Stimuli-Responsive Macrocyclization Scaffold Allows In Situ Self-Assembly of Radioactive Tracers for Positron Emission Tomography Imaging of Enzyme Activity

Abstract

Target-enabled bioorthogonal reaction and self-assembly of a small-molecule probe into supramolecules have shown promise for molecular imaging. In this paper, we report a new stimuli-responsive bioorthogonal reaction scaffold (SF) for controlling in situ self-assembly by engineering the condensation reaction between 2-cyanobenzothiazole and cysteine. For probes with the SF scaffold, intramolecular cyclization took place soon after activation, which could efficiently outcompete free cysteine even at a low concentration and result in efficient aggregation in the target. Through integration with different enzyme-responsive substrates and an ammoniomethyl-trifluoroborate moiety (AmBF3), two radioactive positron emission tomography (PET) tracers, [18F]SF-DEVD and [18F]SF-Glu, were designed, which showed high stability under physiological conditions and could produce clear PET signal in tumors to detect enzyme activity (e.g., caspase-3, γ-glutamyltranspeptidase) timely and accurately. Our results demonstrated that the scaffold SF could serve as a general molecular scaffold in the development of smart PET tracers for noninvasive imaging of enzyme activity, which could contribute to tumor detection and treatment efficacy evaluation.

Biomarker‐Responsive Nanosystems for Chronic Disease Theranostics

“…[97][98][99][100][101] Enzyme-responsive nanoprobes can facilitate the spatial distribution and dynamic variability of enzyme expression profiles. [102][103][104][105][106][107][108][109][110][111][112][113][114] For example, Li et al developed an activatable DNA-based FL nanoprobe (termed TP-AP) for detecting the enzymatic activities of telomerase (TE) and apurinic/apyrimidinic endonuclease 1 (APE1). [115] The TP-AP nanoprobe could orthogonally be activated by TE-mediated DNA extension and APE1-responsive specific cleavage, generating an FL signal for imaging the enzymatic activities in an ANDgated manner (Figure 3A).…”

Switching between DNA binding modes with a photo- and redox-active DNA-targeting ligand, part II: the influence of the substitution pattern

“…2,3 To increase the drug selectivity, prodrugs have been developed, 2,4 namely inactive or inert substances which can be transformed into their desired bioactive form by an external chemical or physical stimulus. 5,6 Along these lines, the application of reductive cleavage of disulfides to activate the prodrug has been established as promising approach because some tumor cells have low oxygen levels and contain higher amounts of l -glutathione (GSH), 5,7,8 which in turn reduces the inactive disulfides to their corresponding bioactive thiols. 5,9,10 In addition, the disulfide functionality provides an additional favorable property because it may increase drug permeability, specifically through cell membranes.…”

β-Galactosidase-instructed intracellular nanofiber formation enhances tumor micro-PET imaging

“…Enzyme-mediated PET imaging based on self-assembly can improve specificity, and this has become a powerful tool in this field. 19,20…”

“…Enzyme-mediated PET imaging based on self-assembly can improve specificity, and this has become a powerful tool in this field. 19,20 In light of the above-mentioned studies, in the present work, we sought to design b-gal-instructed intracellular nanofibers for PET imaging. As displayed in Scheme 1, we conceived a probe for this purpose, namely 2-(Naphthalen-2-yl)acetic-Phe-Phe-Phe-Lys(DOTA-68 Ga)-Tyr(Gal)-OH (Nap-FFFK(DOTA-68 Ga)-Y(Gal)-OH, [ 68 Ga]Nap-1G).…”