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, has been frequently imaged with various probes to reveal the therapeutic efficiencies of different drugs. However, activatable molecular probes with programmable self-assembling behaviors that enable enhanced T₁-weighted magnetic resonance imaging (MRI) of apoptosis remain scarce. Herein, taking advantage of a CBT-Cys click reaction, we rationally designed 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 cleavage in apoptotic cells, DEVDC_S-Gd-CBT underwent CBT-Cys click reaction to form a cyclic dimer, which self-assembled into Gd nanoparticles. With this probe, enhanced T₁-weighted MR images of apoptosis were achieved at low magnetic fields in vitro, in cis-dichlorodiamineplatinum-induced apoptotic cells and in tail-amputation-simulated apoptotic zebrafish. We anticipate that the smart probe DEVDC_S-Gd-CBT could be applied for T₁-weighted MRI of apoptosis-related diseases in the clinic in the future.