Bioimaging Modalities Research Articles

Prominence of curcumin in anticancer strategies and innovation in bioimaging

Curcumin (CUR), a natural polyphenol derived from the rhizomes of Curcuma longa (turmeric), has garnered significant attention in recent years for its multifaceted potential in anticancer therapy and bio-imaging applications. This review article comprehensively explores the diverse anticancer properties of CUR, encompassing its potent anti-inflammatory, antioxidant, and anti-proliferative effects, as well as its ability to induce apoptosis and inhibit angiogenesis, making it a promising candidate in the fight against cancer. In addition to its therapeutic potential, CUR's unique physicochemical properties have enabled its utility as a versatile imaging agent for various bio-imaging modalities, including fluorescence imaging, magnetic resonance imaging (MRI), and positron emission tomography (PET). We investigate the molecular mechanisms underlying CUR's bio-imaging capabilities and discuss its various applications in cancer diagnosis, monitoring treatment responses, and elucidating biological processes. This comprehensive review provides valuable insights into the dual role of CUR as an anticancer agent and a bio-imaging tool, elucidate its potential in the development of novel cancer therapies and diagnostic approaches. The amalgamation of CUR's bio-imaging and therapeutic properties suggests its future as a pivotal player in personalized medicine and precision oncology.

Principal component analysis in application to Brillouin microscopy data

Brillouin microscopy has recently emerged as a new bio-imaging modality that provides information on the microscale mechanical properties of biological materials, cells and tissues. The data collected in a typical Brillouin microscopy experiment represents the high-dimensional set of spectral information, i.e. each pixel within a 2D/3D Brillouin image is associated with hundreds of points of spectral data. Its analysis requires non-trivial approaches due to subtlety in spectral variations as well as spatial and spectral overlaps of measured features. This article offers a guide to the application of Principal Component Analysis (PCA) for processing Brillouin imaging data. Being unsupervised multivariate analysis, PCA is well-suited to tackle processing of complex Brillouin spectra from heterogeneous biological samples with minimal a priori information requirements. We point out the importance of data pre-processing steps in order to improve outcomes of PCA. We also present a strategy where PCA combined with k-means clustering method can provide a working solution to data reconstruction and deeper insights into sample composition, structure and mechanics.

SERS in 3D cell models: a powerful tool in cancer research.

Unraveling the cellular and molecular mechanisms underlying tumoral processes is fundamental for the diagnosis and treatment of cancer. In this regard, three-dimensional (3D) cancer cell models more realistically mimic tumors compared to conventional 2D cell cultures and are more attractive for performing such studies. Nonetheless, the analysis of such architectures is challenging because most available techniques are destructive, resulting in the loss of biochemical information. On the contrary, surface-enhanced Raman spectroscopy (SERS) is a non-invasive analytical tool that can record the structural fingerprint of molecules present in complex biological environments. The implementation of SERS in 3D cancer models can be leveraged to track therapeutics, the production of cancer-related metabolites, different signaling and communication pathways, and to image the different cellular components and structural features. In this review, we highlight recent progress in the use of SERS for the evaluation of cancer diagnosis and therapy in 3D tumoral models. We outline strategies for the delivery and design of SERS tags and shed light on the possibilities this technique offers for studying different cellular processes, through either biosensing or bioimaging modalities. Finally, we address current challenges and future directions, such as overcoming the limitations of SERS and the need for the development of user-friendly and robust data analysis methods. Continued development of SERS 3D bioimaging and biosensing systems, techniques, and analytical strategies, can provide significant contributions for early disease detection, novel cancer therapies, and the realization of patient-tailored medicine.

Animal models of neglected parasitic diseases: In vivo multimodal imaging of experimental trypanosomatid infections.

African trypanosomiases and leishmaniases are significant neglected tropical diseases (NTDs) that affect millions globally, with severe health and socio-economic consequences, especially in endemic regions. Understanding the pathogenesis and dissemination of Trypanosoma brucei and Leishmania spp. parasites within their hosts is pivotal for the development of effective interventions. Whole-body bioluminescence and fluorescence imaging systems (BLI and FLI, respectively), are powerful tools to visualize and quantify the progression and distribution of these parasites in real-time within live animal models. By combining this technology with the engineering of stable T. brucei and Leishmania spp. strains expressing luciferase and/or fluorescent proteins, crucial aspects of the infection process including the parasites' homing, the infection dynamics, the tissue tropism, or the efficacy of experimental treatments and vaccines can be deeply investigated. This methodology allows for enhanced sensitivity and resolution, elucidating previously unrecognized infection niches and dynamics. Importantly, whole-body in vivo imaging is non-invasive, enabling for longitudinal studies during the course of an infection in the same animal, thereby aligning with the "3Rs" principle of animal research. Here, we detail a protocol for the generation of dual-reporter T. brucei and L. major, and their use to infect mice and follow the spatiotemporal dynamics of infection by in vivo imaging systems. Additionally, 3D micro-computed tomography (μCT) coupled to BLI in T. brucei-infected animals is applied to gain insights into the anatomical parasite distribution. This Chapter underscores the potential of these bioimaging modalities as indispensable tools in parasitology, paving the way for novel therapeutic strategies and deeper insights into host-parasite interactions.

Exploiting the Photo-Physical Properties of Metal Halide Perovskite Nanocrystals for Bioimaging.

Perovskite nanomaterials have recently been exploited for bioimaging applications due to their unique photo-physical properties, including high absorbance, good photostability, narrow emissions, and nonlinear optical properties. These attributes outperform conventional fluorescent materials such as organic dyes and metal chalcogenide quantum dots and endow them with the potential to reshape a wide array of bioimaging modalities. Yet, their full potential necessitates a deep grasp of their structure-attribute relationship and strategies for enhancing water stability through surface engineering for meeting the stringent and unique requirements of each individual imaging modality. This review delves into this evolving frontier, highlighting how their distinctive photo-physical properties can be leveraged and optimized for various bioimaging modalities, including visible light imaging, near-infrared imaging, and super-resolution imaging.

Functionalization of and through Melanin: Strategies and Bio-Applications.

A unique feature of nanoparticles for bio-application is the ease of achieving multi-functionality through covalent and non-covalent functionalization. In this way, multiple therapeutic actions, including chemical, photothermal and photodynamic activity, can be combined with different bio-imaging modalities, such as magnetic resonance, photoacoustic, and fluorescence imaging, in a theragnostic approach. In this context, melanin-related nanomaterials possess unique features since they are intrinsically biocompatible and, due to their optical and electronic properties, are themselves very efficient photothermal agents, efficient antioxidants, and photoacoustic contrast agents. Moreover, these materials present a unique versatility of functionalization, which makes them ideal for the design of multifunctional platforms for nanomedicine integrating new functions such as drug delivery and controlled release, gene therapy, or contrast ability in magnetic resonance and fluorescence imaging. In this review, the most relevant and recent examples of melanin-based multi-functionalized nanosystems are discussed, highlighting the different methods of functionalization and, in particular, distinguishing pre-functionalization and post-functionalization. In the meantime, the properties of melanin coatings employable for the functionalization of a variety of material substrates are also briefly introduced, especially in order to explain the origin of the versatility of melanin functionalization. In the final part, the most relevant critical issues related to melanin functionalization that may arise during the design of multifunctional melanin-like nanoplatforms for nanomedicine and bio-application are listed and discussed.

Feasibility Simulation of 3D Benchtop Multi-Pinhole X-ray Fluorescence Computed Tomography with Two Novel Geometries

In this work, we developed and validated two novel imaging geometries of benchtop multi-pinhole X-ray fluorescence computed tomography (XFCT) systems with Geant4 Toolkit. One of the Monte Carlo (MC) models utilized a fan beam source to illuminate a single slice of the object, a detector and a multi-pinhole collimator to image each slice’s X-ray fluorescence (XRF). The other model consisted of a cone-beam X-ray source (designed as a 5 mm wide fan beam to reduce simulation time) to scan the whole object, two detectors and two multi-pinhole collimators to image the emissions. The phantom used in the simulations included four sections, each with three cone-shaped gold nanoparticle (GNP) inserts (5 mm in height, 3 mm in diameter across the top) with center-to-center distances of 4 mm, 4.5 mm and 4.86 mm. The GNPs concentration was 0.1 wt. %, 0.3 wt. %, 0.5 wt. % and 0.7 wt. %, respectively. The diameter of the multi-pinhole collimator was 1 mm. Performance was evaluated for pinhole-detector-distance (PDD) of 5 cm, 3.5 cm and 2.5 cm, and the results for different object layers and for single pinhole and multi-pinhole (9 pinholes) imaging were compared. The data showed that results worsened with decreasing GNPs insert diameters and with decreasing PDD (object-pinhole-distance was fixed). The multi-pinhole configurations performed better than a single pinhole. The detection limit for the first multi-pinhole operation was 0.21 wt. %; the second was 0.24 wt. %. Detection limits for the single pinhole were 0.32 wt. % and 0.35 wt. %, respectively. The first MC model could acquire 2D slice images of the object without rotation and the second MC model could image the 3D object efficiently. These two novel multi-pinhole systems could potentially provide a bioimaging modality for nanomedical applications.

NIR-II fluorescence and PA imaging guided activation of STING pathway in photothermal therapy for boosting cancer immunotherapy by theranostic thermosensitive liposomes.

Photothermal immunotherapy has shown great potential for efficient cancer treatment. However, the immunosuppressive tumor microenvironment forms a heavy barrier for photothermal-induced anti-tumor immunity by inhibiting dendritic cell (DC) maturation and cytotoxic T cell response. Moreover, the lack of reliable spatiotemporal imaging modalities makes photothermal immunotherapy difficult to guide tumor ablation and monitor therapeutic outcomes in real time. Herein, we designed a theranostic thermosensitive liposome (PLDD) as a versatile nanoplatform to boost the adaptive anti-tumor immunity of photothermal immunotherapy and to achieve multiple bioimaging modalities in a real-time manner. PLDD contains two major functional components: a multifunctional photothermal agent (DTTB) and an immune potentiator STING pathway agonist (DMXAA). Upon irradiation, the heat generated by DTTB induced the immunogenic cell death (ICD) of the tumor and dissociated the structure of thermosensitive liposome to release DMXAA, which ultimately activated the STING pathway and promoted the ICD-induced immune response by increasing DC cell maturation and T cell recruitment. Moreover, the DTTB in PLDD displayed excellent second near-infrared (NIR-II) fluorescence and photoacoustic (PA) dual-modal imaging, which provided omnibearing information on the tumor and guided the subsequent therapeutic operation. Therefore, this versatile PLDD with light-triggered promotion of anti-tumor immunity and multiple spatiotemporal imaging profiles holds great potential for the future development of cancer immunotherapy.

A Convolutional Neural Network for COVID-19 Diagnosis: An Analysis of Coronavirus Infections through Chest X-rays

Coronavirus (COVID-19) disease has not only become a pandemic but also an overwhelming strain on the healthcare industry. The conventional diagnostic methods include Antigen Rapid Kits and Reverse Transcription–Polymerase Chain Reaction (RT-PCR) tests. However, they entail several drawbacks such as low precision in diagnosis, increased time in obtaining test results, increased human–patient interaction, and high inaccuracy in the diagnosis of asymptomatic individuals, thus posing a significant challenge in today’s medical practice in curbing an extremely infectious disease such as COVID-19. To overcome these shortcomings, a machine learning (ML) approach was proposed to aid clinicians in more accurate and precise infection diagnoses. A Convolutional Neural Network was built using a sample size of 1920 chest X-rays (CXR) of healthy individuals and COVID-19-infected patients. The developed CNN’s performance was further cross-checked using the clinical results of the validation dataset comprising 300 CXRs. By converting the final output to binary, an intuitive classification of whether a specific CXR is of a healthy or a COVID-infected patient was accomplished. The statistical analysis of the CNN was: Accuracy: 95%; Precision: 96%; Specificity: 95%; Recall: 95%, and F1 score: 95%, thus, proving it to be a promising diagnostic tool in comparison to the other existing ML-based models. The datasets were obtained from Kaggle, GitHub, and European Institute for Biomedical Imaging Research repositories. The prospects of the proposed CNN lie in its flexibility to be altered and extrapolated in diagnosing other lung infections, such as pneumonia and bacterial infections, with relevant training algorithms and inputs. Additionally, the usage of other bio-imaging modalities as input datasets such as CT scans, Lung Ultrasounds and Heat Maps gives the CNN immense potential to assess for better insights on the severity of infection in both infected and asymptomatic patients as well as other related medical diagnoses.

Long‐Lived Second Near‐Infrared Luminescent Probes: An Emerging Role in Time‐Resolved Luminescence Bioimaging and Biosensing

Luminescence bioimaging and biosensing in the second near‐infrared (NIR‐II) spectral window (1,000–1,700 nm wavelengths) is a newly emerging technique that is extensively used in fundamental research and clinical practice. Owing to its advantages, including deep tissue penetration and excellent temporal resolution, this technique has shown tremendous promise for target‐specific imaging and noninvasive monitoring. However, developing bioimaging modalities that enable target‐specific imaging with high resolution and sensitivity remains a great challenge today. Compared with NIR‐II fluorescence imaging, NIR‐II luminescence lifetime imaging with advantages such as lower background noises, higher sensitivity, and higher spatial resolution has opened up new avenues for deep tissue imaging and biomedical applications. Herein, various types of long‐lived NIR‐II luminescent probes, including complex dyes, rare‐earth‐doped nanoparticles, organic compound‐loaded nanoparticles, inorganic‐based dots and nanotubes, as well as the main types of time‐resolved luminescence techniques including time‐domain (e.g., time‐correlated single‐photon counting, time‐gated detection, pulse sampling, etc.) and frequency‐domain systems are first summarized. The unique advantages of long‐lived NIR‐II luminescent probes and their critical roles in bioimaging and biosensing are also highlighted. Finally, the present challenges and future directions of long‐lived NIR‐II luminescent probes in biomedical research, translational research, and (pre‐)clinical studies are discussed.

Fluorinated Protein and Peptide Materials for Biomedical Applications.

Fluorination represents one of the most powerful modern design strategies to impart biomacromolecules with unique functionality, empowering them for widespread application in the biomedical realm. However, the properties of fluorinated protein materials remain unpredictable due to the heavy context-dependency of the surrounding atoms influenced by fluorine’s strong electron-withdrawing tendencies. This review aims to discern patterns and elucidate design principles governing the biochemical synthesis and rational installation of fluorine into protein and peptide sequences for diverse biomedical applications. Several case studies are presented to deconvolute the overgeneralized fluorous stabilization effect and critically examine the duplicitous nature of the resultant enhanced chemical and thermostability as it applies to use as biomimetic therapeutics, drug delivery vehicles, and bioimaging modalities.

Multimodal bioimaging using nanodiamond and gold hybrid nanoparticles

Hybrid core–shell nanodiamond-gold nanoparticles were synthesized and characterized as a novel multifunctional material with tunable and tailored properties for multifunctional biomedical applications. The combination of nanostructured gold and nanodiamond properties afford new options for optical labeling, imaging, sensing, and drug delivery, as well as targeted treatment. ND@Au core–shell nanoparticles composed of nanodiamond (ND) core doped with Si vacancies (SiV) and Au shell were synthesized and characterized in terms of their biomedical applications. Several bioimaging modalities based on the combination of optical and spectroscopic properties of the hybrid nano-systems are demonstrated in cellular and developing zebrafish larvae models. The ND@Au nanoparticles exhibit isolated ND’s Raman signal of sp3 bonded carbon, one-photon fluorescence of SiV with strong zero-phonon line at 740 nm, two-photon excited fluorescence of nanogold with short fluorescence lifetime and strong absorption of X-ray irradiation render them possible imaging agent for Raman mapping, Fluorescence imaging, two-photon Fluorescence Lifetime Imaging (TP-FLIM) and high-resolution hard-X-ray microscopy in biosystems. Potential combination of the imaging facilities with other theranostic functionalities is discussed.

Influence of Synthesis Conditions on Gadolinium-Substituted Tricalcium Phosphate Ceramics and Its Physicochemical, Biological, and Antibacterial Properties.

Gadolinium-containing calcium phosphates are promising contrast agents for various bioimaging modalities. Gadolinium-substituted tricalcium phosphate (TCP) powders with 0.51 wt% of gadolinium (0.01Gd-TCP) and 5.06 wt% of (0.1Gd-TCP) were synthesized by two methods: precipitation from aqueous solutions of salts (1) (Gd-TCP-pc) and mechano-chemical activation (2) (Gd-TCP-ma). The phase composition of the product depends on the synthesis method. The product of synthesis (1) was composed of β-TCP (main phase, 96%), apatite/chlorapatite (2%), and calcium pyrophosphate (2%), after heat treatment at 900 °C. The product of synthesis (2) was represented by β-TCP (main phase, 73%), apatite/chlorapatite (20%), and calcium pyrophosphate (7%), after heat treatment at 900 °C. The substitution of Ca2+ ions by Gd3+ in both β-TCP (main phase) and apatite (admixture) phases was proved by the electron paramagnetic resonance technique. The thermal stability and specific surface area of the Gd-TCP powders synthesized by two methods were significantly different. The method of synthesis also influenced the size and morphology of the prepared Gd-TCP powders. In the case of synthesis route (1), powders with particle sizes of tens of nanometers were obtained, while in the case of synthesis (2), the particle size was hundreds of nanometers, as revealed by transmission electron microscopy. The Gd-TCP ceramics microstructure investigated by scanning electron microscopy was different depending on the synthesis route. In the case of (1), ceramics with grains of 1–50 μm, pore sizes of 1–10 µm, and a bending strength of about 30 MPa were obtained; in the case of (2), the ceramics grain size was 0.4–1.4 μm, the pore size was 2 µm, and a bending strength of about 39 MPa was prepared. The antimicrobial activity of powders was tested for four bacteria (S. aureus, E. coli, S. typhimurium, and E. faecalis) and one fungus (C. albicans), and there was roughly 30% of inhibition of the micro-organism’s growth. The metabolic activity of the NCTC L929 cell and viability of the human dental pulp stem cell study demonstrated the absence of toxic effects for all the prepared ceramic materials doped with Gd ions, with no difference for the synthesis route.

The Multifarious Applications of Copper Nanoclusters in Biosensing and Bioimaging and Their Translational Role in Early Disease Detection.

Nanoclusters possess an ultrasmall size, amongst other favorable attributes, such as a high fluorescence and long-term colloidal stability, and consequently, they carry several advantages when applied in biological systems for use in diagnosis and therapy. Particularly, the early diagnosis of diseases may be facilitated by the right combination of bioimaging modalities and suitable probes. Amongst several metallic nanoclusters, copper nanoclusters (Cu NCs) present advantages over gold or silver NCs, owing to their several advantages, such as high yield, raw abundance, low cost, and presence as an important trace element in biological systems. Additionally, their usage in diagnostics and therapeutic modalities is emerging. As a result, the fluorescent properties of Cu NCs are exploited for use in optical imaging technology, which is the most commonly used research tool in the field of biomedicine. Optical imaging technology presents a myriad of advantages over other bioimaging technologies, which are discussed in this review, and has a promising future, particularly in early cancer diagnosis and imaging-guided treatment. Furthermore, we have consolidated, to the best of our knowledge, the recent trends and applications of copper nanoclusters (Cu NCs), a class of metal nanoclusters that have been gaining much traction as ideal bioimaging probes, in this review. The potential modes in which the Cu NCs are used for bioimaging purposes (e.g., as a fluorescence, magnetic resonance imaging (MRI), two-photon imaging probe) are firstly delineated, followed by their applications as biosensors and bioimaging probes, with a focus on disease detection.

Recent Advances in Second Near-Infrared Region (NIR-II) Fluorophores and Biomedical Applications.

Fluorescence imaging technique, characterized by high sensitivity, non-invasiveness and no radiation hazard, has been widely applicated in the biomedical field. However, the depth of tissue penetration is limited in the traditional (400–700 nm) and NIR-I (the first near-infrared region, 700–900 nm) imaging, which urges researchers to explore novel bioimaging modalities with high imaging performance. Prominent progress in the second near-infrared region (NIR-II, 1000–1700 nm) has greatly promoted the development of biomedical imaging. The NIR-II fluorescence imaging significantly overcomes the strong tissue absorption, auto-fluorescence as well as photon scattering, and has deep tissue penetration, micron-level spatial resolution, and high signal-to-background ratio. NIR-II bioimaging has been regarded as the most promising in vivo fluorescence imaging technology. High brightness and biocompatible fluorescent probes are crucial important for NIR-II in vivo imaging. Herein, we focus on the recently developed NIR-II fluorescent cores and their applications in the field of biomedicine, especially in tumor delineation and image-guided surgery, vascular imaging, NIR-II-based photothermal therapy and photodynamic therapy, drug delivery. Besides, the challenges and potential future developments of NIR-II fluorescence imaging are further discussed. It is expected that our review will lay a foundation for clinical translation of NIR-II biological imaging, and inspire new ideas and more researches in this field.

A Smart Glutathione and H2O2 Dual-Responsive Signal Inversion Magnetic Resonance Imaging Contrast Agent for Tumor Diagnosis

本文主要开发了一种谷胱甘肽（GSH）和H2O2双响应信号反转磁共振成像造影剂SPION@DMSN@PEG，该造影剂主要由可降解介孔二氧化硅纳米粒子（DMSN）和超顺磁性氧化铁纳米粒子（SPION）组成。小鼠体内MRI成像研究显示，该造影剂可在肿瘤部位实现对肿瘤的T2加权成像，随着DMSN在酸性且富含谷胱甘肽和过氧化氢的肿瘤微环境条件下降解，造影剂可从T2信号向T1信号转变，最终转变为T1信号3002 Accurate bioimaging of internal body tissues plays a key role in achieving precise medical diagnosis. Magnetic resonance imaging (MRI) as one of the clinically used bioimaging modalities is largely hampered by the occurrence of false-positive imaging (artifacts). The use of contrast agents has tremendously contributed to the improvement of the accuracy of MRI, however, developing a dual-responsive contrast agent that capable of effectively switching from T 2 to T 1 contrast enhancement in vivo still remains a challenge. Here, we demonstrated the synthesis of a glutathione (GSH) and H 2 O 2 dual-responsive “signal inversion” contrast agent, which mainly comprised of superparamagnetic iron oxide nanoparticles (SPION) and degradable mesoporous silica nanoparticles (DMSN). The contrast agent achieved T 2 -weighted imaging in tumor site, and enabled an efficacious switch to T 1 -weighted imaging upon the GSH- and H 2 O 2 -mediated degradation of DMSN. The characteristics of the signal transformation largely reduced the artifacts to enhance the accuracy of MRI. Interestingly, the in vivo evaluations revealed prominence of the T 2 -weighted imaging up to 2 h post-intravenous injection, which was succeeded by T 1 -weighted imaging that gradually increased with time and became dominant after 24 h. It was therefore expected that the findings shown in this work would guide the development of other contrast agents alike for more robust and accurate bioimaging by using MRI. A glutathione (GSH) and H 2 O 2 dual-responsive “signal inversion” contrast agent (SPION@DMSN@PEG) is synthesized in this work, which achieves T 2 -weighted magnetic resonance imaging (MRI) in tumor site, and enables an efficacious switch to T 1 -weighted MRI upon the GSH- or H 2 O 2 -mediated degradation of DMSN.

Hybrid nano‐ and microgels doped with photoacoustic contrast agents for cancer theranostics

AbstractPhotoacoustic imaging (PAI) is an emerging noninvasive and inexpensive bioimaging modality, which has stimulated a wide interest in recent years for cancer theranostics. Hybrid nano‐ and microgels have been designed as protective carriers to incorporate PAI contrast agents due to their biocompatibility and biodegradability, high loading capacity, versatile surface chemistry, and stimuli‐responsive properties. These key features offer unprecedented opportunities for the design of innovative multifunctional cancer theranostic agents. This review focuses on the recent development of photoacoustic active nano‐ and microgels for biomedical applications in cancer theranostics and cancer hallmark imaging. The various chemical natures of gels and PAI contrast agents and the elaboration methods of hybrid matrices are summarized and discussed. Their applications in multimodal cancer theranostics and cancer hallmark imaging are presented, highlighting their merits and potential in treatment and diagnosis.

Anchor, Spacer, and Ligand-Modified Engineered Exosomes for Trackable Targeted Therapy.

Exosomes have been widely demonstrated as an effective anticancer therapeutic moiety. However, their clinical translation has been limited by the requirement of prohibitively high therapeutic doses due to their lack of specificity in delivery and, consequently, short systemic half-life. To overcome these challenges, we engineered a platform for modifying exosomes with an active targeting modality composed of membrane Anchor (BODIPY)-Spacer (PEG)-targeting Ligands (cyclic RGD peptide) (ASL). Herein, we show that the intramembrane incorporation of a trackable, targeting system renders ASL exosomes (AExs) a modular platform. AExs significantly overcome challenges associated with exosome modification, including potential damage for functionalization, or destabilizing interactions between dyes and drugs. ASL-modification not only enhanced stability in imparting active targeting but also introduced a built-in bioimaging modality. Our studies show that AExs target B16F10 melanoma tumor sites by the specific interaction of cyclic RGD and integrin. Doxorubicin encapsulated AExs (dAExs) significantly inhibited the growth of melanoma in vitro and in vivo. Thus, we conclude that ASL-modification allows exosomes to be transformed into a novel therapeutic vehicle uniquely integrating in vivo tracking and robust targeting with drug delivery. We anticipate that the therapeutic, targeting, and diagnostic modularity provided by ASL will potentiate translational applications of exosome-based vehicles beyond anticancer therapy.

Single Wavelength Laser Excitation Ratiometric NIR-II Fluorescent Probe for Molecule Imaging in Vivo.

Fluorescence (FL) imaging in the second near-infrared window (NIR-II, 1000-1700 nm) has emerged as a promising bioimaging modality that enables noninvasive visualization of deep tissue with an unprecedented resolution. However, there is a paucity of studies on high-quality responsive NIR-II FL molecules. Herein we report a novel activated NIR-II FL molecule, 4,7-bis(5-(4-(diphenylamine)phenyl)-2-thiophene) [1,2,5]selenadiazolo[3,4-f]benzo[c][1,2,5]thiadiazole (SeTT), which exhibits fast and specific responsive capability to hypochlorous acid (HClO). To obtain the NIR-II ratiometric nanoprobe, SeTT was encapsulated on the surface of Er3+-doped down-conversion nanoparticles (DCNP), achieving the DCNP@SeTT nanoprobe. With a single 980 nm laser excitation, the ratiometric FL signal of SeTT at 1150 nm and DCNP at 1550 nm (I1150nm/I1550nm) was linearly correlated with the concentration of HClO with a detection limit of 0.4 μM. The ratiometric nanoprobe was successfully investigated for variations in HClO concentration in the tumor progression, visualization of anatomical structures of the peritoneal cavity in the mice model with inflammation, and quantitative detection of the HClO concentration in a rabbit model of osteoarthritis, achieving a fast response and high selectivity for the detection of HClO. The NIR-II-responsive nanoprobe can serve as a promising and effective tool for highly sensitive monitoring and imaging of HClO in living systems.

Multifunctional gap-enhanced Raman tags for preoperative and intraoperative cancer imaging

Multi-modality imaging agents are desirable for tumor diagnosis because they can provide more alternative and reliable information for accurate detection and therapy of diseases than single imaging technique. However, most reported conventional imaging agents have not been found to successfully overcome the disadvantages of traditional diagnoses such as sensitivity, spatial resolution, short half-decay time and complexity. Therefore, exploring a multifunctional nanocomposite with the combination of their individual modality characteristics has great impact on preoperative imaging and intraoperative diagnosis of cancer. In our study, mesoporous silica gadolinium-loaded gap-enhanced Raman tags (Gd-GERTs) specifically for preoperative and intraoperative imaging are designed and their imaging capability and biosafety are examined. They exhibit strong attenuation property for computed X-ray tomography (CT) imaging, high T1 relaxivity for magnetic resonance (MR) imaging capability and surface-enhanced Raman spectroscopy (SERS) signal with good dispersity and stability, which presents CT/MR/SERS multi-mode imaging performance of the tumor of mice within a given time. Furthermore, in vivo biodistribution and long-term toxicity studies reveal that the Gd-GERTs have good biocompatibility and bio-safety. Therefore, Gd-GERTs are of great potential as a multifunctional nanoplatform for accurate preoperative CT/MRI diagnosis and intraoperative Raman imaging-guide resection of cancers. Statement of SignificanceRecent advances in molecular imaging technology have provided a myriad of opportunities to prepare various nanomaterials for accurate diagnosis and response evaluation of cancer via different imaging modalities. However, single bioimaging modality is still challenging to overcome the issues such as sensitivity, spatial resolution, imaging speed and complexity for clinicians. In this work, we designed a kind of unique multifunctional nanoprobes with computed X-ray tomography/magnetic resonance/surface-enhanced Raman spectroscopy (CT/MR/SERS) triple-modal imaging capabilities. Multifunctional nanotags offer the capabilities of preoperative noninvasive CT/MR imaging for identification of tumors as well as intraoperative real-time SERS imaging for guidance of complete resection of tumors. These multifunctional nanoprobes show critical clinical significance on the improvement of tumor diagnosis and therapy.