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Tumor organoids offer new opportunities for translational cancer research, but unlike animal models, their broader use is hindered by the lack of clinically relevant imaging endpoints. Here, we present a positron-emission microscopy method for imaging clinical radiotracers in patient-derived tumor organoids with spatial resolution 100-fold better than clinical positron emission tomography (PET). Using this method, we quantify 18 F-fluorodeoxyglucose influx to show that patient-derived tumor organoids recapitulate the glycolytic activity of the tumor of origin, and thus, could be used to predict therapeutic response in vitro. Similarly, we measure sodium-iodine symporter activity using 99m Tc- pertechnetate and find that the iodine uptake pathway is functionally conserved in organoids derived from thyroid carcinomas. In conclusion, organoids can be imaged using clinical radiotracers, which opens new possibilities for identifying promising drug candidates and radiotracers, personalizing treatment regimens, and incorporating clinical imaging biomarkers in organoid-based co-clinical trials. Positron emission tomography (PET) radiotracers measure the metabolic activity in cancer cells in patients. Here, the authors develop a microscopy method to image organoids using clinical radiotracers, which allows a direct comparison to PET imaging in patients.

PurposeThe increased glucose metabolism of cancer cells is the basis for 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). However, due to its coarse image resolution, PET is unable to resolve the metabolic role of cancer-associated stroma, which often influences the metabolic reprogramming of a tumor. This study investigates the use of radioluminescence microscopy for imaging FDG uptake in engineered 3D tumor models with high resolution.MethodMulticellular tumor spheroids (A549 lung adenocarcinoma) were co-cultured with GFP-expressing human umbilical vein endothelial cells (HUVECs) within an artificial extracellular matrix to mimic a tumor and its surrounding stroma. The tumor model was constructed as a 200-μm-thin 3D layer over a transparent CdWO4 scintillator plate to allow high-resolution imaging of the cultured cells. After incubation with FDG, the radioluminescence signal was collected by a highly sensitive widefield microscope. Fluorescence microscopy was performed using the same instrument to localize endothelial and tumor cells.ResultsSimultaneous and co-localized brightfield, fluorescence, and radioluminescence imaging provided high-resolution information on the distribution of FDG in the engineered tissue. The microvascular stromal compartment as a whole took up a large fraction of the FDG, comparable to the uptake of the tumor spheroids. In vitro gamma counting confirmed that A549 and HUVEC cells were both highly glycolytic with rapid FDG uptake kinetics. Despite the relative thickness of the tissue constructs, an average spatial resolution of 64 ± 4 μm was achieved for imaging FDG.ConclusionOur study demonstrates the feasibility of imaging the distribution of FDG uptake in engineered in vitro tumor models. With its high spatial resolution, the method can separately resolve tumor and stromal components. The approach could be extended to more advanced engineered cancer models but also to surgical tissue slices and tumor biopsies.

We present a method of reversible photoswitching in carbon nanodots with red emission. A mechanism of electron transfer is proposed. The cationic dark state, formed by the exposure of red light, is revived back to the bright state with the very short exposure of blue light. Additionally, the natural on-off state of carbon dot fluorescence was tuned using an electron acceptor molecule. Our observation can make the carbon dots as an excellent candidate for the super-resolution imaging of nanoscale biomolecules within the cell.

Positron emission tomography (PET), a cornerstone in cancer diagnosis and treatment monitoring, relies on the enhanced uptake of fluorodeoxyglucose ([ 18 F]FDG) by cancer cells to highlight tumors and other malignancies. While instrumental in the clinical setting, the accuracy of [ 18 F]FDG-PET is susceptible to metabolic changes introduced by radiation therapy. Specifically, radiation induces the formation of giant cells, whose metabolic characteristics and [ 18 F]FDG uptake patterns are not fully understood. Through a novel single-cell gamma counting methodology, we characterized the [ 18 F]FDG uptake of giant A549 and H1299 lung cancer cells that were induced by radiation, and found it to be considerably higher than that of their non-giant counterparts. This observation was further validated in tumor-bearing mice, which similarly demonstrated increased [ 18 F]FDG uptake in radiation-induced giant cells. These findings underscore the metabolic implications of radiation-induced giant cells, as their enhanced [ 18 F]FDG uptake could potentially obfuscate the interpretation of [ 18 F]FDG-PET scans in patients who have recently undergone radiation therapy.

The interaction of nanosized materials with living organisms is the central concern in the key applications of nanotechnology. In particular, the protein adsorption to nanomaterial surface has been a major focus of study in the past decade. Unfortunately, the underlying principles and molecular mechanisms are still not well understood, and there have been various approaches to address the issue. Bottom-up approaches like computational simulations at the atomistic level have already proved their potential. Several force fields and models have been developed to simulate realistic dynamics to mimic the interaction of solid surfaces and peptides, even in some cases, the whole protein. However, there are a few major limitations and bottlenecks of these studies, which remain mostly ignored and unexplored. Here, we review the studies that have been the major contributors to our present understanding of the nanoparticle (NP)-protein interaction. As the complexity of this phenomenon arises from different stages, the study of protein-NP interactions from multiple directions is necessary. In the perspective of bioapplications, we discuss the major challenges of this field and future scopes of research that can be designed rationally, sometimes coupled with numerous available experimental techniques to understand NP-protein docking in a more realistic manner.

Purpose Nanoparticles are highly efficient vectors for ferrying contrast agents across cell membranes, enabling ultra-sensitive in vivo tracking of single cells with positron emission tomography (PET). However, this approach must be fully characterized and understood before it can be reliably implemented for routine applications. Methods We developed a Langmuir adsorption model that accurately describes the process of labeling mesoporous silica nanoparticles (MSNP) with 68 Ga. We compared the binding efficiency of three different nanoparticle systems by fitting the model to experimental data. We then chose the MSNP with the highest affinity for 68 Ga to study uptake and efflux kinetics in cancer cells. After intracardiac injection of 50–100 cells in mice, PET imaging was performed to test the effectiveness of cellular radiolabeling. Results We found that highly porous mesoporous nanoparticles (d = 100 nm) with MCM-41 pore structures can achieve radiolabeling efficiency > 30 GBq/mg using 68 Ga, without the need for any chelator. These 68 Ga conjugated particles showed strong serum stability in vitro. In mice, the 68 Ga-MSNPs predominantly accumulated in the liver with a high signal-to-background ratio and no bladder signal, indicating excellent stability of the labeled nanoparticles in vivo . Additionally, these MSNPs were efficiently taken up by B16F10 and MDA-MB-231 cancer cells, as confirmed by confocal imaging, flow cytometry analysis, and gamma counting. Finally, cardiac injection of < 100 68 Ga-MSNP-labeled cells allowed PET/CT tracking of these cells in various organs in mice. Conclusion We characterized the critical parameters of MSNP-mediated direct cellular radiolabeling to improve the use of these nanoparticles as cellular labels for highly sensitive preclinical PET imaging.

Positron emission tomography (PET), a cornerstone in cancer diagnosis and treatment monitoring, relies on the enhanced uptake of fluorodeoxyglucose ([18F]FDG) by cancer cells to highlight tumors and other malignancies. While instrumental in the clinical setting, the accuracy of [18F]FDG-PET is susceptible to metabolic changes introduced by radiation therapy. Specifically, radiation induces the formation of giant cells, whose metabolic characteristics and [18F]FDG uptake patterns are not fully understood. Through a novel single-cell gamma counting methodology, we characterized the [18F]FDG uptake of giant A549 and H1299 lung cancer cells that were induced by radiation, and found it to be considerably higher than that of their non-giant counterparts. This observation was further validated in tumor-bearing mice, which similarly demonstrated increased [18F]FDG uptake in radiation-induced giant cells. These findings underscore the metabolic implications of radiation-induced giant cells, as their enhanced [18F]FDG uptake could potentially obfuscate the interpretation of [18F]FDG-PET scans in patients who have recently undergone radiation therapy.Positron emission tomography (PET), a cornerstone in cancer diagnosis and treatment monitoring, relies on the enhanced uptake of fluorodeoxyglucose ([18F]FDG) by cancer cells to highlight tumors and other malignancies. While instrumental in the clinical setting, the accuracy of [18F]FDG-PET is susceptible to metabolic changes introduced by radiation therapy. Specifically, radiation induces the formation of giant cells, whose metabolic characteristics and [18F]FDG uptake patterns are not fully understood. Through a novel single-cell gamma counting methodology, we characterized the [18F]FDG uptake of giant A549 and H1299 lung cancer cells that were induced by radiation, and found it to be considerably higher than that of their non-giant counterparts. This observation was further validated in tumor-bearing mice, which similarly demonstrated increased [18F]FDG uptake in radiation-induced giant cells. These findings underscore the metabolic implications of radiation-induced giant cells, as their enhanced [18F]FDG uptake could potentially obfuscate the interpretation of [18F]FDG-PET scans in patients who have recently undergone radiation therapy.

Most solid tumors contain regions of hypoxia that pose a significant challenge to the efficacy of radiation therapy. This study introduces a novel 3D lung tumor-on-a-chip (ToC) model designed to replicate the hypoxic tumor microenvironment while also providing a platform for clinically relevant interventions such as radiotherapy and positron emission tomography (PET) imaging. To simulate the heterogeneous oxygen distribution found in tumors, the ToC model incorporates an oxygen gradient achieved through a straightforward chemical oxygen scavenging system. A unique innovation of this device is the integration of a thin scintillator plate, which enables high-resolution radioluminescence microscopy imaging of tumor metabolism under hypoxia and normoxia conditions using clinically approved PET tracers such as fluorodeoxyglucose (FDG). The response of this hypoxic model to radiation therapy (10 Gy X-ray) demonstrated ~4-fold higher radioresistance compared to the normoxic ToC model, as assessed by colony formation potential. Additionally, DNA damage observed in the normoxic ToC model was ~5-fold higher than that in the hypoxic model. Furthermore, the metabolic consumption of glucose was found to mirror the localization of hypoxia, validating the use of this biomarker for planning radiation therapy. The integration of high-resolution radionuclide imaging within ToC models enables on-chip PET imaging and facilitates oncology research and discovery, offering innovative capabilities for the preclinical testing of novel cancer therapies in a clinically relevant environment.

Abstract PURPOSE The increased glucose metabolism of cancer cells is the basis for 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). However, due to its coarse image resolution, PET is unable to resolve the metabolic role of cancer-associated stroma, which often influences the metabolic reprogramming of a tumor. This study investigates the feasibility of imaging engineered 3D tumor models with high resolution using FDG. METHOD Multicellular tumor spheroids (A549 lung adenocarcinoma) were co-cultured with GFP-expressing human umbilical vein endothelial cells (HUVECs) within an artificial extracellular matrix to mimic a tumor and its surrounding stroma. The tumor model was constructed as a thin 3D layer over a transparent CdWO4 scintillator plate to allow high-resolution imaging of the cultured cells. The radioluminescence signal was collected by a highly sensitive microscope and camera. Fluorescence microscopy was performed in the same instrument to localize endothelial and tumor cells. RESULTS Simultaneous brightfield and fluorescence imaging, co-localized with radioluminescence signal, provided high-resolution information on FDG accumulation in the engineered tissue. The microvascular stromal compartment took up a large fraction of FDG, comparable to the tumor spheroids. In vitro gamma counting also revealed that both A549 and HUVEC cells were highly glycolytic and characterized by rapid FDG-uptake kinetics. CONCLUSION Our study demonstrates the feasibility of imaging FDG distribution in tumor and stromal components separately with high spatial resolution in engineered in vitro tumor models. Our imaging method is safe, simple, rapid, and can be easily used for other in vitro cancer models, surgical tissue slices, and tumor biopsies to interrogate PET radiotracer uptake at high resolution. Competing Interest Statement The authors have declared no competing interest. Footnotes * Declarations Funding: This project was funded in part by a grant from the Stanford-Tuebingen Collaboration on Imaging Immunotherapy * Availability of data and material: All data related to this study is included in the manuscript. Additional data that support the findings of this study are available from the corresponding author upon reasonable request. * Code availability: Not applicable

Organoid tumor models have found application in a growing array of cancer studies due to their ability to closely recapitulate the structural and functional characteristics of solid tumors. However, organoids are too small to be compatible with common radiological tools used in oncology clinics. Here, we present a microscopy method to image 18F-fluorodeoxyglucose in patient-derived tumor organoids with spatial resolution up to 100-fold better than that of clinical positron emission tomography (PET). When combined with brightfield imaging, this metabolic imaging approach functionally mirrors clinical PET/CT scans and provides a quantitative readout of cell glycolysis. In particular, the specific avidity of a tumor for FDG, or lack thereof, was maintained when the tumor cells were grown ex vivo as tumor organoids. In addition, cisplatin treatment caused a dose-dependent decrease in the metabolic activity of these organoids, with the exception of one patient whose tumor was also resistant to cisplatin treatment. Thus, FDG-imaging of organoids could be used to predict the response of individual patients to different treatments and provide a more personalized approach to cancer care. Competing Interest Statement The authors have declared no competing interest.