Tailoring a Near‐Infrared Macrocyclization Scaffold Allows the Control of In Situ Self‐Assembly for Photoacoustic/PET Bimodal Imaging

Abstract

Enzyme-triggered macrocyclization and in situ self-assembly of small molecules into nanoparticles has shown promise to design activatable probes for molecular imaging. However, controlling macrocyclization and self-assembly to concurrently augment positron emission tomography (PET) and photoacoustic (PA) signals for bimodality imaging is challenging. Herein, we report the engineering of a triazole-IR780 fluorophore as a versatile macrocyclization scaffold for controlling in situ selfassembly and design a caspase-3-activatable PA/PET bimodal probe ([ 18 F]-IR780-1) for in vivo imaging of tumor apoptosis. By leveraging the high-sensitivity whole-body imaging signals offered by PET with the high-resolution imaging signals offered by PA, [ 18 F]-IR780-1 can provide a promising tool for the early evaluation of antitumor efficacy, helpful for optimizing the therapeutic protocol for patients. This scaffold may be adopted to design other activatable bimodal probes for in vivo imaging.

Protease-Triggered, Spatially Controlled DNA Assembly in Apoptotic Cells for Early Evaluation of Therapeutic Efficacy

“…In addition, the fluorescence enhancement in P-Asms-treated cells was dependent on STS concentrations (Figure S15). To verify the role of Casp-3 in the DNA assembly, apoptotic cells were pretreated with Z-VAD-fmk, an irreversible pancaspase inhibitor, 37 followed by incubation with P-Asms NPs. As a result, a significantly decreased fluorescence signal was observed in the cells pre-treated with the inhibitor (Figure 3a,b), confirming the Casp-3 activation mechanism.…”

“…We chose hybridization chain reaction (HCR), in which metastable DNA hairpins can undergo successive hybridization reactions in the presence of an initiator strand, as a DNA assembly model. In addition, caspase-3 (Casp-3), a central scavenging protease that commits cells to programmed death, , was selected to demonstrate our design. In the approach, DNA hairpins were engineered with Casp-3-responsive peptides through the use of peptide nucleic acid (PNA) as a building bridge to inhibit their self-assembly activity, while Casp-3-mediated cleavage of the peptides enables the activation of DNA assembly powered by cascaded hybridization reactions.…”

Confinement of Assemblies of Peptides by Chemical Reactions in Living Cells

“…Using such a probe, they obtain a high‐resolution 3D reconstruction image, which can be used to investigate the activity of caspase‐3 and the distribution of caspase‐3 inside apoptotic tumors. Based on the above discovery, they recently develop a new stimuli‐response photoacoustic (PAI)/PET bimodal imaging probe [26] . The designed PAI/PET probe ( 16‐1 ) consists of a triazole‐IR780 scaffold modified with four functional components (Figure 7C), including a CHQ group, a D‐Cys residue modified with a caspase‐3‐responsive sequence (DEVD), a GSH‐cleavable disulfide bond, and an 18 F‐labeled zwitterionic organotrifluoroborate ([ 18 F]‐AMBF 3 ) moiety.…”

“…Based on the above discovery, they recently develop a new stimuli-response photoacoustic (PAI)/PET bimodal imaging probe. [26] The designed PAI/PET probe (16-1) consists of a triazole-IR780 scaffold modified with four functional components (Figure 7C), including a CHQ group, a D-Cys residue modified with a caspase-3-responsive sequence (DEVD), a GSH-cleavable disulfide bond, and an 18 F-labeled zwitterionic organotrifluoroborate ([ 18 F]-AMBF 3 ) moiety. After the proteolysis action by caspase-3 and GSH-mediated reduction, the intramolecular cyclization gives rise to 16-MC, then the hydrophobic interaction and π-π stacking promote the formation of NIR absorptive and radioactive nanoparticles (16NPs) through selfassembly.…”

CBT‐Cys click reaction for optical bioimaging in vivo

“…Encouraged by above findings, we and other groups have recently designed a series of smart CBT‐Cys imaging probes to reveal pathological events at the molecular level 20–23 . These probes are able to be activated by pathological stimuli of interest, undergo CBT‐Cys reaction to form cyclic dimers, followed by nanostructure formation through self‐assembly.…”