Ping Shi

Far‐Red and Near‐IR AIE‐Active Fluorescent Organic Nanoprobes with Enhanced Tumor‐Targeting Efficacy: Shape‐Specific Effects

The rational design of high-performance fluorescent materials for cancer targeting in vivo is still challenging. A unique molecular design strategy is presented that involves tailoring aggregation-induced emission (AIE)-active organic molecules to realize preferable far-red and NIR fluorescence, well-controlled morphology (from rod-like to spherical), and also tumor-targeted bioimaging. The shape-tailored organic quinoline-malononitrile (QM) nanoprobes are biocompatible and highly desirable for cell-tracking applications. Impressively, the spherical shape of QM-5 nanoaggregates exhibits excellent tumor-targeted bioimaging performance after intravenously injection into mice, but not the rod-like aggregates of QM-2.

Förster Resonance Energy Transfer Switchable Self-Assembled Micellar Nanoprobe: Ratiometric Fluorescent Trapping of Endogenous H2S Generation via Fluvastatin-Stimulated Upregulation

H2S produced in small amounts by mammalian cells has been identified in mediating biological signaling functions. However, the in situ trapping of endogenous H2S generation is still handicapped by a lack of straightforward methods with high selectivity and fast response. Here, we encapsulate a semi-cyanine-BODIPY hybrid dye (BODInD-Cl) and its complementary energy donor (BODIPY1) into the hydrophobic interior of an amphiphilic copolymer (mPEG-DSPE), especially for building up a ratiometric fluorescent H2S nanoprobe with extraordinarily fast response. A remarkable red-shift in the absorption band with a gap of 200 nm in the H2S response can efficiently switch off the Förster resonance energy transfer (FRET) from BODIPY1 to BODInD-Cl, subsequently recovering the donor fluorescence. Impressively, both the interior hydrophobicity of supramolecular micelles and electron-withdrawing nature of indolium unit in BODInD-Cl can sharply increase aromatic nucleophilic substitution with H2S. The ratiometric strategy based on the unique self-assembled micellar aggregate NanoBODIPY achieves an extremely fast response, enabling in situ imaging of endogenous H2S production and mapping its physiological and pathological consequences. Moreover, the amphiphilic copolymer renders the micellar assembly biocompatible and soluble in aqueous solution. The established FRET-switchable macromolecular envelope around BODInD-Cl and BODIPY1 enables cellular uptake, and makes a breakthrough in the trapping of endogenous H2S generation within raw264.7 macrophages upon stimulation with fluvastatin. This study manifests that cystathione γ-lyase (CSE) upregulation contributes to endogenous H2S generation in fluvastatin-stimulated macrophages, along with a correlation between CSE/H2S and activating Akt signaling pathway.

Real-Time Tracking and In Vivo Visualization of β-Galactosidase Activity in Colorectal Tumor with a Ratiometric Near-Infrared Fluorescent Probe

Development of smart noninvasive bioimaging probes for trapping specific enzyme activities is highly desirable for cancer therapy in vivo. Given that β-galactosidase (β-gal) is an important biomarker for cell senescence and primary ovarian cancers, we design an enzyme-activatable ratiometric near-infrared (NIR) probe (DCM-βgal) for the real-time fluorescent quantification and trapping of β-gal activity in vivo and in situ. DCM-βgal manifests significantly ratiometric and turn-on NIR fluorescent signals simultaneously in response to β-gal concentration, which makes it favorable for monitoring dynamic β-gal activity in vivo with self-calibration in fluorescent mode. We exemplify DCM-βgal for the ratiometric tracking of endogenously overexpressed β-gal distribution in living 293T cells via the lacZ gene transfection method and OVCAR-3 cells, and further realize real-time in vivo bioimaging of β-gal activity in colorectal tumor-bearing nude mice. Advantages of our system include light-up ratiometric NIR fluorescence with large Stokes shift, high photostability, and pH independency under the physiological range, allowing for the in vivo real-time evaluation of β-gal activity at the tumor site with high-resolution three-dimensional bioimaging for the first time. Our work provides a potential tool for in vivo real-time tracking enzyme activity in preclinical applications.

Insight into aggregation-induced emission characteristics of red-emissive quinoline-malononitrile by cell tracking and real-time trypsin detection

Water-soluble, long wavelength fluorescent aggregation-induced emission (AIE)-active materials are in great demand for high contrast biosensing and bioimaging. The substitution position effects of the sulfonate group on the basis of two quinoline-malononitrile (QM) derivatives (EDS and EDPS) provide insight into efficient modulation in the hydrophilicity, emitting color, and specific AIE characteristics. EDS shows a unique AIE behaviour in aqueous solution, but EDPS does not. The abnormal non-fluorescence aggregation for EDS in pure water is capsule-like with loose packing characteristics, but still has enough cavities or free volume to consume the radiative energy, resulting in nearly no fluorescence. When binding with the protein BSA, the sulfonate unit as a conformation function group (CFG) plays a vital role in altering its initial loose ensemble into tightly compact aggregation with light-up AIE characteristics. By cell tracking, dynamic light scattering (DLS) and transmission electron microscopy (TEM), the key role of sulfonate groups in the conformation alteration has been well demonstrated for the first time. Moreover, EDS is successfully exploited in a label-free real time AIE fluorescent assay for trypsin detection and inhibitor screening. The hydrophilic sulfonate group from the different substitution position in the AIE-active QM building blocks provides an effective way to tailor the intermolecular aggregation associated with molecular stacking, especially for in situ cell tracking and real-time trypsin detection.

Rational design of novel near-infrared fluorescent DCM derivatives and their application in bioimaging

The development of innovative strategies for high-performance near-infrared (NIR) fluorescent materials is in urgent demand for bioimaging. By replacing the stronger electron-withdrawing groups or extending the π-conjugated system, novel NIR fluorescent materials of DCM analogues have been developed, along with several striking characteristics: bright NIR fluorescence over 700 nm, large Stokes shift and good photo-stability. It is demonstrated that introducing a stronger electron-withdrawing unit to the acceptor moiety of DCM analogues is a favourably efficient strategy to tune and prolong the emission wavelength into the NIR region with a large Stokes shift. In comparison with the commercial NIR dye ICG, S-DCM-N and S-DCM-P display excellent photostability and low photobleaching. The large Stokes Shift and NIR fluorescence channel of S-DCM-N and S-DCM-P are very favourable for fluorescence labelling with a high signal-to-noise ratio in living species.

Fabrication of mesoporous silica nanoparticles hybridised with fluorescent AIE-active quinoline-malononitrile for drug delivery and bioimaging

A novel type of fluorescent mesoporous silica nanoparticle (FMSN) has been successfully synthesised by hybridising mesoporous silica nanospheres with an aggregation-induced emission luminogen, a quinoline-malononitrile derivative. The FMSNs with uniform morphology show excellent AIE-active luminescence and good biocompatibility. Transmission electron microscopy (TEM) demonstrates that the well-ordered mesoporous structure in FMSNs is beneficial for drug delivery. When loaded with doxorubicin (DOX), DOX@FMSNs demonstrate pH-dependent release character and high cytotoxicity towards MCF-7 cancer cells. These FMSNs are expected to be promising multifunctional candidates as both bioimaging agents and drug carriers in cancer therapy.

Facile synthesis of manganese silicate nanoparticles for pH/GSH-responsive T1-weighted magnetic resonance imaging

Contrast agents (CAs) play an important role in enhancing the magnetic resonance imaging (MRI) performance for accurate tumor diagnosis, which, however, may give rise to unexceptional issues such as in vivo accumulation and bio-toxicity. Here we report on manganese silicate nanoparticles (denoted as MnSNs) as highly biocompatible and pH/GSH-responsive T1-weighted MRI CAs. The MnSNs were synthesized via a facile, cost-effective and environmentally friendly route based on one-step rapid precipitation between the Mn2+ cation and the SiO3 2- anion in aqueous solution at room temperature without any other additives, and showed excellent dispersion stability in water or PBS for weeks without any surface modification at ambient temperature. The MnSNs present an efficient pH/GSH-responsive T1-MRI feature based on the rapid changes in the relaxation rate in a mildly acidic/reducing environment both in vitro and in vivo, and furthermore, MnSNs showed negligible cellular cytotoxicity in vitro, no distinct tissue toxicity in vivo and fast clearance from the body organs and tissues in 24-72 h. Thus, the MnSNs are able to serve as a novel class of highly promising T1-MRI CAs for clinical cancer diagnosis.