CBT‐Cys click reaction for optical bioimaging in vivo

Abstract

Derived from the D‐luciferin regeneration pathway in firefly body, the click condensation reaction between 2‐cyanobenzothiazole (CBT) and D‐cysteine (Cys) (CBT‐Cys click reaction) possesses unique advantages, including superior biocompatibility, high second order reaction rate, and metal‐free mild conditions, emerging as a powerful bioorthogonal tool for a variety of chemical biological applications. Moreover, owing to its programmable controllability (e.g., pH, reduction, or enzyme), CBT‐Cys click reaction is exploited to fabricate stimuli‐activatable imaging probes with self‐assembling behaviors in physiological context. At stimuli‐rich pathological lesions of interest, these probes undergo CBT‐Cys click reaction to form cyclic dimers/oligomers or linear polymers, and further self‐assemble into nanostructures. The in situ formed nanostructures promote the selective accumulation and retention of imaging agent cargos at pathological lesions, thus enabling precise and enhanced in vivo imaging of diseases (especially tumors). To address the significance and recent breakthroughs of smart CBT‐Cys probes for enhanced optical imaging of tumors/other diseases, we herein propose this mini‐review, in which advances (particularly in recent 5 years) and potential challenges (or chances) in this field are emphasized.

Legumain-Triggered Macrocyclization of Radiofluorinated Tracer for Enhanced PET Imaging

“…16 Recently, the stimuli-mediated approach on the basis of the rapid condensation reaction between 2-cyanobenzothiazole (CBT) and D-cysteine (Cys) has shown great promise for amplifying imaging signals. 17,18 Nevertheless, the CBT-Cys condensation reaction may be influenced due to a high concentration of endogenous free Cys. 19 To settle the issue, our group designed a new molecular scaffold SF, which can reduce the interference of free cysteine.…”

Enzyme-Instructed CBT-Cys-like Click Cyclization Reactions for Bioimaging

“…Both of these two click reactions can be easily activated by relevant stimuli within the body (e.g., pH, reduction, or enzymes). Among these stimuli, enzymes as ubiquitous active substances in organisms and play pivotal roles in numerous physiological and pathological processes. , Extensive research has consistently demonstrated a direct correlation between aberrant enzyme expression and various diseases, thereby establishing that enzymes as widely acknowledged crucial biomarkers for multiple ailments may contribute to more precise molecular imaging . Harnessing the potential of enzymes facilitates the development of “smart” probes, which can offer enhanced imaging contrast compared with conventional probes and thereby realize more accurate disease diagnoses …”

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

“…As our group and other groups found, these CAs enabled enhanced T 1 -weighted MRI of pathological analytes at low magnetic fields (e.g., 0.5 T, 1.0 T) with superior selectivity, sensitivity, and tumor retention. − In 2014, Ye et al proposed a Gd-based self-assembling probe for MRI imaging of apoptosis in vivo , in which the probe was able to form intramolecular cyclic structures through a reaction between 2-cyano-6-hydroxyquinoline (CHQ) and d -cysteine (CHQ-Cys). , In fact, CHQ-Cys is a modified version of the reaction between 2-cyanobenzothiazole (CBT) and d -cysteine (CBT-Cys). CBT-Cys is an original click reaction derived from the d -luciferin regeneration pathway in the firefly body and has been employed to fabricate versatile self-assembling probes for expanded bioapplications since 2010. − In terms of biocompatibility, we believe that CBT-Cys has better potential over CHQ-Cys for in vivo applications, owing to its “firefly-derived” nature. This motivated us (and we were also inspired by the work of Ye et al) to design a “smart” Gd-based CBT-Cys probe to study apoptosis in vivo , which has not been reported.…”