A novel NIR-II albumin-escaping probe for cerebral arteries and perfusion imaging in stroke mice model.

In order to guide the formulation of post-stroke treatment strategy in time, it is necessary to have real-time feedback on collateral circulation and revascularization. Currently used near-infrared II (NIR-II) probes have inherent binding with endogenous albumin, resulting in significant background signals and uncontrollable pharmacokinetics. Therefore, the albumin-escaping properties of the new probe, IR-808AC, was designed, which achieved timely excretion and low background signal, enabling the short-term repeatable injection for visualization of cerebral vessels and perfusion. We further achieved continuous observation of changes in collateral vessels and perfusion during the 7-d period in middle cerebral artery occlusion mice using IR-808AC in vivo. Furthermore, using IR-808AC, we confirmed that remote ischemic conditioning could promote collateral vessels and perfusion. Finally, we evaluated the revascularization after thrombolysis on time in embolic stroke mice using IR-808AC. Overall, our study introduces a novel methodology for safe, non-invasive, and repeatable assessment of collateral circulation and revascularization in real-time that is crucial for the optimization of treatment strategies.

Albumin-seeking dyes with adjustable assemblies in situ enable programmable imaging windows and targeting tumor imaging.

Cyanine dyes are widely used organic probes for in vivo imaging due to their tunable fluorescence. They can form complexes with endogenous albumin, resulting in enhanced brightness and photostability. However, this binding is uncontrollable and irreversible, leading to considerable nonspecific background signals and unregulated circulation time. Methods: Here, we connect varying numbers of 4-(4-iodophenyl) butanoic acid (IP) as albumin-binding moieties (ABM) to the cyanine dye, enabling dynamic and controllable binding with albumin. Meanwhile, we provide a blocking method to completely release the dye from covalent capture with albumin, resulting in specific targeting fluorescence. Furthermore, we evaluate the pharmacokinetics and tumor targeting of the developed dyes. Results: The engineered dyes can dynamically and selectively bind with multiple albumins to change the in situ size of assemblies and circulation time, providing programmable regulation over the imaging time window. The nucleophilic substitution of meso-Cl with water-soluble amino acids or targeting peptides for IP-engineered dye further addresses the nonspecific signals caused by albumin, allowing for adjustable angiography time and efficient tumor targeting. Conclusion: This study rationalizes the binding modes of dyes and proteins, applicable to a wide range of near-infrared (NIR) dyes for improving their in vivo molecular imaging.

Biomimetic NIR-II fluorescent proteins created from chemogenic protein-seeking dyes for multicolor deep-tissue bioimaging.

Near-infrared-I/II fluorescent proteins (NIR-I/II FPs) are crucial for in vivo imaging, yet the current NIR-I/II FPs face challenges including scarcity, the requirement for chromophore maturation, and limited emission wavelengths (typically < 800 nm). Here, we utilize synthetic protein-seeking NIR-II dyes as chromophores, which covalently bind to tag proteins (e.g., human serum albumin, HSA) through a site-specific nucleophilic substitution reaction, thereby creating proof-of-concept biomimetic NIR-II FPs. This chemogenic protein-seeking strategy can be accomplished under gentle physiological conditions without catalysis. Proteomics analysis identifies specific binding site (Cys 477 on DIII). NIR-II FPs significantly enhance chromophore brightness and photostability, while improving biocompatibility, allowing for high-performance NIR-II lymphography and angiography. This strategy is universal and applicable in creating a wide range of spectrally separated NIR-I/II FPs for real-time visualization of multiple biological events. Overall, this straightforward biomimetic approach holds the potential to transform fluorescent protein-based bioimaging and enables in-situ albumin targeting to create NIR-I/II FPs for deep-tissue imaging in live organisms.

NIR-II Protein-Escaping Dyes Enable High-Contrast and Long-Term Prognosis Evaluation of Flap Transplantation.

Real-time vascular positioning, postoperative flap monitoring, and vascular reconstruction assessment are of great importance in flap transplantation. Cyanine dyes offer the advantage of high resolution in the Near-infrared-II (NIR-II) imaging window. However, the nonspecific binding of many cyanine dyes to endogenous albumin leads to high organ accumulation and skin absorption, resulting in low-quality imaging and poor reproducibility of contrast during long-term (e.g., 7 days) postoperative monitoring. Here, a novel strategy is proposed that can be widely applied to prevent protein binding for NIR-I/II Cl-containing cyanine dyes. This strategy produces protein-escaping dyes, ensuring high fluorescence enhancement in the blood with rapid clearance and no residual fluorescence, allowing for short-term repeatable injections for vascular imaging. This strategy in the perioperative monitoring of pedicle perforator flap models in mice and rats is successfully applied. Furthermore, leveraging the universality of this strategy, multiple nonoverlapping protein-escaping probes that achieve dual-excitation (808 and 1064 nm) interference-free imaging of nerve-vessel and tumor-vessel simultaneously are designed and synthesized. These protein-escaping dyes enable long-term repeatable dual-color imaging of tumor localization, resection, and tumor-vessel reconstruction at the wound site.

Ultra-Bright Heptamethine Dye Clusters Based on a Self-Adaptive Co-Assembly Strategy for NIR-IIb Biomedical Imaging.

Despite the wide range of applications of bright NIR-II polymethine scaffolds in biomedical imaging, their solvatochromism and aggregation-caused quenching (ACQ) effects in aqueous solutions limit their inherent brightness using traditional encapsulation methods, and effective hydrophilization strategies are still scarce. Here, a new set of Flav dyes is synthesized and PEGylated, followed by manufacturing DSPE@FlavP2000 nanoparticles using a self-adaptive co-assembly strategy to overcome these limitations. FlavP2000 can autonomously adjust its conformation when co-assembled with DSPE-PEG2000 , resulting in high-efficiency luminescence (≈44.9% fluorescence of Flav in DMSO). DSPE@FlavP2000 enables NIR-IIb (>1500 nm) angiography with high signal-to-noise ratios. Notably, this co-assembly can occur in situ between FlavP2000 with proteins in the living body based on a novel mechanism of brightness activation induced by disassembly (BAD), achieving consistent brightness as DSPE@FlavP2000 in blood or serum. The self-adaptive co-assembly strategy can be enhanced by incorporating an IPA moiety, which dynamically binds to albumin to prolong the dye's blood circulation time. Thus, the "enhanced" BAD is successfully applied to long-term vascular imaging and sciatic nerve imaging. Both the self-adaptive co-assembly strategy and BAD phenomenon improve the selectivity and availability of the hydrophilization methods, paving the way for efficient biological applications of polymethine dyes.

Protein@Cyanine-Based NIR-II Lymphography Enables the Supersensitive Visualization of Lymphedema and Tumor Lymphatic Metastasis.

Visualization of the lymphatic system is clinically indispensable for the diagnosis and/or treatment of lymphatic diseases. Although indocyanine green (ICG) lymphography becomes an alternate imaging modality compared to traditional lymphoscintigraphy, it is still far from ideal due to the insufficient detection depth and low spatiotemporal resolution. Herein, protein@cyanine probes are rationally developed to solve the limitations of the current near-infrared-I (NIR-I) lymphography. The protein@cyanine probes are synthesized following a chlorine-containing dye-labeling strategy based on structure-selectivity (facile covalent binding between the dye and protein with a 1:1 molar ratio). As expected, the probes display exceptional NIR-II imaging ability with much-improved imaging contrast/resolution and controllable pharmacokinetics, superior to the clinical ICG. The protein@cyanine probes locate lymph nodes and delineate lymphatic vessels with super-high sensitivity and signal-to-background ratio, enabling real-time diagnosing lymphatic diseases such as lymphedema and tumor lymphatic metastasis. In particular, the NIR-II lymphography provides an opportunity to discover the disparate morbidity rate of primary lymphedema in different types of mice. Given the fact of lacking clinically transferable NIR-II probes, this work not only provides a promising strategy for enriching of the current library of NIR-II probes, but also promotes the clinical translation of NIR-II lymphography technology.

Entertainment apps, limited attention and investment performance.

With the advent of the "information age," investors are now faced with the challenges of the "mobile age," which has had a profound impact on the daily lives of people worldwide. Investors must process more information while experiencing increasing mobile phone-related distractions, particularly those generated by the fast-growing entertainment-type app industry. Attention is a limited cognitive resource that is vital for deliberate and thoughtful analysis. We analyzed data from an online peer-to-peer lending market to evaluate the impact of mobile distractions on investment performance. Our findings revealed that investors with a large number of mobile phone entertainment apps were more likely to exhibit higher default rates and lower investment returns. The results are robust, even when using exogenous internet service outage of the entertainment server and instrumental variables. We observed that the negative impact of distraction was more pronounced on Fridays and in regions with high-speed Internet access. A further examination of the mechanisms underlying this phenomenon revealed that investment decisions made while being distracted by mobile apps were influenced by information neglect and familiarity biases.

Architecture of Nanoantioxidant Based on Mesoporous Organosilica Trp-Met-PMO with Dipeptide Skeleton.

A nanoantioxidant of mesoporous organosilica (Trp-Met-PMO) based on the framework of tryptophan-methionine dipeptide was first designed and constructed by condensation between self-created dipeptide organosilica precursor (Trp-Met-Si) and tetraethyl orthosilicate (TEOS) in alkaline conditions under the template hexadecyl trimethyl ammonium bromide (CTAB). Trp-Met-Si was prepared by the reaction between dipeptide Trp-Met and conventional organosilicon coupling agent isocyanatopropyltriethoxysilane (IPTES) via a multiple-step reaction method. The material Trp-Met-PMO was confirmed by XRD, FT-IR and N2 adsorption-desorption analysis. The material Trp-Met-5-PMO with low amounts of organosilica precursor remained a mesoporous material with well-ordered 2D hexagonal (P6mm) structure. With increasing amounts of organosilica precursor, a mesoporous structure was still formed, as shown in the material Trp-Met-100-PMO with the highest amounts of organosilica precursor. Moreover, pore size distribution, surface area and porosity of Trp-Met-PMO are regulated with different amounts of organosilica precursor Trp-Met-Si. The antioxidant activity of Trp-Met-PMO was evaluated by ABTS free radical-scavenging assay. The results showed that antioxidant activity was largely enhanced with increasing contents of organosilica precusor Trp-Met-Si in the skeleton. The material Trp-Met-40-PMO exhibited maximum scavenging capacity of ABTS free radicals, the inhibition percent was 5.88%. This study provides a design strategy for nanoantioxidant by immobilizing short peptides within the porous framework of mesoporous material.

Light-Activated Reactive Oxygen Species-Responsive Nanocarriers for Enhanced Photodynamic Immunotherapy of Cancer.

Exploring polymeric nanoplatforms combined with reactive oxygen species (ROS) responsiveness with mitochondria targeting has emerged as an effective strategy for enhanced photodynamic therapy (PDT). Amphiphilic copolymers were synthesized by reacting acrylamide thioketal (TK) linkers with amino-terminated triphenylphosphonium-polyethylene glycol and dodecylamine for encapsulating chlorin e6 (Ce6) via self-assembly. Then, anionic cladding with tumor targeting deshelled in tumor acidic microenvironments was surface-anchored by electrostatic forces (BioPEGDMA@RM). After sequential targeting to the mitochondria of cancerous cells, BioPEGDMA@RM could be light-activated with Ce6 released upon ROS cleavage of TK linkages. It was found that Ce6-loaded BioPEGDMA@RM exhibited higher cytotoxicity on CT26 cells and performed stronger ability on the production of ROS than that without TK linkers. Moreover, a minimum illumination of 3 and 5 min could be required for achieving the maximum release of Ce6 and high in vitro cytotoxicity for Ce6-loaded BioPEGDMA@RM, respectively. Furthermore, Ce6-loaded BioPEGDMA@RM showed 1.29-fold and 1.21-fold higher tumor inhibition on BALB/c nude mice and Kunming mice and stimulated immunologic reactions with more generation of IFN-γ and TNF-α and activation of CD3+, CD4+, and CD8+ T-lymphocytes and DCs than that of Ce6-loaded nanoparticles without TK bonds. This work provided an academic reference for the development of ROS-responsive drug delivery systems for advanced PDT efficiency.

Near-Infrared-II Cyanine/Polymethine Dyes, Current State and Perspective.

The development of near-infrared-II (NIR-II) fluorescence imaging has implemented real-time detection of biological cells, tissues and body, monitoring the disease processes and even enabling the direct conduct of surgical procedures. NIR-II fluorescence imaging provides better imaging contrast and penetration depth, benefiting from the reducing photon scattering, light absorption and autofluorescence. The majority of current NIR-II fluorophores suffer from uncontrollable emission wavelength and low quantum yields issues, impeding the clinical translation of NIR-II bioimaging. By lengthening the polymethine chain, tailoring heterocyclic modification and conjugating electron-donating groups, cyanine dyes have been proved to be ideal NIR-II fluorophores with both tunable emission and brightness. However, a simpler and faster method for synthesizing NIR-II dyes with longer wavelengths and better stability still needs to be explored. This minireview will outline the recent progress of cyanine dyes with NIR-II emission, particularly emphasizing their pharmacokinetic enhancement and potential clinical translation.