Displaying In Vivo “Assembly–Disassembly” Cascade with “Off–On–Off” Magnetic Resonance Imaging Signals in Tumor
Haidong Xu, Xianbao Sun, Zheng Huang, Xiaotong Cheng, Xinxing Fu, Jiayu Li, Ziwen Wei, Junchao Qian, Gaolin Liang
Abstract
“Assembly–Disassembly” cascade has been utilized as a highly effective approach for tumor theranostics, but its real-time in vivo monitoring remains challenging. Current strategies face a fundamental trade-off between penetration depth and real-time nature, while there is still no report on integrating both features to display this dynamic cascade in a living organism. In this work, we develop a gadolinium (Gd) probe Cys(StBu)-Asp-Asp-Asp-Asp-Lys-Lys(DOTA(Gd))-CBT ( Gd-AD ) to display an in vivo “Assembly–Disassembly” cascade via T 1 -weighted “Off–On–Off” 1 H magnetic resonance imaging (MRI) signals. Under reduction conditions, Gd-AD undergoes a CBT-Cys click reaction to assemble into a Gd nanoparticle, with enhanced 1 H MRI signals of 59.3% and 25.4% in cells and in tumors, respectively (“Off–On”). Upon enterokinase (ENTK) cleavage, the nanoparticle disassembles, rendering decreased 1 H MRI signals of 23.4% and 15.2% in cells and in tumors, respectively (“On–Off”). A scrambled control probe Asp-Asp-Asp-Asp-Lys-Cys(StBu)-Lys(DOTA(Gd))-CBT ( Gd-A ), which responds to reduction and ENTK to assemble into a Gd nanoparticle with “Off–On” 1 H MRI signals, is designed and studied in parallel. During 1 h tumor imaging, while Gd-A only displays “Off–On” 1 H MRI signals, Gd-AD clearly shows “Off–On–Off” signals to reflect the “Assembly–Disassembly” cascade of Gd nanoparticles in tumor. We expect that our strategy of real-time display of in vivo “Assembly–Disassembly” cascade could help people to optimize their nanodrug-based tumor theranostics in the near future.