Near-infrared Fluorescence Intensity Research Articles

AIEgens Cross‐linked Iron Oxide Nanoparticles Synchronously Amplify Bimodal Imaging Signals in Situ by Tumor Acidity‐Mediated Click Reaction

AbstractActivatable dual‐modal molecular imaging probes present a promising tool for the diagnosis of malignant tumors. However, synchronously enhancing dual‐modal imaging signals under a single stimulus is challenging. Herein, we propose an activatable bimodal probe that integrates aggregation‐induced emission luminogens (AIEgens) and iron oxide nanoparticles (IOs) to synergistically enhance near‐infrared fluorescence (NIRF) intensity and magnetic resonance (MR) contrast through a tumor acidity‐mediated click reaction. Tumor acidity‐responsive IOs containing dibenzocyclooctyne groups (termed cDIOs) and AIEgens containing azide groups (termed AATs) can be covalently cross‐linked in response to tumor acidity, which leads to a simultaneous enhancement in NIRF intensity (≈12.4‐fold) and r2 relaxivity (≈2.8‐fold). cDIOs and AATs were effectively activated in mice orthotropic breast tumor, and the cross‐linking prolonged their retention in tumor, further augmenting the bimodal signals and expanding imaging time frame. This facile strategy leverages the inherent properties of probes themselves and demonstrates promise in future translational studies.

AIEgens Cross-linked Iron Oxide Nanoparticles Synchronously Amplify Bimodal Imaging Signals in Situ by Tumor Acidity-Mediated Click Reaction.

Activatable dual-modal molecular imaging probes present a promising tool for the diagnosis of malignant tumors. However, synchronously enhancing dual-modal imaging signals under a single stimulus is challenging. Herein, we propose an activatable bimodal probe that integrates aggregation-induced emission luminogens (AIEgens) and iron oxide nanoparticles (IOs) to synergistically enhance near-infrared fluorescence (NIRF) intensity and magnetic resonance (MR) contrast through a tumor acidity-mediated click reaction. Tumor acidity-responsive IOs containing dibenzocyclooctyne groups (termed cDIOs) and AIEgens containing azide groups (termed AATs) can be covalently cross-linked in response to tumor acidity, which leads to a simultaneous enhancement in NIRF intensity (≈12.4-fold) and r2 relaxivity (≈2.8-fold). cDIOs and AATs were effectively activated in mice orthotropic breast tumor, and the cross-linking prolonged their retention in tumor, further augmenting the bimodal signals and expanding imaging time frame. This facile strategy leverages the inherent properties of probes themselves and demonstrates promise in future translational studies.

An NIR Fluorescence Turn‐on and MRl Bimodal Probe for Concurrent Real‐time in vivo Sensing and Labeling of β‐Galactosidase

AbstractTo realize sensing and labeling biomarkers is quite challenging in terms of designing multimodal imaging probes. In this study, we developed a novel β‐galactosidase (β‐gal) activated bimodal imaging probe that combines near‐infrared (NIR) fluorescence and magnetic resonance imaging (MRI) to enable real‐time visualization of activity in living organisms. Upon β‐gal activation, Gal‐Cy‐Gd‐1 exhibits a remarkable 42‐fold increase in NIR fluorescence intensity at 717 nm, allowing covalent labeling of adjacent target enzymes or proteins and avoiding molecular escape to promote probe accumulation at the tumor site. This fluorescence reaction enhances the longitudinal relaxivity by approximately 1.9 times, facilitating high‐resolution MRI. The unique features of Gal‐Cy‐Gd‐1 enable real‐time and precise visualization of β‐gal activity in live tumor cells and mice. The probe's utilization aids in identifying in situ ovarian tumors, offering valuable assistance in the precise removal of tumor tissue during surgical procedures in mice. The fusion of NIR fluorescence and MRI activation through self‐immobilizing target enzymes or proteins provides a robust approach for visualizing β‐gal activity. Moreover, this approach sets the groundwork for developing other activatable bimodal probes, allowing real‐time in vivo imaging of enzyme activity and localization.

An NIR Fluorescence Turn-on and MRl Bimodal Probe for Concurrent Real-time in vivo Sensing and Labeling of β-Galactosidase.

To realize sensing and labeling biomarkers is quite challenging in terms of designing multimodal imaging probes. In this study, we developed a novel β-galactosidase (β-gal) activated bimodal imaging probe that combines near-infrared (NIR) fluorescence and magnetic resonance imaging (MRI) to enable real-time visualization of activity in living organisms. Upon β-gal activation, Gal-Cy-Gd-1 exhibits a remarkable 42-fold increase in NIR fluorescence intensity at 717 nm, allowing covalent labeling of adjacent target enzymes or proteins and avoiding molecular escape to promote probe accumulation at the tumor site. This fluorescence reaction enhances the longitudinal relaxivity by approximately 1.9 times, facilitating high-resolution MRI. The unique features of Gal-Cy-Gd-1 enable real-time and precise visualization of β-gal activity in live tumor cells and mice. The probe's utilization aids in identifying in situ ovarian tumors, offering valuable assistance in the precise removal of tumor tissue during surgical procedures in mice. The fusion of NIR fluorescence and MRI activation through self-immobilizing target enzymes or proteins provides a robust approach for visualizing β-gal activity. Moreover, this approach sets the groundwork for developing other activatable bimodal probes, allowing real-time in vivo imaging of enzyme activity and localization.

Enhancing near-infrared fluorescence intensity and stability of PLGA-b-PEG micelles by introducing Gd-DOTA at the core boundary.

Micelles have been extensively used in biomedicine as potential carriers of hydrophobic fluorescent dyes. Their small diameters can potentially enable them to evade recognition by the reticuloendothelial system, resulting in prolonged circulation. Nevertheless, their lack of stability in physiological environments limits the imaging utility of micelles. In particular, when a dye sensitive to water, such as IR-1061, is encapsulated in the micelle core, the destabilized structure leads to interactions between water and dye, degrading the fluorescence. In this study, we investigated a method to improve micelle stability utilizing the electrical effect of gadolinium (Gd3+ ) and tetraazacyclododecane tetraacetic acid (DOTA), introduced into the micelles. Three micellar structures, one containing a poly(lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-b-PEG) block copolymer, and two other structures, including PLGA-b-PEG with DOTA or Gd-DOTA introduced at the boundary of PLGA and PEG, were prepared with IR-1061 in the core. Structures that contained DOTA at the border of the PLGA core and PEG shell exhibited much higher fluorescence intensity than probes without DOTA. With Gd3+ ions at the DOTA center, fluorescence stability was enhanced remarkably in physiological environments. Most interesting is the finding that fluorescence is enhanced with increased Gd-DOTA concentrations. In conclusion, we found that overall fluorescence and stability are improved by introducing Gd-DOTA at the boundary of the PLGA core and PEG shell. Improving micelle stability is crucial for further biomedical applications of micellar probes such as bimodal fluorescence and magnetic resonance imaging.

A Reaction-Based Optical Fingerprinting Strategy for the Recognition of Fat-Soluble Samples: Discrimination of Motor Oils.

Optical "fingerprints" are widely used for chemometrics-assisted recognition of samples of different types. An emerging trend in this area is the transition from obtaining "static" spectral data to reactions analyzed over time. Indicator reactions are usually carried out in aqueous solutions; in this study, we developed reactions that proceed in an organic solvent, thereby making it possible to recognize fat-soluble samples. In this capacity, we used 5W40, 10W40, and 5W30 motor oils from four manufacturers, with six samples in total. The procedure involved mixing a dye, sample, and reagents (HNO3, HCl, or tert-butyl hydroperoxide) in an ethanolic solution in a 96-well plate and measuring absorbance or near-infrared fluorescence intensity every several minutes for 20-55 min. The obtained photographic images were processed by linear discriminant analysis (LDA) and the k-nearest neighbors algorithm (kNN). Discrimination accuracy was evaluated by a validation procedure. A reaction of oxidation of a dye by nitric acid allowed us to recognize all six samples with 100% accuracy for LDA. Merging of data from the four reactions that did not provide complete discrimination ensured an accuracy of 93% for kNN. The newly developed indicator systems have good prospects for the discrimination of other fat-soluble samples. Overall, the results confirm the viability of the kinetics-based discrimination strategy.

Indocyanine Green (ICG) Fluorescence Is Dependent on Monomer with Planar and Twisted Structures and Inhibited by H-Aggregation.

The optical properties of indocyanine green (ICG) as a near-infrared (NIR) fluorescence dye depend on the nature of the solvent medium and the dye concentration. In the ICG absorption spectra of water, at high concentrations, there were absorption maxima at 700 nm, implying H-aggregates. With ICG dilution, the main absorption peak was at 780 nm, implying monomers. However, in ethanol, the absorption maximum was 780 nm, and the shapes of the absorption spectra were identical regardless of the ICG concentration, indicating that ICG in ethanol exists only as a monomer without H-aggregates. We found that emission was due to the monomer form and decreased with H-aggregate formation. In the fluorescence spectra, the 820 nm emission band was dominant at low concentrations, whereas at high concentrations, we found that the emission peaks were converted to 880 nm, suggesting a new form via the twisted intramolecular charge transfer (TICT) process of ICG. The NIR fluorescence intensity of ICG in ethanol was approximately 12- and 9-times brighter than in water in the NIR-I and -II regions, respectively. We propose an energy diagram of ICG to describe absorptive and emissive transitions through the ICG structures such as the monomer, H-aggregated, and TICT monomer forms.

Evaluation of the Utilization of Near-Infrared Fluorescent Contrast Agent ASP5354 for In Vivo Ureteral Identification in Renal Diseases Using Rat Models of Gentamicin-Induced Acute Kidney Injury.

ASP5354 was recently developed as a near-infrared fluorescence (NIRF) contrast agent for intraoperative ureteral identification, and its use has been evaluated in healthy animals. However, the utilization of ASP5354 for ureteral identification has not been evaluated in animals with renal injury. In this study, we assessed the application of ASP5354 for ureteral imaging using rat models of gentamicin-induced mild, moderate, and severe acute kidney injury (AKI), using a clinically available NIRF detection system. NIRF was detected in the abdominal cavity and ureters after laparotomy, and the efficiency of ASP5354 was evaluated based on the NIRF signal intensity over 60 min. After the intravenous injection of ASP5354 into rats with mild or moderate AKI, the ureters were clearly imaged at a high ratio of NIRF intensity in the ureter to that in the tissues around the ureter. Six days after intravenous injection, the use of ASP5354 in rats with moderate AKI did not affect the biochemical kidney functions or histopathological conditions of the kidney tissues, as compared to those with no injection of ASP5354. In rats with severe AKI, ureteral imaging was not effective due to the relatively strong NIRF expression in the tissues around the ureters. These data indicate that ASP5354 holds potential as a contrast agent for intraoperative ureteral identification in patients with limited renal injury.

Thermal Stability Improvement of Cr3+‐Activated Broadband Near‐Infrared Phosphors via State Population Optimization

AbstractTechnological progress has accelerated the researches into broadband near‐infrared (NIR) luminescent materials as next‐generation intelligent NIR light sources; however, poor thermal stability restricts the applications of NIR phosphors. Herein, new insights into Cr3+‐activated NIR phosphors with improved thermal stability are provided. The photoluminescence intensity originating from the 4T2→4A2 broadband emission of CaLu2Al4SiO12:Cr3+(CLAS:Cr) with optimal electron occupation (4T2/2E) increases up to 118% at 475 K compared with that at room temperature, which is the best for Cr3+‐activated broadband NIR phosphor. Accordingly, new ideas for the design of thermally stable phosphors are proposed by optimizing the thermal population between4T2and2E states and electron migration from2E to4T2state. Finally, multifunctional applications of CLAS:Cr in NIR fluorescence intensity ratio thermometry, X‐ray detection, NIR phosphor‐converted light‐emitting diodes, and bio‐imaging are demonstrated.

In vivo near-infrared fluorescence imaging of gastric cancer in an MKN-45 gastric cancer xenograft mouse model using intraoperative ureteral identification agent ASP5354.

Accurate intraoperative identification of gastric cancer lesions and determination of the extent of resection are important for curability and function preservation. This study aimed to investigate the potential of the near-infrared fluorescence (NIRF) imaging agent ASP5354 for in vivo fluorescence imaging of gastric cancer. The capability of ASP5354 was evaluated using an MKN-45 human gastric cancer xenograft mouse model. A single dose of ASP5354 was intravenously administered to the mice at a concentration of 120nmol (0.37mg)/kg body weight. In vivo NIRF images of the mouse backs were obtained using an NIRF camera system. Moreover, the cancer tissues were dissected, and the NIRF intensity in the tissue sections was measured using the NIRF camera system. ASP5354 uptake in MKN-45 cells was assessed in vitro using the NIRF microscope. The NIRF signal of ASP5354 was selectively detected in gastric cancer tissues immediately after the intravenous administration of ASP5354. The cancer tissues emitted stronger NIRF signals than adjacent normal tissues. The difference in the NIRF intensity between the normal and cancer tissues was clearly observed at the boundary between them in the macrolevel NIRF images. Cancer tissues can be distinguished from normal tissues based on the measurement of the NIRF of ASP5354, using an NIRF camera system. ASP5354 is a promising agent for NIRF imaging of gastric cancer tissues.

MOF-based surface tailoring the near-infrared luminescence property of gold nanoclusters for ratiometric fluorescence sensing of acetylcholinesterase

Ultrasmall gold nanoclusters (AuNCs) with distinct photoluminescence properties are promising fluorophores for optical applications. However, it remains a great challenge to precisely modulate their near-infrared (NIR) fluorescence properties via a simple yet efficient strategy. Herein, we report a new, surface tailoring strategy for effectively modulating the NIR fluorescence property of AuNCs by harnessing the attractive property of metal-organic frameworks. With zeolite imidazolate frameworks-8 (ZIF-8) as the example, we showed that highly fluorescent AuNCs can be in situ encapsulated into ZIF-8 via a one-pot reaction, yielding AuNCs@ZIF-8 composites with enhanced NIR fluorescence intensity. Particularly, AuNCs@ZIF-8 composites exhibit an emission maximum at 830 nm, which is 190 nm longer than the emission wavelength of AuNCs without the ZIF-8 encapsulation. Mechanism studies based on fluorescence decay spectra and X-ray photoelectron spectroscopy revealed that ZIF-8 mainly poses a significant effect on the ligand-metal charge transfer process of AuNCs due to the confinement effect. By incorporating Rhodamine B (RhB) into NIR-emitting AuNCs@ZIF-8 composites, we established a ratiometric fluorescent sensing platform for the detection of acetylcholinesterase (AChE) based on the turn-on fluorescence response of AuNCs towards thiolates. The AuNCs@ZIF-8/RhB system exhibits a high sensitivity with a detection limit of 0.4 mU/mL and good specificity towards common biological interferences. Moreover, the present ratiometric fluorescence assay shows good recovery for AChE detection in human serum, suggesting its potential application for real sample analysis. Finally, the fluorescence response mechanism of both AuNCs@ZIF-8 and AuNCs towards AChE is elucidated by fluorescence lifetime analysis and density functional theory (DFT) calculation. This study demonstrates the feasibility of modulating the NIR fluorescence property of AuNCs by MOF-based surface tailoring strategy towards enhanced biosensing application.

Estimation of doses absorbed by potato tubers under electron beam or X-ray irradiation using an optical fingerprinting strategy

High-energy electron beam and X-ray processing of foods can be used for extending their storage life and for combating pests and pathogens. Several instrumental techniques are used to estimate irradiation doses in foods, but these methods are complex and laborious, require expensive equipment, and do not always allow to determine low doses. This study was aimed at developing simple methods for detecting irradiation in potato tubers and for dose estimation. We used a “fingerprinting” strategy that does not involve quantitation of any compound; instead, the rate of indicator reactions involving carbocyanine dyes is measured. The dye content was monitored by its near-infrared fluorescence intensity and visible-light absorption. Potatoes not subjected to treatment and those irradiated with different doses (10, 100, 1000, 5000, or 10,000 Gray) could be distinguished by linear discriminant analysis. Thus, the order of magnitude of the absorbed dose can be estimated with 89% ± 3% accuracy for a mixture of tubers of two potato varieties irradiated with an electron beam or with 95% ± 8% accuracy for one variety irradiated with an X-ray source.

Near-stoichiometric Er3+ doped LiNbO3 thin films prepared by vapor transport equilibration treatment

A post-growth Li-rich vapor transport equilibration (VTE) technique was used to prepare near-stoichiometric Er3+ doped LiNbO3 thin films. Er3+ fluorescence property, defect feature and Li2O content of the films were characterized. The results show that the visible and near-infrared fluorescence intensity increases remarkably by ∼10 times the VTE time is increased from 0 to 5 h. The enhancement can be explained from viewpoint of Nb4+ defects concentration. X-ray photoelectron spectrometer study confirms presence of antisite NbLi4+ in the films and NbLi4+ is major defect. Its concentration decreases with increased VTE time. The Li2O content in the films is evaluated to be 48.8–49.7 mol% from the birefringence results. It increases with a rise in VTE time, matching with the characteristic of antisite defects. As defects concentration decreases, the non-radiative transition weakens , which is beneficial to improve fluorescence properties.

Luminescence property in Er3+/Tm3+/Ag NPs doped tellurite glass applied for broadband amplifier

In this study, tellurite glasses co-doped with Er3+/Tm3+ were synthesized through the melt-quenching technique. Under 808 nm excitation, the spectral overlap of 1.53 µm band fluorescence generated by the transition of Er3+:4I13/2→4I15/2 and 1.47 µm band fluorescence generated by the transition of Tm3+:3H4→3F4 achieved the near-infrared (NIR) broadband flat fluorescence emission in the range of 1350–1650 nm, in which the most flat fluorescence emission was achieved when the doping amount of Er2O3 and Tm2O3 was 0.1 and 0.8 mol%, respectively, and the full width at half maximum (FWHM) reached 161 nm. Subsequently, the NIR fluorescence intensity was enhanced by introducing silver nanoparticles (Ag NPs) based on broadband flat fluorescence emission. The optimal conditions conducive to broadband fluorescence enhancement were explored by changing the heat-treated time that could affect the formation and growth of Ag NPs. When the amount of AgCl is 0.5 mol%, tellurite glass co-doped with Er3+/Tm3+ ions heat-treated at temperature 410 ℃ for 6 h has the best enhancement effect of 81 %. After transmission electron microscopy (TEM) measurement, the introduced Ag NPs’ diameter at this time is about 18 nm. Some important spectral parameters of Er3+ and Tm3+ ions, for instance the radiative transition probability together with radiative lifetime were calculated from the absorption spectra according to the Judd-Ofelt theory. Structural characteristics based on X-ray diffraction analysis and thermal stability based on differential scanning calorimeter analysis was presented. Based on the above research, the enhanced broadband and flat fluorescence in the 1350–1650 nm range is of great significance for the application of broadband optical amplifiers in modern WDM networks.

Construction of GSH activated near-infrared fluorescent and photoacoustic dual-modal probe for in vivo tumor imaging

The probe plays a pivotal role in the early diagnosis of tumor, especially tumor microenvironment (TME)-responsive probe, which could exploit differences between tumor and normal tissue to achieve better signal-to-noise ratio. In view of overexpressed glutathione (GSH) in microenvironment considered as one of the important characteristics of tumor distinct from normal tissue, we constructed a GSH activated near-infrared fluorescent (NIRF) and photoacoustic (PA) dual-modal probe (Probe-GSH) based on the hybrid of xanthene-based hemicyanines and dicyanoisophorone. The activated Probe-GSH could exhibit 8-fold PA signal/10-fold NIRF intensity enhancement. Besides, compared with the existing xanthene-based hemicyanines (XBH), Probe-GSH possessed longer absorbance/emission wavelength and larger Stokes shift. More importantly, Probe-GSH has been successfully applied to the image of 4T1-bearing tumor mice under NIRF and PA dual modality.

Near-Infrared Fluorescence Imaging of Renal Cell Carcinoma with ASP5354 in a Mouse Model for Intraoperative Guidance.

Renal cell carcinoma is a prevalent disease associated with high morbidity and mortality rates. Partial nephrectomy is a first-line surgical option because it allows the preservation of renal function. Clear differentiation between normal and cancerous tissues is critical for increasing the negative margin rates. This study investigated the capability of the near-infrared (NIR) fluorescent imaging agent ASP5354 for in vivo fluorescence imaging of renal cell carcinoma. ASP5354 at a single dose of 12 nmol (0.037 mg)/kg body weight was intravenously administered to healthy and orthotopic renal cell carcinoma mice under anesthesia. NIR images of the abdominal cavity were obtained using a near-infrared fluorescence (NIRF) camera system. In addition, the cancerous kidneys were harvested, and the NIRF in their sections was measured using an NIRF microscope. Normal renal tissue emitted strong NIRF but the cancer tissue did not. The difference in NIRF intensity between the normal and cancer tissues clearly presented the boundary between the normal and cancer tissues in macro and micro NIRF imaging. ASP5354 can distinguish cancer tissue from normal tissue using NIRF. Thus, ASP5354 is a promising agent for renal cell carcinoma tissue imaging in partial nephrectomy for renal cell carcinoma patients.

Normalization of Time-Intensity Curves for Quantification of Foot Perfusion Using Near-Infrared Fluorescence Imaging With Indocyanine Green

Purpose: Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) is gaining popularity for the quantification of tissue perfusion, including foot perfusion in patients with lower extremity arterial disease (LEAD). However, the absolute fluorescence intensity is influenced by patient—and system-related factors limiting reliable and valid quantification. To enhance the quality of quantitative perfusion assessment using ICG NIR fluorescence imaging, normalization of the measured time-intensity curves seems useful. Materials and Methods: In this cohort study, the effect of normalization on 2 aspects of ICG NIR fluorescence imaging in assessment of foot perfusion was measured: the repeatability and the region selection. Following intravenous administration of ICG, the NIR fluorescence intensity in both feet was recorded for 10 mins using the Quest Spectrum platform®. The effect of normalization on repeatability was measured in the nontreated foot in patients undergoing unilateral revascularization preprocedural and postprocedural (repeatability group). The effect of normalization on region selection was performed in patients without LEAD (region selection group). Absolute and normalized time-intensity curves were compared. Results: Successful ICG NIR fluorescence imaging was performed in 54 patients (repeatability group, n = 38; region selection group, n = 16). For the repeatability group, normalization of the time-intensity curves displayed a comparable inflow pattern for repeated measurements. For the region selection group, the maximum fluorescence intensity (Imax) demonstrated significant differences between the 3 measured regions of the foot (P = .002). Following normalization, the time-intensity curves in both feet were comparable for all 3 regions. Conclusion: This study shows the effect of normalization of time-intensity curves on both the repeatability and region selection in ICG NIR fluorescence imaging. The significant difference between absolute parameters in various regions of the foot demonstrates the limitation of absolute intensity in interpreting tissue perfusion. Therefore, normalization and standardization of camera settings are essential steps toward reliable and valid quantification of tissue perfusion using ICG NIR fluorescence imaging.

A Reduction Active Theranostic Nanoparticle for Enhanced Near-Infrared Imaging and Phototherapy by Reducing Glutathione Level in Cancer Cells.

Facile preparation of a tumoral-stimuli-activated theranostic nanoparticle with simple constituents remains a challenge for tumor theranostic nanosystems. Herein we design a simple reductionresponsive turn-on theranostic nanoparticle for achieving fluorescent imaging and phototherapy combination. The theranostic nanoparticle is prepared by a simple one-step dialysis method of reduction active amphiphilic hyperbranched poly(β-amidoamines) and a near-infrared (NIR) dye indocyanine green (ICG). The fluorescence of ICG is quenched by the aggregation-caused quenching (ACQ) effect. The fluorescent intensity of free ICG at 816 nm was ∼40 times as high as that of particulate ICG. After reductive nanoparticles incubated with dithiothreitol (DTT), the size of the nanoparticles increased from 160 nm to 610 nm by Dynamic light scattering (DLS). As nanoparticles were internalized by cancer cells, the disulfide bonds would be cleaved by intracellular reduction agents like glutathione (GSH), leading to the release of entrapped ICG. The released ICG regained its fluorescence for self-monitoring the release and therapeutic effect of ICG by fluorescence spectra and the quantitative evaluation of NIR fluorescence intensity. Remarkably, nanoparticles can also reinforce antitumor efficacy through photodynamic therapy and GSH depletion property. This study provides new insights into designing turn-on theranostic systems.

Ultra-sensitive responsive near-infrared fluorescent nitroreductase probe with strong specificity for imaging tumor and detecting the invasiveness of tumor cells

Hypoxia plays an important role in cancer progression, which is a characteristic feature of the tumor micro-environment and reflects the invasiveness of tumor cells. Nitroreductase (NTR) is overexpressed in hypoxic tumors, which making it an efficient target for detecting the hypoxic state in tumor. In this work, a new type of nitro-based fluorescent probe, named HNT-NTR, has been proposed, HNT-NTR could detect specifically and rapidly the NTR degree, which reflects the level of hypoxia in bidimensional (2D) tumor cells, three-dimensional (3D) tumor spheres and even the real tumors in vivo without biological toxicity. Most importantly, according to the research, HNT-NTR even could distinguish tumor cells from other normal cells in vivo and reflect the invasiveness of tumor cells by the near-infrared fluorescence intensity, which provides a new way of clinical pathologic diagnosis. All in all, HNT-NTR not only is proven to be an ideal probe for detecting solid tumors in vivo, but also has great potential to distinguish if cells are benign or malignant and even guide therapeutic applications in the clinic.

Thrombus-specific theranostic nanocomposite for codelivery of thrombolytic drug, algae-derived anticoagulant and NIR fluorescent contrast agent

Thrombolysis is a standard treatment for rapidly restoring blood flow. However, the application of urokinase-type plasminogen activator (Uk) in clinical therapy is limited due to its nonspecific distribution and inadequate therapeutic accumulation. Precise thrombus imaging and site-specific drug delivery can enhance the diagnostic and therapeutic efficacy for thrombosis. Accordingly, we developed a P-selectin-specific, photothermal theranostic nanocomposite for thrombus-targeted codelivery of Uk and indocyanine green (ICG, a contrast agent for near-infrared (NIR) fluorescence imaging). We evaluated its capabilities for thrombus imaging and enzyme/hyperthermia combined thrombolytic therapy. Mesoporous silica-coated gold nanorods (Si-AuNRs) were functionalized with an arginine-rich peptide to create an organic template for the adsorption of ICG and fucoidan (Fu), an algae-derived anticoagulant. Uk was loaded into the SiO2 pores of the Si-AuNRs through the formation of a Fu-Uk-ICG complex on the peptide-functionalized template. The Fu-Uk/ICG@SiAu NRs nanocomposite increased the photostability of ICG and improved its targeting/accumulation at blood clot sites with a strong NIR fluorescence intensity for precise thrombus imaging. Furthermore, ICG incorporated into the nanocomposite enhanced the photothermal effect of Si-AuNRs. Fu, as a P-selectin-targeting ligand, enabled the nanocomposite to target a thrombus site where platelets were activated. The nanocomposite enabled a faster release of Uk for rapid clearing of blood clots and a slower release of Fu for longer lasting prevention of thrombosis regeneration. The nanocomposite with multiple functions, including thrombus-targeting drug delivery, photothermal thrombolysis, and NIR fluorescence imaging, is thus an advanced theranostic platform for thrombolytic therapy with reduced hemorrhaging risk and enhanced imaging/thrombolysis efficiency. Statement of significanceHerein, for the first time, a P-selectin specific, photothermal theranostic nanocomposite for thrombus-targeted co-delivery of urokinase and NIR fluorescence contrast agent indocyanine green (ICG) was developed. We evaluated the potential of this theranostic nanocomposite for thrombus imaging and enzyme/hyperthermia combined thrombolytic therapy. The nanocomposite showed multiple functions including thrombus targeting and imaging, and photothermal thrombolysis. Besides, it allowed faster release of the thrombolytic urokinase for rapidly clearing blood clots and slower release of a brown algae-derived anticoagulant fucoidan (also acting as a P-selectin ligand) for prevention of thrombosis regeneration. The nanocomposite is thus a new and advanced theranostic platform for targeted thrombolytic therapy.