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Molecular imaging of telomerase and the enzyme activity-triggered drug release by using a conformation-switchable nanoprobe in cancerous cells
摘要： So far, the development of a unique strategy for specific biomolecules activity monitoring and precise drugs release in cancerous cells is still challenging. Here, we designed a conformation-switchable smart nanoprobe to monitor telomerase activity and to enable activity-triggered drug release in cancerous cells. The straightforward nanoprobe contained a gold nanoparticle (AuNP) core and a dense layer of 5-carboxyfluorescein (FAM)-labeled hairpin DNA shell. The 3′ region of hairpin DNA sequence could function as the telomerase primer to be elongated in the presence of telomerase, resulting in the conformational switch of hairpin DNA. As a result, the FAM fluorescence was activated and the anticancer drug doxorubicin (Dox) molecules which intercalated into the stem region of the hairpin DNA sequence were released into cancerous cells simultaneously. The smart method could specifically distinguish cancerous cells from normal cells based on telomerase activity. It also showed a good performance for monitoring telomerase activity in the cytoplasm by molecular imaging and precise release of Dox triggered by telomerase activity in cancerous cells. These advantages may offer a great potential of this method for monitoring telomerase activity in cancer progression and estimating therapeutic effect.
关键词： drug release,molecular imaging,nanoprobe,telomerase,cancerous cells
更新于2025-09-23 15:21:21
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Enhancing Anti-PD-1/PD-L1 Immune Checkpoint Inhibitory Cancer Therapy by CD276-Targeted Photodynamic Ablation of Tumor Cells and Tumor Vasculature
摘要： Antiangiogenic therapies have been demonstrated to improve the efficacy of immune checkpoint inhibition by overcoming the immunosuppressive status of tumor microenvironment. However, most of the current antiangiogenic agents cannot discriminate tumor angiogenesis from physiological angiogenesis. The aim of this study was to investigate whether a photodynamic therapy (PDT) agent that targets CD276, a receptor overexpressed in various tumor cells and tumor vasculature but with limited expression in normal tissue vasculature, could improve the tumor inhibitory efficacy of PD-1/PD-L1 blockade. A CD276-targeting agent (IRD-αCD276/Fab) was synthesized by conjugating the Fab fragment of an anti-CD276 antibody with a photosensitizer IRDye700. The in vivo tumor-targeting and therapeutic effect of IRD-αCD276/Fab with or without anti-PD-1/PD-L1 blockade was tested in subcutaneous and lung metastatic tumor models. PDT using IRD-αCD276/Fab significantly suppressed the growth of subcutaneous 4T1 tumor and inhibited its lung metastasis. Moreover, it triggered in vivo antitumor immunity by increasing the activation and maturation of dendritic cells. Tumor PD-L1 levels were also markedly increased after PDT using IRD-αCD276/Fab, as evidenced by noninvasive PD-L1-targeted small-animal PET imaging. In combination with anti-PD-1/PD-L1 blockade, IRD-αCD276/Fab PDT markedly suppressed the growth of tumors and prevented their metastasis to the lung by recruiting the tumor infiltration of CD8+ T cells. Our data provide evidence for the role of CD276-targeted PDT for local immune modulation, and its combination with PD-L1/PD-1 axis inhibition is a promising strategy for eliminating primary tumors as well as disseminated metastases, by generating local and systemic antitumor responses.
关键词： Molecular imaging,Checkpoint inhibition,Photoimmunotherapy,PET imaging,Angiogenesis
更新于2025-09-23 15:21:01
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P1217Zirconium-89 labelled probe for molecular imaging of inflammation in experimental atherosclerosis
摘要： Early detection of in?amed atherosclerotic lesions by molecular imaging might improve risk assessment beyond that of vascular stenosis and plaque morphology imaging, and improve the clinical management of high-risk patients. To target the key features of unstable atherosclerotic lesions, we studied the feasibility of our radiotracer, based on modi?ed human serum albumin (HSA), to identify in?amed atherosclerotic lesions by in vivo molecular imaging. We applied a maleylated HSA (Mal-HSA) probe, recognised by scavenger receptors on macrophages, in an experimental imaging study of atherosclerosis. Mal-HSA was coupled with a positron-emitting metal ion, Zirconium-89 (89Zr). The targeting potential of this probe was evaluated and compared with unspeci?c 89Zr-HSA and 18F-FDG in a mouse model of atherosclerosis (Apoe?/?, n=22) and compared with wild-type (WT) mice (C57BL/6, n=21) as controls. Radiotracer accumulation in the aortic arch was analysed in vivo by the fusion of positron emission tomography–magnetic resonance imaging (PET-MRI), radiotracer bio-distribution was measured ex vivo by gamma counter, and plaque uptake was evaluated by phosphor imaging (PI) autoradiography (ARG). PET-MRI, gamma counter measurements, and PI-ARG showed the accumulation of 89Zr-Mal-HSA in the atherosclerotic lesions of Apoe?/? mice. The maximum standardised uptake value (SUVmax) for 89Zr-Mal-HSA at 16 and 20 weeks were 26% and 20% higher (P<0.05) in Apoe?/? mice than control WT mice, whereas no difference in SUVmax was found for 18F-FDG in the same animals. 89Zr-Mal-HSA uptake in the aorta as evaluated by gamma counter 48 h post-injection was 32% higher (P<0.01) for Apoe?/? mice compared to WT mice, and the aorta-to-blood ratio was 10-fold higher (P<0.001) for 89Zr-Mal-HSA compared with unspeci?c 89Zr-HSA. HSA probes were mainly distributed to the liver, spleen, kidneys, bone and lymph nodes. The PI-ARG results corroborated the PET and gamma counter measurements, showing higher accumulation of 89Zr-Mal-HSA in the aortas of Apoe?/? mice compared to WT mice; 9.4±1.4 vs 0.8±0.3% (P<0.001). The modi?ed HSA-based radiotracer showed in vivo targeting of in?amed atherosclerotic lesions of mouse aorta, which could also be veri?ed ex vivo. 89Zr-Mal-HSA seems to be a promising diagnostic tool for the identi?cation of vascular in?ammation. Further methodological studies are needed to verify its applicability for detecting rupture-prone plaques.
关键词： atherosclerosis,inflammation,Zirconium-89,PET-MRI,molecular imaging,Nuclear cardiology
更新于2025-09-23 15:19:57
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Rapid, non-invasive fluorescence margin assessment: Optical specimen mapping in oral squamous cell carcinoma
摘要： Objective: Surgical resection remains the primary treatment for the majority of solid tumors. Despite efforts to obtain wide margins, close or positive surgical margins (< 5 mm) are found in 15–30% of head and neck cancer patients. Obtaining negative margins requires immediate, intraoperative feedback of margin status. To this end, we propose optical specimen mapping of resected tumor specimens immediately after removal. Materials and methods: A first-in-human pilot study was performed in patients (n = 8) after infusion of fluorescently labeled antibody, panitumumab-IRDye800 to allow surgical mapping of the tumor specimen. Patients underwent standard of care surgical resection for head and neck squamous cell carcinoma (HNSCC). Optical specimen mapping was performed on the primary tumor specimen and correlated with pathological findings after tissue processing. Results: Optical mapping of the specimen had a 95% sensitivity and 89% specificity to detect cancer within 5 mm (n = 160) of the cut surface. To detect tumor within 2 mm of the specimen surface, the sensitivity of optical specimen mapping was 100%. The maximal observed penetration depth of panitumumab-IRDye800 through human tissue in our study was 6.3 mm. Conclusion: Optical specimen mapping is a highly sensitive and specific method for evaluation of margins within < 5 mm of the tumor mass in HNSCC specimens. This technology has potentially broad applications for ensuring adequate tumor resection and negative margins in head and neck cancers.
关键词： Near-infrared,Oral cancer,Fluorescence imaging,Squamous cell carcinoma,Molecular imaging,Optical specimen mapping
更新于2025-09-19 17:15:36
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Magnetic Semiconductor Gd-Doping CuS Nanoparticles as Activatable Nanoprobes for Bimodal Imaging and Targeted Photothermal Therapy of Gastric Tumors
摘要： Targeted delivery of enzyme-activatable probes into cancer cells to facilitate accurate imaging and on-demand photothermal therapy (PTT) of cancers with high spatiotemporal precision promises to advance cancer diagnosis and therapy. Here, we report a tumor-targeted and matrix metalloprotease-2 (MMP-2)-activatable nanoprobe (T-MAN) formed by covalent modification of Gd-doping CuS micellar nanoparticles with cRGD and an MMP-2-cleavable fluorescent substrate. T-MAN displays a high r1 relaxivity (~60.0 mM-1s-1 per Gd3+ at 1 T) and a large near-infrared (NIR) fluorescence turn-on ratio (~185-fold) in response to MMP-2, allowing high-spatial-resolution magnetic resonance imaging (MRI) and low-background fluorescence imaging of gastric tumors as well as lymph node (LN) metastasis in living mice. Moreover, T-MAN has a high photothermal conversion efficiency (PCE, ~70.1%) under 808 nm laser irradiation, endowing it with the ability to efficiently generate heat to kill tumor cells. We demonstrate that T-MAN can accumulate preferentially in gastric tumors (~23.4% ID%/g at 12 h) after intravenous injection into mice, creating opportunities for fluorescence/MR bimodal imaging-guided PTT of subcutaneous and metastatic gastric tumors. For the first time, accurate detection and laser irradiation-initiated photothermal ablation of orthotopic gastric tumors in intraoperative mice was also achieved. This study highlights the versatility of using a combination of dual biomarker recognition (i.e., αvβ3 and MMP-2) and dual modality imaging (i.e., MRI and NIR fluorescence) to design tumor-targeting and activatable nanoprobes with improved selectivity for cancer theranostics in vivo.
关键词： molecular imaging,gastric tumor,CuS nanoparticles,activatable probe,photothermal therapy
更新于2025-09-19 17:15:36
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Real-time molecular optical micro-imaging of EGFR mutations using a fluorescent erlotinib based tracer
摘要： Background: EGFR mutations are routinely explored in lung adenocarcinoma by sequencing tumoral DNA. The aim of this study was to evaluate a fluorescent-labelled erlotinib based theranostic agent for the molecular imaging of mutated EGFR tumours in vitro and ex vivo using a mice xenograft model and fibred confocal fluorescence microscopy (FCFM). Methods: The fluorescent tracer was synthesized in our laboratory by addition of fluorescein to an erlotinib molecule. Three human adenocarcinoma cell lines with mutated EGFR (HCC827, H1975 and H1650) and one with wild-type EGFR (A549) were xenografted on 35 Nude mice. MTT viability assay was performed after exposure to our tracer. In vitro imaging was performed at 1 μM tracer solution, and ex vivo imaging was performed on fresh tumours excised from mice and exposed to a 1 μM tracer solution in PBS for 1 h. Real-time molecular imaging was performed using FCFM and median fluorescence intensity (MFI) was recorded for each experiment. Results: MTT viability assay confirmed that addition of fluorescein to erlotinib did not suppress the cytotoxic of erlotinib on tumoral cells. In vitro FCFM imaging showed that our tracer was able to distinguish cell lines with mutated EGFR from those lines with wild-type EGFR (p < 0.001). Ex vivo FCFM imaging of xenografts with mutated EGFR had a significantly higher MFI than wild-type (p < 0.001). At a cut-off value of 354 Arbitrary Units, MFI of our tracer had a sensitivity of 100% and a specificity of 96.3% for identifying mutated EGFR tumours. Conclusion: Real time molecular imaging using fluorescent erlotinib is able to identify ex vivo tumours with EGFR mutations.
关键词： Lung cancer,Erlotinib,Theranostic,EGFR,Epidermal growth factor,Fibred confocal fluorescence microscopy,Molecular imaging
更新于2025-09-19 17:15:36
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<i>In vivo</i> multiplex molecular imaging of vascular inflammation using surface-enhanced Raman spectroscopy
摘要： Vascular immune-inflammatory responses play a crucial role in the progression and outcome of atherosclerosis. The ability to assess localized inflammation through detection of specific vascular inflammatory biomarkers would significantly improve cardiovascular risk assessment and management; however, no multi-parameter molecular imaging technologies have been established to date. Here, we report the targeted in vivo imaging of multiple vascular biomarkers using antibody-functionalized nanoparticles and surface-enhanced Raman scattering (SERS). Methods: A series of antibody-functionalized gold nanoprobes (BFNP) were designed containing unique Raman signals in order to detect intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and P-selectin using SERS. Results: SERS and BFNP were utilized to detect, discriminate and quantify ICAM-1, VCAM-1 and P-selectin in vitro on human endothelial cells and ex vivo in human coronary arteries. Ultimately, non-invasive multiplex imaging of adhesion molecules in a humanized mouse model was demonstrated in vivo following intravenous injection of the nanoprobes. Conclusion: This study demonstrates that multiplexed SERS-based molecular imaging can indicate the status of vascular inflammation in vivo and gives promise for SERS as a clinical imaging technique for cardiovascular disease in the future.
关键词： vascular inflammation,molecular imaging,multiplexing,atherosclerosis,surface-enhanced Raman spectroscopy (SERS)
更新于2025-09-19 17:15:36
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[IEEE 2019 IEEE 4th International Conference on Integrated Circuits and Microsystems (ICICM) - Beijing, China (2019.10.25-2019.10.27)] 2019 IEEE 4th International Conference on Integrated Circuits and Microsystems (ICICM) - A Laser Modulation Driver in 130-nm CMOS Technology for Quantum Key Distribution System
摘要： The imaging of dysregulated cell-surface receptors (or biomarkers) is a potential means of identifying the presence of cancer with high sensitivity and specificity. However, due to heterogeneities in the expression of protein biomarkers in tumors, molecular imaging technologies should ideally be capable of visualizing a multiplexed panel of cancer biomarkers. Recently, surface-enhanced Raman-scattering (SERS) nanoparticles (NPs) have attracted wide interest due to their potential for sensitive and multiplexed biomarker detection. In this review, we focus on the most recent advances in tumor imaging using SERS-coded NPs. A brief introduction of the structure and optical properties of SERS NPs is provided, followed by a detailed discussion of key imaging issues such as the administration of NPs in tissue (topical versus systemic), the optical configuration and imaging approach of Raman imaging systems, spectral demultiplexing methods for quantifying NP concentrations, and the disambiguation of specific versus nonspecific sources of contrast through ratiometric imaging of targeted and untargeted (control) NP pairs. Finally, future challenges and directions are briefly outlined.
关键词： molecular imaging,fiberoptic probes,Biomarkers,cancer detection,nanomedicine,tumors,Raman spectroscopy,biomedical optical imaging
更新于2025-09-19 17:13:59
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Intravascular Molecular Imaging to Detect High-Risk Vulnerable Plaques: Current Knowledge and Future Perspectives
摘要： Purpose of Review 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. Recent Findings 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. Summary 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.
关键词： Molecular imaging,Vulnerable plaque,Near-infrared spectroscopy,OCT,Atherosclerosis,Near-infrared fluorescence,IVUS
更新于2025-09-19 17:13:59
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Synthesis, radiolabelling and initial biological characterisation of <sup>18</sup> F-labelled xanthine derivatives for PET imaging of Eph receptors
摘要： Eph receptor tyrosine kinases, particularly EphA2 and EphB4, represent promising candidates for molecular imaging due to their essential role in cancer progression and therapy resistance. Xanthine derivatives were identified to be potent Eph receptor inhibitors with IC50 values in the low nanomolar range (1–40 nm). These compounds occupy the hydrophobic pocket of the ATP-binding site in the kinase domain. Based on lead compound 1, we designed two fluorine-18-labelled receptor tyrosine kinase inhibitors ([18F]2/3) as potential tracers for positron emission tomography (PET). Docking into the ATP-binding site allowed us to find the best position for radiolabelling. The replacement of the methyl group at the uracil residue ([18F]3) rather than the methyl group of the phenoxy moiety ([18F]2) by a fluoropropyl group was predicted to preserve the affinity of the lead compound 1. Herein, we point out a synthesis route to [18F]2 and [18F]3 and the respective tosylate precursors as well as a labelling procedure to insert fluorine-18. After radiolabelling, both radiotracers were obtained in approximately 5% radiochemical yield with high radiochemical purity (>98%) and a molar activity of >10 GBq μmol?1. In line with the docking studies, first cell experiments revealed specific, time-dependent binding and uptake of [18F]3 to EphA2 and EphB4-overexpressing A375 human melanoma cells, whereas [18F]2 did not accumulate at these cells. Since both tracers [18F]3 and [18F]2 are stable in rat blood, the novel radiotracers might be suitable for in vivo molecular imaging of Eph receptors with PET.
关键词： xanthine derivatives,molecular imaging,positron emission tomography (PET),fluorine-18-labelled,Eph receptor tyrosine kinases
更新于2025-09-19 17:13:59