Near-infrared Fluorescent Agent Research Articles

Letrozole-Based Near-Infrared Dynamic Imaging Targeting Ductal-Vascular RhoJ From Pancreatic Intraepithelial Neoplasia to Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) relies heavily on neoangiogenesis for its progression, making early detection crucial. Here, LTZi-MHI148 (Letrozole inhibitor bonding with MHI-148 dye), a near-infrared (NIR) fluorescent agent is developed, to target RhoJ (Ras Homolog Family Member J), a protein expressed in neonatal vasculature, for both imaging and therapy of early PDAC. This agent is synthesized by conjugating Letrozole with MHI-148, exhibiting excellent NIR characteristics and photostability. In vitro studies showed that LTZi-MHI148 selectively accumulated within pancreatic cancer cells through Organic Anion Transporting Polypeptide (OATP) transporters and bound to cytoplasmic RhoJ. In vivo, the probe effectively targeted neoangiogenesis and Pancreatic Intraepithelial Neoplasias (PanINs) in various PDAC models, including the orthotopic, ectopic, spontaneous, and tamoxifen-induced tumors. Notably, LTZi-MHI148 detected preneoplastic PanIN lesions with Overexpressed RhoJ and active neoangiogenesis in both spontaneous and tamoxifen-induced PDAC murine models. Longitudinal imaging studies revealed that RhoJ-targeted neoangiogenesis tracks lesion progression, highlighting LTZi-MHI148's utility in monitoring disease progression. Furthermore, multiple LTZi-MHI148 administrations attenuated PanINs to PDAC progression, suggesting its potential as a therapeutic intervention. These findings underscore the translational potential of LTZi-MHI148 for the early detection and targeted therapy of PDAC, utilizing NIR-I/II imaging to monitor RhoJ overexpression in precancerous ductal neoplasia associated with neoangiogenesis.

Rapid Assessment of Bio-distribution and Antitumor Activity of the Photosensitizer Bremachlorin in a Murine PDAC Model: Detection of PDT-induced Tumor Necrosis by IRDye® 800CW Carboxylate, Using Whole-Body Fluorescent Imaging

Photodynamic therapy (PDT) is a light-based anticancer therapy that can induce tumor necrosis and/or apoptosis. Two important factors contributing to the efficacy of PDT are the concentration of the photosensitizer in the tumor tissue and its preferential accumulation in the tumor tissue compared to that in normal tissues. In this study, we investigated the use of optical imaging for monitoring whole-body bio-distribution of the fluorescent (660 nm) photosensitizer Bremachlorin in vivo, in a murine pancreatic ductal adenocarcinoma (PDAC) model. Moreover, we non-invasively, examined the induction of tumor necrosis after PDT treatment using near-infrared fluorescent imaging of the necrosis avid cyanine dye IRDye®-800CW Carboxylate. Using whole-body fluorescence imaging, we observed that Bremachlorin preferentially accumulated in pancreatic tumors. Furthermore, in a longitudinal study we showed that 3 hours after Bremachlorin administration, the fluorescent tumor signal reached its maximum. In addition, the tumor-to-background ratio at all-time points was approximately 1.4. Ex vivo, at 6 hours after Bremachlorin administration, the tumor-to-muscle or -normal pancreas ratio exhibited a greater difference than it did at 24 hours, suggesting that, in terms of efficacy, 6 hours after Bremachlorin administration was an effective time point for PDT treatment of PDAC. In vivo administration of the near infrared fluorescence agent IRDye®-800CW Carboxylate showed that PDT, 6 hours after administration of Bremachlorin, selectively induced necrosis in the tumor tissues, which was subsequently confirmed histologically. In conclusion, by using in vivo fluorescence imaging, we could non-invasively and longitudinally monitor, the whole-body distribution of Bremachlorin. Furthermore, we successfully used IRDye®-800CW Carboxylate, a near-infrared fluorescent necrosis avid agent, to image PDT-induced necrotic cell death as a measure of therapeutic efficacy. This study showed how fluorescence can be applied for optimizing, and assessing the efficacy of, PDT.

Self-assembling dendrimer nanosystems for specific fluorine magnetic resonance imaging and effective theranostic treatment of tumors

Fluorine magnetic resonance imaging (19F-MRI) is particularly promising for biomedical applications owing to the absence of fluorine in most biological systems. However, its use has been limited by the lack of safe and water-soluble imaging agents with high fluorine contents and suitable relaxation properties. We report innovative 19F-MRI agents based on supramolecular dendrimers self-assembled by an amphiphilic dendrimer composed of a hydrophobic alkyl chain and a hydrophilic dendron. Specifically, this amphiphilic dendrimer bears multiple negatively charged terminals with high fluorine content, which effectively prevented intra- and intermolecular aggregation of fluorinated entities via electrostatic repulsion. This permitted high fluorine nuclei mobility alongside good water solubility with favorable relaxation properties for use in 19F-MRI. Importantly, the self-assembling 19F-MRI agent was able to encapsulate the near-infrared fluorescence (NIRF) agent DiR and the anticancer drug paclitaxel for multimodal 19F-MRI and NIRF imaging of and theranostics for pancreatic cancer, a deadly disease for which there remains no adequate early detection method or efficacious treatment. The 19F-MRI and multimodal 19F-MRI and NIRF imaging studies on human pancreatic cancer xenografts in mice confirmed the capability of both imaging modalities to specifically image the tumors and demonstrated the efficacy of the theranostic agent in cancer treatment, largely outperforming the clinical anticancer drug paclitaxel. Consequently, these dendrimer nanosystems constitute promising 19F-MRI agents for effective cancer management. This study offers a broad avenue to the construction of 19F-MRI agents and theranostics, exploiting self-assembling supramolecular dendrimer chemistry.

Near-IR nanolignin sensitizers based on pyrene-conjugated chlorin and bacteriochlorin for ROS generation, DNA intercalation and bioimaging.

Near-infrared (NIR) fluorescent agents are extensively used for biomedical imaging due to their ability for deep tissue penetration. Tetrapyrrole-based photosensitizers are promising candidates in this regard. Further, the extended conjugation of such macromolecules with chromophores can enhance their fluorescence efficiency and DNA intercalation ability. Herein, pyrene-conjugated NIR photosensitizers, such as chlorin (PyChl) and bacteriochlorin (PyBac), were synthesized from the corresponding pyrene-porphyrin (PyP). The correlation between the theoretical and experimental optical properties (absorption and fluorescence spectroscopy results) was determined using the DFT/TD-DFT computational approach. Next, studies on the photophysical properties, reactive oxygen species (ROS) production, and DNA binding were conducted on these macrocycles to study the effect of pyrene conjugation on the pyrrolic ring. Furthermore, each photosensitizer was loaded into lignin nanoparticles (LNPs) using the solvent-antisolvent method to accomplish fluorescence-guided imaging. The developed near-IR chlorin- and bacteriochlorin-doped lignin nanocarriers (PyChl-LNCs and PyBac-LNCs) exhibited significant in vitro singlet oxygen generation upon red LED light exposure. Moreover, these macrocycle-loaded nanolignin sensitizers showed good fluorescence-guided bioimaging with fungal cells (Candida albicans). Further, the nanoprobes exhibited pH-dependent release profiles for biological applications. These nanolignin sensitizers demonstrated promising potential to be utilized in near-IR image-guided photodynamic therapy.

De Novo Design of Near-Infrared Fluorescent Agents Activated by Peroxynitrite and Glutathione-Responsive Imaging for Diabetic Liver Disease.

Diabetes and its complications, such as diabetes liver disease, is a major problem puzzling people's health. The detection of redox states in its pathological process can effectively help us gain a deeper understanding of the disease. The pair of oxidation-reduction substances peroxynitrite (ONOO- ) and glutathione (GSH) is considered to be closely related to their occurrence and development. Thus, direct visualization of ONOO- and GSH in diabetes liver disease is critical to evaluate the disease at the molecular level. Herein, two activatable agents NTCF-ONOO- and NTCF-GSH are prepared for selectively detecting ONOO- and GSH through protection and deprotection strategies based on hydroxyl and amino groups of near-infrared fluorophore. Fluorescence imaging of exogenous and endogenous ONOO- and GSH changes in living cells and in vivo is observed. The ONOO- and GSH level in the diabetes liver disease cellular model are visualized and the possible redox imbalance mechanism related to the oxidized (NAD+ ) and reduced (NADH) nicotinamide adenine dinucleotides is explored in this process. Moreover, these probes can sensitively recognize ONOO- and GSH in the process of oxidative stress resulting from streptozotocin and streptozotocin/acetaminophen-induced complex diabetic liver disease in vivo. In addition, they can be applied for monitoring the clinical serum sample related with diabetic patients.

Orthogonally Engineered Albumin with Attenuated Macrophage Phagocytosis for the Targeted Visualization and Phototherapy of Liver Cancer.

The five-year survival rate of hepatocellular carcinoma (HCC) remains unsatisfactory. This reflects, in part, the paucity of effective methods that allow the target-specific diagnosis and therapy of HCC. Here, we report a strategy based on engineered human serum albumin (HSA) that permits the HCC-targeted delivery of diagnostic and therapeutic agents. Covalent cysteine conjugation combined with the exploitation of host-guest chemistry was used to effect the orthogonal functionalization of HSA with two functionally independent peptides. One of these peptides targets glypican-3 (GPC-3), an HCC-specific biomarker, while the second reduces macrophage phagocytosis through immune-checkpoint stimulation. This orthogonally engineered HSA proved effective for the GPC-3-targeted delivery of near-infrared fluorescent and phototherapeutic agents, thus permitting target-specific optical visualization and photodynamic ablation of HCC in vivo. This study thus offers new insights into specificity-enhanced fluorescence-guided surgery and phototherapy of HCC through the orthogonal engineering of biocompatible proteins.

Ready vascular permeability of a near-infrared fluorescent agent ASP5354 for intraoperative ureteral identification enables imaging of carcinoma tissues

This study investigates the ability of a near-infrared fluorescence (NIRF) imaging agent, ASP5354, for in vivo fluorescence imaging of esophageal squamous cell carcinoma (ESCC) tissues. The ability of ASP5354 was evaluated using a single dose of ASP5354 or indocyanine green (ICG), which was intravenously administered to a KYSE850 human ESCC xenograft mouse model. Subsequently, in vivo NIRF images of the mouse were obtained using a clinically available camera system. ASP5354-specific NIRF signals were strongly detectable in KYSE850 carcinoma tissues immediately (30 s) following ASP5354 administration compared with normal tissues. Meanwhile, ICG could not distinguish between normal and carcinomatous tissues. To elucidate the associated imaging mechanisms, the vascular permeability of ASP5354 and ICG was investigated in rat back dermis treated with saline or histamine, which enhances vascular permeability, using in vivo NIRF imaging. ASP5354 exhibited higher vascular permeability in histamine-treated skin than in normal skin. KYSE850 carcinoma tissues can be distinguished from normal tissues based on the measurement of ASP5354-specific NIRF signals, and the mechanism that enables imaging relies on the specific and rapid leakage of ASP5354 from the capillaries into the stroma of carcinoma tissues.

Hyperbaric oxygen enhanced the chemotherapy of mitochondrial targeting molecule IR-780 in bladder cancer.

Bladder cancer has a high rate of recurrence and drug resistance due to the lack of effective therapies. IR-780 iodide, a near-infrared (NIR) mitochondria-targeting fluorescent agent, has been demonstrated to achieve higher selectivity than other drugs in different tumor types and exhibited tumor-killing effects in some cancers. However, this therapeutic strategy is rarely studied in bladder cancer. The accumulation of IR-780 in bladder cancer was measured by NIR imaging. Human bladder cell lines (T24, 5637, and TCCSUP) were treated with IR-780 or combined IR-780 and hyperbaric oxygen (HBO). Cell viability, cell apoptosis, cellular ATP production, mitochondrial reactive oxygen species (ROS), and plasma membrane potential were detected. Mitochondrial complex I protein NDUFS1 was measured by western blot. To confirm the anti-tumor efficacy of IR-780 + HBO, mouse bladder cell line (MB49) tumor-bearing mice were established and tumor size and weight were recorded. Besides, cell apoptosis and tumor size were assessed in drug-resistant bladder cancer cells (T24/DDP) and xenografts to evaluate the effect of IR-780 + HBO on drug-resistant bladder cancer. IR-780 selectively accumulated in bladder cancer (bladder cancer cells, transplanted tumors, and bladder cancer tissue from patients) and could induce cancer cell apoptosis by targeting the mitochondrial complex I protein NDUFS1. The combination with HBO could significantly enhance the anti-tumor effect of IR-780 in vitro by promoting cancer cell uptake and inducing excessive mitochondrial ROS production, while suppressing tumor growth and recurrence in animal models without causing apparent toxicity. Moreover, this combination antitumor strategy was also demonstrated in drug-resistant bladder cancer cells (T24/DDP) and xenografts. We identified for the first time a combination of IR-780 and HBO (IR-780 + HBO), which exhibits mitochondria-targeting and therapeutic capabilities, as a novel treatment paradigm for bladder cancer.

Application of a wavelength-swept laser for spectrally resolved wide-field near-infrared fluorescence imaging

We propose the proof-of-concept of a novel method for wide-field spectrally resolved near-infrared fluorescence (NIRF) imaging using a wavelength-swept laser. The performance of our method is evaluated on a biotissue-like phantom bearing two inclusions, one filled with indocyanine green (ICG) dissolved in distilled water and the second one in dimethyl sulfoxide (DMSO). A near-infrared wavelength-swept laser covering wavelengths around the peak absorption of ICG was used. The difference in the absorption spectra of these two ICG solutions gives rise to an additional spectral contrast. The distinction between the emitted fluorescence light from the two different solutions is performed using a principal component analysis (PCA)-based method. Results show that the two different ICG solutions were successfully resolved using this approach. This technique can be a powerful method to simultaneously spatio-spectrally image multiple near-infrared fluorescence agents.

A Method ofTumor In Vivo Imaging with a New Peptide-Based Fluorescent Probe.

Precise surgical resection directly influences the prognosis and survival of patients with solid tumors. However, it is often difficult to distinguish tumor from normal tissue during resection without any intraoperative imaging guidance. Image-guided surgery particularly when coupled with a near-infrared (NIR) fluorescent agent may improve positive-margin rate thereby improving the overall prognosis. We have developed a unique tumor-targeting fluorescence imaging agent that can aid in the accurate localization of human cancer cells in preclinical settings. The NIR imaging agent, ICG-p28, a water-soluble, nontoxic, and pan-tumor targeting probe consisting of a cell-penetrating peptide (p28) conjugated to indocyanine green (ICG), can accurately localize tumors in vivo. Development of the noninvasive, targeted imaging agent can potentially improve in the resections of tumors by enabling the localization of lesions that are currently difficult or impossible to detect by visual observation or palpation. Here, we describe the methodsof preclinical animal imaging models by using NIR fluorescence imager coupled with a new tumor-targeting agent.

A Novel Fluorescent Dye Invades Mitochondria to Selectively Kill Cancer Stem Cells via Increased ROS Production.

Development of multiple agents has a significant impact on the cancer diagnosis and therapy. Several fluorescent dyes including near-infrared (NIR) fluorescent agents have been already well studied in the field of photodynamic therapy (PDT). In the present study, we reported a novel fluorescent dye could obviously inhibit cancer cell proliferation with slight toxic effects on the biological organism. Furthermore, it displayed selective staining on cancer cells, particularly on cancer stem cells (CSCs), rather than normal cells. Mechanically, this dye preferred to invading mitochondria of cancer cells and inducing overwhelming reactive oxygen species (ROS) production. The in vivo experiments further demonstrated that this dye could image cancer cells and even CSCs in a short-time intratumor injection manner using a zebrafish model and subsequently inhibit cancer cell proliferation after a relatively long-time drug exposure. Taken together, the future development of this agent will promise to make an essential contribution to the cancer diagnosis and therapeutics.

Near-Infrared Fluorescent Agent for In Vitro Screening of Endometrial Cancer and Precancerous Lesions.

The lack of cytopathologists delays the advancement of screening for endometrial cancer. It was urgent to develop a new dye for rapid diagnosis. Our study aimed to synthesize a targeted folate receptor-α near-infrared (NIR) fluorescent agent, folic acid-zwitterionic NIR fluorophore (ZW-FA), and explore the feasibility for screening of endometrial cancer and precancerous change. Folic acid was conjugated with zwitterionic NIR fluorophore. The preparation of ZW-FA was validated by 1H NMR, mass spectrometric, ultraviolet spectra and fluorescence spectra. ZW-FA was incubated with endometrial cytology samples obtained from patients who underwent dilation and curettage or total hysterectomy. Diagnostic utility was calculated by applying laser confocal microscope, Image-J and statistical models, such as enumeration, receiver operating characteristic curve, logistic regression, support vector machine and decision tree were used. The purity of ZW-FA was > 95% determined by 1H NMR. ZW-FA had the strongest absorption peak at 633 nm in ultraviolet spectra. Photostability of ZW-FA was over 8 hours. In clinical validation, a total of 92 patients were enrolled. The cut-off value of ZW-FA was 49 in enumeration, which was used to distinguish the type of samples. Indicators about diagnostic utility are as follows: sensitivity 90.77%, specificity 62.96%, false-positive rate 37.04%, false-negative rate 9.23%, positive predictive value 85.51% and negative predictive value 73.91%. The samples processed by ZW-FA did not affect further Hematoxylin-Eosin staining and pathological diagnosis. It was an effective cytologic strategy for in vitro diagnosis of endometrial cancer and precancerous change by using ZW-FA.Clinical Trial Registration http://www.chictr.org.cn/index.aspx, identifier ChiCTR1800020123.

Synthesis and evaluation of multivalent nitroimidazole-based near-infrared fluorescent agents for neuroblastoma and colon cancer imaging

Hypoxia is one of key characteristics of microenvironments of solid tumors, and evaluation of hypoxia status in solid tumors is important to determine cancer stage and appropriate treatment. In the present study, novel, multivalent, near-infrared (NIR) fluorescent imaging agents were developed to measure tumor hypoxia. These agents were synthesized using an amino acid as a backbone to connect mono-, bis-, or tris-2-nitroimidazole as a hypoxia-sensitive moiety to enhance uptake by the tumor and to attach sulfo-Cyanine 5.5 as an NIR fluorophore to visualize tumor accumulation. Studies of physical characteristics demonstrated that the novel NIR imaging agents showed suitable optical properties for in vitro and in vivo imaging and were stable in serum. In vitro cellular uptake studies in SK-N-BE(2) and SW620 cell lines demonstrated that NIR imaging agents bearing 2-nitroimidazole structures showed significantly higher tumor uptake in hypoxic cells than in normoxic cells. Moreover, in vivo optical imaging studies using SK-N-BE(2) and SW620 xenografted mice demonstrated that novel, multivalent, 2-nitroimadazole NIR imaging agents with two or three 2-nitroimidazole moieties showed higher uptake in tumor than the control agents with only one 2-nitroimidazole. These observations suggest that novel, multivalent, NIR agents could serve as potential optical imaging agents for evaluating tumor hypoxia.

Preclinical Development and Validation of ASP5354: A Near-Infrared Fluorescent Agent for Intraoperative Ureter Visualization.

Iatrogenic ureteral injury (IUI) can complicate minimally invasive and open abdominopelvic surgery. The incidence of IUI is low and dependent on the type of surgery (< 10 %), but it is associated with high morbidity. Therefore, intraoperative visualization of the ureter is critical to reduce the incidence of IUI, and some methodologies for ureter visualization have been developed. Amongst these, near-infrared fluorescence (NIRF) visualization is thought to bring an advantage with real-time retroperitoneal visualization through the retroperitoneum. We investigated an indocyanine green (ICG) derivative, ASP5354, which emits NIRF at 820 nm when exposed to near-infrared light at a wavelength of 780 nm, in a rodent and porcine model. Wistar rats and Göttingen minipigs under anesthesia were laparotomized and then administered ASP5354 chloride intravenously at dose of 0.03 and 0.3 mg/kg for rats and 0.001 and 0.01 mg/kg for minipigs, respectively. Videos of the abdominal cavity in minipigs were taken using a near-infrared fluorescent camera (pde-neo) and assessed visually by three independent clinicians. Toxicological evaluation was demonstrated with cynomolgus monkeys. The proportion of animals whose ureters were visible up to 3 h after administration of ASP5354 chloride were 33 % at 0.001 mg/kg and 100 % at 0.01 mg/kg, respectively. In a toxicological study in cynomolgus monkeys, ASP5354 chloride demonstrated no significant toxicity, suggesting that 0.01 mg/kg provides an optimal dose when used clinically and could allow for ureter visualization during routine surgical procedures. The dose of 0.01 mg/kg provided an optimal dose for ureter visualization up to 3 h after administration. ASP5354 shows promise for ureter visualization during abdominopelvic surgery, which may potentially lower the risk of IUI.

Interventional NIR Fluorescence Imaging of Cancer: Review on Next Generation of Dye-Loaded Protein-Based Nanoparticles for Real-Time Feedback During Cancer Surgery

The use of fluorescence imaging technique for visualization, resection and treatment of cancerous tissue, attained plenty of interest once the promise of whole body and deep tissue near-infrared (NIR) imaging emerged. Why is NIR so desired? Contrast agents with optical properties in the NIR spectral range offer an upgrade for the diagnosis and treatment of cancer, by dint of the deep tissue penetration of light in the NIR region of the electromagnetic spectrum, also known as the optical window in biological tissue. Thus, the development of a new generation of NIR emitting and absorbing contrast agents able to overcome the shortcomings of the basic free dye administration is absolutely essential. Several examples of nanoparticles (NPs) have been successfully implemented as carriers for NIR dye molecules to the tumour site owing to their prolonged blood circulation time and enhanced accumulation within the tumour, as well as their increased fluorescence signal relative to free fluorophore emission and active targeting of cancerous cells. Due to their versatile structure, good biocompatibility and capability to efficiently load dyes and bioconjugate with diverse cancer-targeting ligands, the research area of developing protein-based NPs encapsulated or conjugated with NIR dyes is highly promising but still in its infancy. The current review aims to provide an up-to-date overview on the biocompatibility, specific targeting and versatility offered by protein-based NPs loaded with different classes of NIR dyes as next-generation fluorescent agents. Moreover, this study brings to light the newest and most relevant advances involving the state-of-the-art NIR fluorescent agents for the real-time interventional NIR fluorescence imaging of cancer in clinical trials.

Near-Infrared Fluorescence Imaging and Photodynamic Therapy for Liver Tumors.

Surgery with fluorescence equipment has improved to treat the malignant viscera, including hepatobiliary and pancreatic neoplasms. In both open and minimally invasive surgeries, optical imaging using near-infrared (NIR) fluorescence is used to assess anatomy and function in real time. Here, we review a variety of publications related to clinical applications of NIR fluorescence imaging in liver surgery. We have developed a novel nanoparticle (indocyanine green lactosome) that is biocompatible and can be used for imaging cancer tissues and also as a drug delivery system. To date, stable particles are formed in blood and have an ~10–20 h half-life. Particles labeled with a NIR fluorescent agent have been applied to cancer tissues by the enhanced permeability and retention effect in animals. Furthermore, this article reviews recent developments in photodynamic therapy with NIR fluorescence imaging, which may contribute and accelerate the innovative treatments for liver tumors.

Cyanine-Based Polymer Dots with Long-Wavelength Excitation and Near-Infrared Fluorescence beyond 900 nm for In Vivo Biological Imaging

Bioimaging in the near-infrared window is of great importance to study the dynamic processes in vivo with deep penetration, high spatiotemporal resolution, and minimal tissue absorption, scattering, and autofluorescence. In spite of the huge progress on the synthesis of small organic fluorophores and inorganic nanomaterials with emissions beyond 900 nm, it remains a tough challenge to synthesize semiconducting polymers with fluorescence over this region. Here, we synthesized a series of heptamethine cyanine-based polymers with both absorption and emission in the near-infrared region. We prepared these polymers as semiconducting polymer dots (Pdots) in pure water with great biocompatibility. The fluorescence quantum yield of the Pdots can be as high as 14% with a full width at half-maximum of 53 nm, and their single-particle brightness is more than 20 times higher than commercial quantum dots or ∼300 times brighter than Food and Drug Administration (FDA)-approved indocyanine green (ICG) dyes. We further demonstrated the use of cyanine-based Pdots for specific cellular labeling and long-term tumor targeting in mice. We anticipate that these cyanine-based ultrabright Pdots could open up an avenue for next generations of near-infrared fluorescent agents.

Quicker, deeper and stronger imaging: A review of tumor-targeted, near-infrared fluorescent dyes for fluorescence guided surgery in the preclinical and clinical stages

Cancer is a public health problem and the main cause of human mortality and morbidity worldwide. Complete removal of tumors and metastatic lymph nodes in surgery is significantly beneficial for the prognosis of patients. Tumor-targeted, near-infrared fluorescent (NIRF) imaging is an emerging field of real-time intraoperative cancer imaging based on tumor-targeted NIRF dyes. Targeted NIRF dyes contain NIRF fluorophores and specific binding ligands such as antibodies, peptides and small molecules. The present article reviews recently updated tumor-targeted NIRF dyes for the molecular imaging of malignant tumors in the preclinical stage and clinical trials. The strengths and challenges of NIRF agents with tumor-targeting ability are also summarized. Smaller ligands, near infrared II dyes, dual-modality dyes and activatable dyes may contribute to quicker, deeper, stronger imaging in the nearest future. In this review, we highlighted tumor-targeted NIRF dyes for fluorescence-guided surgery and their potential clinical translation.

Intravascular Molecular Imaging to Detect High-Risk Vulnerable Plaques: Current Knowledge and Future Perspectives

To describe vulnerable plaque pathobiology and summarize potential targets for molecular imaging with a focus on intravascular near-infrared fluorescence (NIRF) and its translatable applications. Structural imaging alone is unable to precisely identify high-risk plaques in patients with coronary artery disease (CAD). Intravascular near-infrared fluorescence (NIRF) imaging is an emerging translational approach that can image specific in vivo molecular processes and cells that characterize vulnerable plaques. High-priority NIRF targets imaged by intravascular NIRF imaging thus far include macrophages, cathepsin protease activity, oxidized low-density lipoprotein (oxLDL), and abnormal endothelial permeability. The newest generation of NIRF catheters is multimodal in nature and combines NIRF with either IVUS or OCT, providing simultaneous co-registered morphological and pathobiological assessment of atherosclerotic plaques. While most intravascular NIRF studies have been performed in a preclinical environment, a first-in-human NIR autofluorescence-OCT trial has recently been performed. These developments suggest that clinical intravascular NIRF molecular imaging will be available within the next 3 years. Molecular imaging is a powerful approach to enhance our understanding of atherosclerosis pathophysiology. Intravascular NIRF/OCT and NIRF/IVUS molecular imaging is nearing its use in atherosclerosis patients and will initially leverage indocyanine green (ICG) as an FDA-approved NIRF agent that reports on abnormal plaque permeability. Clinical trials are needed to assess the value of intravascular NIRF imaging using ICG as well as other novel NIRF imaging agents to better understand vulnerable plaque pathobiology, event prediction, and to enable personalized pharmacotherapy of high-risk plaques and patients.

Tumor microenvironment-activated NIR-II reagents for tumor imaging and therapy.

Second near-infrared window (NIR-II, 1000-1700 nm) absorption and fluorescent agents have attracted great attention because they can overcome the penetration limitation of the first near-infrared window (NIR-I, 750-1000 nm). However, these always "on" agents face the severe problem of being susceptible to retention and phagocytosis by the reticuloendothelial system after intravenous administration, which results in signal interference during diagnosis and side effects during treatment. Accordingly, tumor microenvironment-responsive smart agents (smart NIR-II agents), whose imaging and therapeutic functions can only be triggered in tumors, can overcome this limitation. Thus, NIR-II smart agents, which exhibit a combined response to the tumor microenvironment and NIR-II, make full use of the advantages of both triggers and improve the precision diagnosis and effective treatment of cancer. This review summarizes the recent advances in tumor microenvironment-activated NIR-II agents for tumor diagnosis and treatment, including smart NIR-II fluorescence imaging, photoacoustic imaging, photothermal therapy and photodynamic therapy. Finally, the challenges and perspectives of NIR-II smart agents for tumor diagnosis and treatment are proposed.