Intracellular Self-Assembly and Disassembly of ¹⁹F Nanoparticles Confer Respective “Off” and “On” ¹⁹F NMR/MRI Signals for Legumain Activity Detection in Zebrafish

Abstract

(19)F MRI has higher selectivity but lower sensitivity than (1)H MRI for in vivo diagnosis. Therefore, to avoid using a high injection dose of the (19)F probe while, in the meantime, maintaining the high sensitivity of (19)F MRI has remained challenging. Local self-assembly and disassembly of (19)F nanoparticles could be one of the "smart" strategies to achieve this goal. Herein, we report a dual-functional probe 1 for glutathione (GSH)-controlled self-assembly and subsequent legumain (Lgmn)-controlled disassembly of its nanoparticles (i.e., 1-NPs). Self-assembly and disassembly of 1-NPs confer (19)F magnetic resonance (MR) signals "off" and "on", respectively. Employing this strategy, we successfully applied 1 for consecutive detections of GSH and Lgmn in vitro and in cells, imaging Lgmn activity in HEK 293T tumors in zebrafish at a low dosage under 14.1 T.

Self-assembling peptide-based building blocks in medical applications

“…designed self-assembling particles that assemble via the reduction-condensation reaction as described earlier [75,76]. They then disassemble in presence of Legumain (Lgmn), an asparaginyl endopeptidase associated with various physiological events, such as protein catabolism and renal homeostasis, and also with diseases including the inhibition of osteoclast formation and bone resorption, atherosclerosis, stroke, and cancer [78]. In vivo investigations in zebrafish showed exceptional selectivity of the self-assembling and Lgmn-mediated disassembling probe, thus opening exciting avenues for future research in 19 F MRI techniques [78].…”

Furin‐Controlled Fe3O4 Nanoparticle Aggregation and 19F Signal “Turn‐On” for Precise MR Imaging of Tumors

“…[17] Briefly, 12 µL carboxyl-modified IONP (5 g L −1 Fe, 10 nm), EDC (2 µmol), and NHS (2 µmol) into 500 µL 2-(N-morpholino) ethanesulfonic acid (MES) buffer (50 × 10 −3 m, pH 6) was added. [20] The data were recorded and analyzed with Bruker's Topspin 3.1 software. The obtained IONP-NHS ester was redispersed into 500 µL furin buffer (pH 7.4), to which 1 or 1-Scr (400 nmol) was added.…”

“…The mixture was stirred at room temperature for 2 h. After that, the mixture was centrifugated at 15 000 rpm to wash off EDC and NHS and the precipitates were washed with MES buffer three times. The chemical shift of trifluoroacetic acid at −74.5 ppm was used as internal standard to calibrate 19 were set for the 1 [20] Typically, the following optimized parameters were applied to obtain the 19 F MR phantom images; repetition time/echo time (flash imaging pulse sequence): 2000/7.9 ms, flip angle: 180°, FOV: 3 × 3 cm, slice thickness: 5 mm, matrix size: 64 × 64, accumulation times: 32 400, the excitation pulse width: 2740 Hz. The resulting dispersions were stirred overnight at room temperature.…”

“…[13,14] Larger SPIO NPs or SPIO NP aggregates show higher magnetization and markedly nonlinear higher R 2 than that of mono-dispersive SPIO NPs. [20] By integrating the high sensitivity of an SPIO NP CA and the superior selectivity of an 19 F MRI probe, it is possible to design an 1 H and 19 F binuclear MRI probe to achieve precise MR imaging of tumor. [15,16] Thus, intracellular enzyme-controlled organization of SPIO NPs should be a feasible strategy for elevating T 2 MRI of tumors.…”

Organic Nanoprobes for Fluorescence and 19F Magnetic Resonance Dual‐Modality Imaging

“…Alternatively, 19 F MRI holds several unique advantages such as low endogenous background signals, high signal-to-noise ratio (SNR), 100% natural isotopic abundance, relatively high sensitivity (83% of proton) and broad range of chemical shifts. [26][27][28][29] To date, some exogenous contrast agents such as molecular probes with a number of equivalent fluorine atoms, [27,[30][31][32][33][34][35] polymeric tracers containing high numbers of fluorine atoms, [28,[36][37][38][39][40][41][42] and fluorinated metallic nanoparticles [43][44][45][46] have been developed and employed for 19 F MRI. Despite great successes, it is highly desirable and still challenging to develop suitable 19 F MRI contrast agents with satisfied performance as well as multi-modalities.…”