Ratiometric Afterglow Luminescent Imaging of Matrix Metalloproteinase-2 Activity via an Energy Diversion Process.

Ratiometric afterglow luminescent (AGL) probes are attractive for in vivo imaging due to their high sensitivity and signal self-calibration function. However, there are currently few ratiometric AGL probes available for imaging enzymatic activity in living organisms. Here, we present an energy diversion (ED) strategy that enables the design of an enzyme-activated ratiometric AGL probe (RAG-RGD) for in vivo afterglow imaging. The ED process provides RAG-RGD with a radiative transition for an 'always on' 520-nm AGL signal (AGL520) and a cascade three-step energy transfer (ET) process for an 'off-on' 710-nm AGL signal (AGL710) in response to a specific enzyme. Using matrix metalloproteinase-2 (MMP-2) as an example, RAG-RGD shows a significant ~11-fold increase in AGL710/AGL520 toward MMP-2. This can sensitively detect U87MG brain tumors through ratiometric afterglow imaging of MMP-2 activity, with a high signal-to-background ratio and deep imaging depth. Furthermore, by utilizing the self-calibration effect of ratiometric imaging, RAG-RGD demonstrated a strong negative correlation between the AGL710/AGL520 value and the size of orthotopic U87MG tumor, enabling accurate monitoring of orthotopic glioma growth in vivo. This ED process may be applied for the design of other enzyme-activated ratiometric afterglow probes for sensitive afterglow imaging.

A Near-infrared Fluorescence and Positron Emission Tomography Bimodal Probe for In Vivo Imaging of Amyloid-ß Species.

Noninvasive imaging of amyloid-ß (Aß) species in vivo is important for the early diagnosis of Alzheimer's disease (AD). In this paper, we report a near-infrared (NIR) fluorescence (FL) and positron emission tomography (PET) bimodal probe (NIR-[68Ga]) for in vivo imaging of both soluble and insoluble Aß species. NIR-[68Ga] holds a high binding affinity, high selectivity and high sensitivity toward Aß42 monomers, oligomers, and aggregates in vitro. In vivo imaging results show that NIR-[68Ga] can cross the blood-brain-barrier (BBB), and produce significantly higher PET and NIR FL bimodal signals in the brains of APP/PS1 transgenic AD mice relative to that of age-matched wild-type mice, which are also validated by the ex vivo autoradiography and histological staining images. Our results demonstrate that NIR-[68Ga] is an efficient NIR FL and PET bimodal probe for the sensitive imaging of soluble and insoluble Aß species in AD mice.

Engineering of donor-acceptor-donor curcumin analogues as near-infrared fluorescent probes for in vivo imaging of amyloid-ß species.

Near-infrared (NIR) fluorescent imaging of both soluble and insoluble Aß species in the brain of Alzheimer's disease (AD) is crucial for the early diagnosis and intervention of AD. To date, a variety of NIR fluorescent probes have been reported for the detection of Aß species. Among these probes, CRANAD-58 was reported to have the capability to detect both soluble and insoluble Aß species, which is vital to monitor the changes of Aß species during the pathological course of the disease. Though CRANAD-58 has shown promise to noninvasively detect Aß species in transgenic AD mice, the emission wavelength (~670 nm) is still too short for further applications. Therefore, new probes with longer emission wavelength and improved physiological properties are in highly demand. Herein, we report the design and engineering of nine donor-acceptor-donor molecules as "off-on" near-infrared fluorescent probes for in vivo imaging of both soluble and insoluble Aß species in living AD mice owing to its improved in vitro properties and in vivo performance. Methods: We report a two-round strategy to develop nine "off-on" NIR fluorescence probes via structural modification of a curcumin analogue-based donor-acceptor-donor architecture. In round one, probes 1 and 2 were synthesized, and probe 2 was identified to be an optimum probe as it showed distinct "off-on" NIR fluorescence at > 690 nm upon binding to Aß monomers, oligomers and aggregates. To further improve the in vivo performance, further structural modification of probe 2 into probes 3-9 was then conducted. The fluorescence response with Aß species and histological staining in vitro and in vivo imaging of Aß species in APP/PS1 transgenic AD mice and age-matched wild-type mice were performed. Results: We demonstrate that, compared to probe 2, probe 9 with improved physiological properties hold the fastest kinetics (~10 min) to produce not only higher brain fluorescence intensity in 10-month-old APP/PS1 transgenic AD mice, but also afford a higher discrepancy in brain fluorescence to discriminate AD mice from wild-type (WT) mice. Probe 9 also hold the ability to detect soluble Aß species in 6-month-old APP/PS1 transgenic mice. Probe 9 was further applied for dynamic visualization of Aß plaques in a skull-thinning 14-month-old APP/PS1 mouse, which revealed its immediate penetration into brain parenchyma and selective labeling of both parenchymal and angiopathic Aß plaques. In addition, probe 9 possessed significantly high attenuation effect on the aggregation of Aß monomers. Conclusion: Our results demonstrate the good potential of probe 9 for longitudinal NIR fluorescence imaging of soluble and insoluble Aß species in APP/PS1 transgenic AD mice, which may act as a useful tool for early diagnosis and intervention of AD.

Sulfoximines Assisted Rh(III)-Catalyzed C-H Activation/Annulation Cascade to Synthesize Highly Fused Indeno-1,2-benzothiazines.

A facile access to highly fused tetracyclic indeno-1,2-benzothiazines has been established via a Rh(III)-catalyzed C-H bond activation and intramolecular annulation cascade between sulfoximides and all-carbon diazo indandiones. This strategy is characterized by the fact that the diazo coupling partners do not require preactivation, along with its high efficiency, broad substrate generality, and facile transformation. Particularly, the highly conjugated tetracyclic products demonstrate good optical properties and can easily enter cells to emit bright fluorescence for live cell imaging.

Synthesis of Highly Fused Pyrano[2,3-b]pyridines via Rh(III)-Catalyzed C-H Activation and Intramolecular Cascade Annulation under Room Temperature.

A facile access to the polycyclic-fused pyrano[2,3-b]pyridines has been established under room temperature via Rh(III)-catalyzed C-H bond activation and intramolecular cascade annulation. This strategy features high efficiency, unique versatility, and generality and it can occur under mild conditions in good to excellent yields. More importantly, this strategy can be extended to the late-stage functionalization of drugs possessing the CN group.

Activatable NIR Fluorescence/MRI Bimodal Probes for in Vivo Imaging by Enzyme-Mediated Fluorogenic Reaction and Self-Assembly.

Stimuli-responsive in situ self-assembly of small molecules to form nanostructures in living subjects has produced promising tools for molecular imaging and tissue engineering. However, controlling the self-assembly process to simultaneously activate multimodality imaging signals in a small-molecule probe is challenging. In this paper, we rationally integrate a fluorogenic reaction into enzyme-responsive in situ self-assembly to design small-molecule-based activatable near-infrared (NIR) fluorescence and magnetic resonance (MR) bimodal probes for molecular imaging. Using alkaline phosphatase (ALP) as a model target, we demonstrate that probe (P-CyFF-Gd) can be activated by endogenous ALP overexpressed on cell membranes, producing membrane-localized assembled nanoparticles (NPs) that can be directly visualized by cryo-SEM. Simultaneous enhancements in NIR fluorescence (>70-fold at 710 nm) and r1 relaxivity (∼2.3-fold) enable real-time, high-sensitivity, high-spatial-resolution imaging and localization of the ALP activity in live tumor cells and mice. P-CyFF-Gd can also delineate orthotopic liver tumor foci, facilitating efficient real-time, image-guided surgical resection of tumor tissues in intraoperative mice. This strategy combines activatable NIR fluorescence via a fluorogenic reaction and activatable MRI via in situ self-assembly to promote ALP activity imaging, which could be applicable to design other activatable bimodal probes for in vivo imaging of enzyme activity and locations in real time.

Acoustic Emission from Porous Collapse and Moving Dislocations in Granular Mg-Ho Alloys under Compression and Tension.

We identified heterogeneous Mg-Ho alloys as an ideal material to measure the most extensive acoustic emission spectra available. Mg-Ho alloys are porous and show a high density of dislocations, which slide under external tension and compression. These dislocations nucleate near numerous heterogeneities. Two mechanisms compete under external forcing in the structural collapse, namely collapsing holes and the movements of dislocations. Their respective fingerprints in acoustic emission (AE) measurements are very different and relate to their individual signal strengths. Porous collapse generates very strong AE signals while dislocation movements create more but weaker AE signals. This allows the separation of the two processes even though they almost always coincide temporarily. The porous collapse follows approximately mean-field behavior (ε = 1.4, τ' = 1.82, α = 2.56, x = 1.93, χ = 1.95) with mean field scaling fulfilled. The exponents for dislocation movement are greater (ε = 1.92, τ' = 2.44, α = 3.0, x = 1.7, χ = 1.42) and follows approximately the force integrated mean-field predictions. The Omori scaling is similar for both mechanisms. The Bath's law is well fulfilled for the porous collapse but not for the dislocation movements. We suggest that such 'complex' mixing behavior is dominant in many other complex materials such as (multi-) ferroics, entropic alloys and porous ferroelastics, and, potentially, homogeneous materials with the simultaneous appearance of different collapse mechanisms.

Facile fabrication of zinc oxide coated superhydrophobic and superoleophilic meshes for efficient oil/water separation.

Zinc oxide (ZnO) coated superhydrophobic and superoleophilic stainless steel meshes are facilely fabricated via chemical immersion growth and subsequent surface modification. The as-prepared meshes show good mechanical durability, chemical stability and corrosion-resistant properties due to a combination of the hierarchical ZnO structure and the low surface energy modification. More importantly, the as-prepared meshes are used for highly efficient separation of various oil/water mixtures. Meanwhile, a new oil skimmer based on the as-prepared mesh is proposed to spontaneously collect floating oil with high separation efficiency and desirable durability.

Effect of Ca addition on the microstructure and mechanical properties of as-cast Mg-Sm alloys.

This study investigated the effect of Ca addition on the microstructure and mechanical properties of as-cast Mg-4Sm alloys. The addition of 1.0 wt% Ca led to a significant grain refinement of Mg-4.0Sm alloys owing to the formation of rod-like Mg2Ca phases that acted as active nucleates for the Mg matrix. The as-cast Mg-4.0Sm-1.0Ca alloy showed the smallest grain size at 45 µm. Furthermore, the Mg-4.0Sm-1.0Ca alloy exhibited greater hardness, higher tensile strength, and higher yield tensile strength and elongation than the other two alloys with different Ca contents. These results were attributed to the grain refinement and precipitation strengthening of the Mg2Ca and Mg41Sm5 phases. Microsc. Res. Tech. 79:707-711, 2016. © 2016 Wiley Periodicals, Inc.

New horizon for high performance Mg-based biomaterial with uniform degradation behavior: Formation of stacking faults.

Designing the new microstructure is an effective way to accelerate the biomedical application of magnesium (Mg) alloys. In this study, a novel Mg-8Er-1Zn alloy with profuse nano-spaced basal plane stacking faults (SFs) was prepared by combined processes of direct-chill semi-continuous casting, heat-treatment and hot-extrusion. The formation of SFs made the alloy possess outstanding comprehensive performance as the biodegradable implant material. The ultimate tensile strength (UTS: 318 MPa), tensile yield strength (TYS: 207 MPa) and elongation (21%) of the alloy with SFs were superior to those of most reported degradable Mg-based alloys. This new alloy showed acceptable biotoxicity and degradation rate (0.34 mm/year), and the latter could be further slowed down through optimizing the microstructure. Most amazing of all, the uniquely uniform in vitro/vivo corrosion behavior was obtained due to the formation of SFs. Accordingly we proposed an original corrosion mechanism for the novel Mg alloy with SFs. The present study opens a new horizon for developing new Mg-based biomaterials with highly desirable performances.

Microstructures, aging behaviour and mechanical properties in hydrogen and chloride media of backward extruded Mg-Y based biomaterials.

Microstructures, aging behaviour from room temperature to 300 °C and mechanical properties in different media of backward extruded (BE) Mg-Y based biomaterial have been investigated. The results reveal that BE-Mg-Y based alloy is mainly composed of polygon-shaped grains and fine precipitates. The results of aging response show that BE-Mg-Y based alloy exhibits remarkable age hardening behaviour when the aging temperature is 200 °C and higher. The high mechanical properties of aged BE-Mg-Y based alloy are mostly associated with fine microstructure, solid solution strengthening and the existence of homogeneous precipitates. The hydrogen embrittlement dependence on the aging time is confirmed in BE-Mg-Y based alloy. Additionally, the strength and elongation of BE-Mg-Y based alloy are significantly influenced by the ion concentration in media. These results offer some implications for understanding the reduced strength of Mg based implants in body environment. It is demonstrated that the temporary high mechanical strength in air of BE-Mg-Y based biomaterials is insufficient to evaluate the in vivo mechanical integrity.