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Emissive excimers, which are formed by planar polycyclic aromatic fluorophores (e.g., coumarin), enable high contrast tumor imaging. However, it is still challenging to "turn on" excimer fluorescence in physiological dilute solutions. The biocompatible CBT-Cys click condensation reaction enables both intra- and intermolecular aggregations of the as-loaded fluorophores on the probe molecules, which may promote the generation of emissive excimers in a synergistic manner. As a proof-of-concept, we herein design a fluorescence probe Cbz-Gly-Pro-Cys(StBu)-Lys(coumarin)-CBT (

The deep penetration, real-time monitoring ability, and high resolution of near-infrared (NIR) fluorescence imaging make it suitable for tumor diagnosis. However, the lack of specificity and selectivity restricts its further application. Here, for the first time, we applied a CBT-Cys click condensation reaction to synthesize an acidity-initiated molecular probe (AIM-Probe, Cys(StBu)-Lys(Cy 5.5)-EDA-PMA-CBT), which could self-assemble into nanoparticles (AIM-NP) with self-quenched fluorescence under glutathione (GSH) reduction. AIM-NP could accumulate in tumors after intravenous injection. Subsequently, the EDA-PMA part of AIM-Probe in AIM-NP is fractured by the unique subacid condition in the tumor microenvironment, and AIM-NP disassembles into a small AIM-cleaved molecule (PMA-CBT-Cys-Lys(Cy5.5)-EDA) along with fluorescence switching on. As a result, AIM-NP could switch on fluorescence at the tumor site, thereby achieving tumor-targeted imaging. To our knowledge, utilizing tumor acidity to initiate the disassembly of self-assembled nanoparticles through a CBT-Cys click condensation reaction has not been reported.

Magnetic resonance imaging (MRI) is advantageous in the diagnosis of deep internal cancers, but contrast agents (CAs) are always needed to improve MRI sensitivity. Gadolinium (Gd)-based agents are routinely used as T1-dominated CAs in clinic but using intracellularly formed Gd nanoparticles to enhance the T2-weighted MRI of tumor in vivo at high magnetic field has not been reported. Herein, we rationally designed a "smart" Gd-based probe Glu-Cys(StBu)-Lys(DOTA-Gd)-CBT (1), which was subjected to γ-glutamyltranspeptidase (GGT) cleavage and an intracellular CBT-Cys condensation reaction to form Gd nanoparticles (i.e., 1-NPs) to enhance the T2-weighted MR contrast of tumor in vivo at 9.4 T. Living cell experiments indicated that the 1-treated HeLa cells had an r2 value of 27.8 mM-1 s-1 and an r2/r1 ratio of 10.6. MR imaging of HeLa tumor-bearing mice indicated that the T2 MR contrast of the tumor enhanced 28.6% at 2.5 h post intravenous injection of 1. We anticipate that our probe 1 could be employed for T2-weighted MRI diagnosis of GGT-related cancers in the future when high magnetic field is available in clinic.

Photoacoustic (PA) imaging is advantageous for the diagnosis of superficial cancer with high spatial resolution. However, to the best of our knowledge, using an alkaline phosphatase (ALP)-activatable probe for the enhanced PA imaging of tumors has not been reported. In this work, we rationally designed a NIR probe IR775-Phe-Phe-Tyr(H2PO3)-OH (1P) for PA imaging ALP activity in vitro and in tumor. Under the catalysis of ALP, 1P was efficiently converted to IR775-Phe-Phe-Tyr-OH (1), which self-assembled into the nanoparticles 1-NPs. The formation of 1-NPs induced a 6.4-fold enhancement of the 795 nm PA signal of 1P. In vivo tumor PA imaging results indicated that, compared to that in the ALP inhibitor-treated control group, PA contrast in the experimental group enhanced 2.3 folds at 4 h after 1P injection. By replacing the Phe-Phe-Tyr(H2PO3)-OH motif in 1P with other enzyme-cleavable ones, we hope that more PA probes could be developed for the precise diagnoses of their corresponding cancers in the near future.

Magnetic resonance imaging (MRI) is advantageous in the diagnosis of deep internal cancers, but contrast agents (CAs) are always needed to improve MRI sensitivity. Gadolinium (Gd)-based agents are routinely used as T

Large magnetic nanoparticles or aggregates are advantageous in their magnetic resonance properties over ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles (NPs), but the former are cleared faster from the blood pool. Therefore, the "smart" strategy of intracellular aggregation of USPIO NPs is required for enhanced T2-weighted MR imaging. Herein, employing an enzyme-instructed condensation reaction, we rationally designed a small molecule Ac-Asp-Glu-Val-Asp-Cys(StBu)-Lys-CBT (1) to covalently modify USPIO NPs to prepare monodispersive Fe3O4@1 NPs. In vitro results showed that Fe3O4@1 NPs could be subjected to caspase 3 (Casp3)-instructed aggregation. T2 phantom MR imaging showed that the transverse molar relaxivity (r2) of Fe3O4@1 NPs with Casp3 or apoptotic HepG2 cells was significantly larger than those of control groups. In vivo tumor MR imaging results indicated that Fe3O4@1 NPs could be specifically applied for enhanced T2 MR imaging of tumor apoptosis. We propose that the enzyme-instructed intracellular aggregation of Fe3O4 NPs could be a novel strategy for the design of "smart" probes for efficient T2 MR imaging of in vivo biomarkers.