tissues. In vivo experiments showed that the tumor uptake of the new probe was higher than that of the previous probe, while the liver uptake of the new probe was significantly reduced. The new probe might be promising in imaging apoptotic tumors with suitable pharmacokinetics.
早期评估治疗效果可以促进抗肿瘤药物的开发和治疗方法的优化。Caspase-3 是早期细胞凋亡的关键生物标志物。检测 caspase-3 的活性对于快速评估疗效至关重要。我们已经报道了一种 PET 探针，可用于体内成像药物诱导的肿瘤细胞凋亡。然而，其较高的肝脏摄取限制了其应用。为了优化先前探针的药代动力学性质，我们引入了一个亲水肽序列以最小化肝脏摄取。通过质谱和核磁共振证实了新探针的结构。该探针可以自由穿过细胞膜，并可以通过 2-氰基-6-氨基苯并噻唑（CBT）和半胱氨酸在细胞内激活的 caspase-3 和谷胱甘肽（GSH）的缩合反应转化为二聚体。疏水性二聚体进一步自组装成纳米颗粒，这可以增强凋亡肿瘤组织中探针的聚集。体内实验表明，新探针在肿瘤中的摄取量高于前一个探针，而新探针在肝脏中的摄取量则显著降低。这种新的探针具有合适的药代动力学特性，有望用于成像凋亡肿瘤。
