Caspase-3-Triggered Intracellular Gadolinium Nanoparticle Formation for T₁-Weighted Magnetic Resonance Imaging of Apoptosis In Vivo

Apoptosis,with a hallmark of upregulated protease Caspase-3, hasbeen frequently imaged with various probes to reveal the therapeuticefficiencies of different drugs. However, activatable molecular probeswith programmable self-assembling behaviors that enable enhanced T-1-weighted magnetic resonance imaging (MRI) of apoptosis remainscarce. Herein, taking advantage of a CBT-Cys click reaction, we rationallydesigned a Caspase-3-activatable self-assembling probe Ac-Asp-Glu-Val-Asp-Cys(StBu)-Lys(DOTA(Gd))-CBT(DEVDC ( S ) -Gd-CBT)for apoptosis imaging in vivo. After Caspase-3 cleavagein apoptotic cells, DEVDC ( S ) -Gd-CBT underwent CBT-Cys click reaction to form a cyclicdimer, which self-assembled into Gd nanoparticles. With this probe,enhanced T-1-weighted MR images of apoptosis were achievedat low magnetic fields in vitro, in cis-dichlorodiamineplatinum-induced apoptotic cells and in tail-amputation-simulatedapoptotic zebrafish. We anticipate that the smart probe DEVDC ( S ) -Gd-CBT could be applied forT(1)-weighted MRI of apoptosis-related diseases in the clinicin the future.