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Molecular imaging holds great promise in the noninvasive monitoring of several diseases with nanoparticles (NPs) being considered an efficient imaging tool for cancer, central nervous system, and heart- or bone-related diseases and for disorders of the mononuclear phagocytic system (MPS). In the present study, we used an iron-based nanoformulation, already established as an MRI/SPECT probe, as well as to load different biomolecules, to investigate its potential for nuclear planar and tomographic imaging of several target tissues following its distribution via different administration routes. Iron-doped hydroxyapatite NPs (FeHA) were radiolabeled with the single photon γ-emitting imaging agent [99mTc]TcMDP. Administration of the radioactive NPs was performed via the following four delivery methods: (1) standard intravenous (iv) tail vein, (2) iv retro-orbital injection, (3) intratracheal (it) instillation, and (4) intrarectal installation (pr). Real-time, live, fast dynamic screening studies were performed on a dedicated bench top, mouse-sized, planar SPECT system fromt=0to 1 hour postinjection (p.i.), and consequently, tomographic SPECT/CT imaging was performed, for up to 24 hours p.i. The administration routes that have been studied provide a wide range of possible target tissues, for various diseases. Studies can be optimized following this workflow, as it is possible to quickly assess more parameters in a small number of animals (injection route, dosage, and fasting conditions). Thus, such an imaging protocol combines the strengths of both dynamic planar and tomographic imaging, and by using iron-based NPs of high biocompatibility along with the appropriate administration route, a potential diagnostic or therapeutic effect could be attained.

(1) Background: Theranostic approaches in the management of cholecystokinin subtype 2 receptor (CCK

This work describes the preparation, characterization and functionalization with magnetic nanoparticles of a bone tissue-mimetic scaffold composed of collagen and hydroxyapatite obtained through a biomineralization process. Bone remodeling takes place over several weeks and the possibility to follow it

Purpose Over the last few years studies are conducted, highlighting the feasibility of Gold Nanoparticles (GNPs) to be used in clinical CT imaging and as an efficient contrast agent for cancer research. After ensuring that GNPs formulations are appropriate for in vivo or clinical use, the next step is to determine the parameters for an X-ray system’s optimal contrast for applications and to extract quantitative information. There is currently a gap and need to exploit new X-ray imaging protocols and processing algorithms, through specific models avoiding trial-and-error procedures and provide an imaging prognosis tool. Such a model can be used to confirm the accumulation of GNPs in target organs before radiotherapy treatments with a system easily available in hospitals, as low energy X-rays. Methods In this study a complete, easy-to-use, simulation platform is designed and built, where simple parameters, as the X-ray’s specifications and experimentally defined biodistributions of specific GNPs are imported. The induced contrast and images can be exported, and accurate quantification can be performed. This platform is based on the GATE Monte Carlo simulation toolkit, based on the GEANT4 toolkit and the MOBY phantom, a realistic 4D digital mouse. Results We have validated this simulation platform to predict the contrast induction and minimum detectable concentration of GNPs on any given X-ray system. The study was applied to preclinical studies but is also expandable to clinical studies. Conclusions According to our knowledge, no other such validated simulation model currently exists, and this model could help radiology imaging with GNPs to be truly deployed.

Background The transmembrane-TNF transgenic mouse, TgA86, has been shown to develop spontaneously peripheral arthritis with signs of axial involvement. To assess similarity to human spondyloarthritis, we performed detailed characterization of the axial, peripheral, and comorbid pathologies of this model. Methods TgA86 bone pathologies were assessed at different ages using CT imaging of the spine, tail vertebrae, and hind limbs and characterized in detail by histopathological and immunohistochemical analysis. Cardiac function was examined by echocardiography and electrocardiography and bone structural parameters by μCT analysis. The response of TgA86 mice to either early or late anti-TNF treatment was evaluated clinically, histopathologically, and by μCT analysis. Results TgA86 mice developed with 100% penetrance spontaneous axial and peripheral pathology which progressed with time and manifested as reduced body weight and body length, kyphosis, tail bendings, as well as swollen and distorted hind joints. Whole-body CT analysis at advanced ages revealed bone erosions of sacral and caudal vertebrae as well as of sacroiliac joints and hind limbs and, also, new ectopic bone formation and eventually vertebral fusion. The pathology of these mice highly resembled that of SpA patients, as it evolved through an early inflammatory phase, evident as enthesitis and synovitis in the affected joints, characterized by mesenchymal cell accumulation, and neutrophilic infiltration. Subsequently, regression of inflammation was accompanied by ectopic bone formation, leading to ankylosis. In addition, both systemic bone loss and comorbid heart valve pathology were evident. Importantly, early anti-TNF treatment, similar to clinical treatment protocols, significantly reduced the inflammatory phase of both the axial and peripheral pathology of TgA86 mice. Conclusions The TgA86 mice develop a spontaneous peripheral and axial biphasic pathology accompanied by comorbid heart valvular dysfunction and osteoporosis, overall reproducing the progression of pathognomonic features of human spondyloarthritis. Therefore, the TgA86 mouse represents a valuable model for deciphering the role of transmembrane TNF in the pathogenic mechanisms of spondyloarthritis and for assessing the efficacy of human therapeutics targeting different phases of the disease.

In the current work, a pix2pix conditional generative adversarial network has been evaluated as a potential solution for generating adequately accurate synthesized morphological X-ray images by translating standard photographic images of mice. Such an approach will benefit 2D functional molecular imaging techniques, such as planar radioisotope and/or fluorescence/bioluminescence imaging, by providing high-resolution information for anatomical mapping, but not for diagnosis, using conventional photographic sensors. Planar functional imaging offers an efficient alternative to biodistribution ex vivo studies and/or 3D high-end molecular imaging systems since it can be effectively used to track new tracers and study the accumulation from zero point in time post-injection. The superimposition of functional information with an artificially produced X-ray image may enhance overall image information in such systems without added complexity and cost. The network has been trained in 700 input (photography)/ground truth (X-ray) paired mouse images and evaluated using a test dataset composed of 80 photographic images and 80 ground truth X-ray images. Performance metrics such as peak signal-to-noise ratio (PSNR), structural similarity index measure (SSIM) and Fréchet inception distance (FID) were used to quantitatively evaluate the proposed approach in the acquired dataset.

Additional file 1: Table S1. Clinical evaluation of peripheral arthritis (hind limbs). Table S2. Clinical evaluation of axial spondylitis (tail). Table S3. Histopathological evaluation of peripheral inflammation (hind limbs). Table S4. Histopathological evaluation of axial inflammation (per vertebra). Table S5. Histopathological evaluation of new bone formation. Figure S1. Clinical and histopathological score of peripheral and axial pathology of TgA86 males and females at 20 weeks. In vivo arthritis (joints) and axial spondylitis (tails) pathology was evaluated at 20-week old males (M) and females (F). Histopathological evaluation of peripheral (joints) and axial (tails) inflammation was performed on H&E stained sections. (Data are presented as individual values, with mean ± SEM). Figure S2. Histopathological and functional analysis of the TgA86 hearts reveal comorbid aortic heart valve dysfunction. (A, B) Representative immunohistochemical stainings of aortic valve sections of wt and TgA86 mice at the age of 20 weeks with anti-Vimentin and anti-Gr1 antibodies (A) reveal that the thickened areas of the valve (B) are mainly composed by Vimentin+ resident fibroblasts as well as few Gr1+ infiltrated neutrophils. (C, D) Blood aortic (AoV) and mitral (MV E and A) velocity measurements, acquired by Doppler analysis of TgA86 mice and wt littermates at 40 weeks of age, reveal increased AoV, indicating aortic valve stenosis, while the function of mitral valve remains unaffected (data are presented as individual values, with mean ± SEM). (E) Reduced Ejection fraction (EF%) of TgA86 mice at 40 weeks of age, indicate contractile dysfunction of their left ventricle. (Data are presented as individual values, with mean ± SEM; **P

Background: Peptide radioligands may serve as radionuclide carriers to tumor sites overexpressing their cognate receptor for diagnostic or therapeutic purposes. Treatment of mice with the neprilysin (NEP)-inhibitor phosphoramidon was previously shown to improve the metabolic stability and tumor uptake of biodegradable radiopeptides. Aiming to clinical translation of this methodology, we herein investigated the impact of the approved pill Entresto, releasing the potent NEP-inhibitor LBQ657 in vivo, on the stability and tumor uptake of two radiopeptides. Methods: The metabolic stability of [99mTc]Tc-DB4 (DB4, N4-Pro-Gln-Arg-Tyr-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Nle-NH2) and [111In]In-SG4 (SG4, DOTA-DGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) was tested in LBQ657/Entresto-treated mice vs. untreated controls. The uptake in gastrin-releasing peptide receptor (GRPR)-, or cholecystokinin subtype 2 receptor (CCK2R)-positive tumors respectively, was compared between LBQ657/Entresto-treated mice and untreated controls. Results: LBQ657/Entresto treatment induced marked stabilization of [99mTc] Tc-DB4 and [111In]In-SG4 in peripheral mice blood, resulting in equally enhanced tumor uptake at 4 h post-injection. Accordingly, the [99mTc]Tc-DB4 uptake of 7.13 &plusmn, 1.76%IA/g in PC-3 tumors increased to 16.17 &plusmn, 0.71/17.50 &plusmn, 3.70%IA/g (LBQ657/Entresto) and the [111In]In-SG4 uptake of 3.07 &plusmn, 0.87%IA/g in A431-CCK2R(+) tumors to 8.11 &plusmn, 1.45/9.61 &plusmn, 1.70%IA/g. Findings were visualized by SPECT/CT. Conclusions: This study has shown the efficacy of Entresto to notably improve the profile of [99mTc]Tc-DB4 and [111In]In-SG4 in mice, paving the way for clinical translation of this approach.

[EN] Bone is a dynamic tissue that constantly undergoes modeling and remodeling. Bone tissue engineering relying on the development of novel implant scaffolds for the treatment of pre-clinical bone defects has been extensively evaluated by histological techniques. The study of bone remodeling, that takes place over several weeks, is limited by the requirement of a large number of animals and time-consuming and labor-intensive procedures. X-ray-based imaging methods that can non-invasively detect the newly formed bone tissue have therefore been extensively applied in pre-clinical research and in clinical practice. The use of other imaging techniques at a pre-clinical level that act as supportive tools is convenient. This review mainly focuses on nuclear imaging methods (single photon emission computed tomography and positron emission tomography), either alone or used in combination with computed tomography. It addresses their application to small animal models with bone defects, both untreated and filled with substitute materials, to boost the knowledge on bone regenerative processes., The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is part of a project that has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 645757. This study was co-supported through the Program of Industrial Scholarships of Stavros Niarchos Foundation and through IKY scholarships and co-financed by the European Union (European Social Fund ESF) and Greek national funds through the action entitled Reinforcement of Postdoctoral Researchers, in the framework of the Operational Program Human Resources Development Program, Education and Lifelong Learning of the National Strategic Reference Framework (NSRF) 2014-2020.

To present a prototype tri-modal imaging system, consisting of a single photon emission computed tomography (SPET), a positron emission tomography (PET), and a computed tomography (CT) subsystem, evaluated in planar mode.The subsystems are mounted on a rotating gantry, so as to be able to allow tomographic imaging in the future. The system, designed and constructed by our group, allows whole body mouse imaging of competent performance and is currently, to the best of our knowledge, unequaled in a national and regional level. The SPET camera is based on two Position Sensitive Photomultiplier Tubes (PSPMT), coupled to a pixilated Sodium Iodide activated with Thallium (NaI(Tl)) scintillator, having an active area of 5x10cmThe scintigraphic mode has a spatial resolution of 1.88mm full width at half maximum (FWHM) and a sensitivity of 107.5cpm/0.037MBq at the collimator surface. The coincidence PET mode has an average spatial resolution of 3.5mm (FWHM) and a peak sensitivity of 29.9cpm/0.037MBq. The X-rays spatial resolution is 3.5lp/mm and the contrast discrimination function value is lower than 2%.A compact tri-modal system was successfully built and evaluated for planar mode operation. The system has an efficient performance, allowing accurate and informative anatomical and functional imaging, as well as semi-quantitative results. Compared to other available systems, it provides a moderate but comparable performance, at a fraction of the cost and complexity. It is fully open, scalable and its main purpose is to support groups on a national and regional level and provide an open technological platform to study different detector components and acquisition strategies.

Nuclear cardiac imaging is a noninvasive, sensitive method providing information on cardiac structure and physiology. Single photon emission tomography (SPECT) evaluates myocardial perfusion, viability, and function and is widely used in clinical routine. The quality of the tomographic image is a key for accurate diagnosis. Image filtering, a mathematical processing, compensates for loss of detail in an image while reducing image noise, and it can improve the image resolution and limit the degradation of the image. SPECT images are then reconstructed, either by filter back projection (FBP) analytical technique or iteratively, by algebraic methods. The aim of this study is to review filters in cardiac 2D, 3D, and 4D SPECT applications and how these affect the image quality mirroring the diagnostic accuracy of SPECT images. Several filters, including the Hanning, Butterworth, and Parzen filters, were evaluated in combination with the two reconstruction methods as well as with a specified MatLab program. Results showed that for both 3D and 4D cardiac SPECT the Butterworth filter, for different critical frequencies and orders, produced the best results. Between the two reconstruction methods, the iterative one might be more appropriate for cardiac SPECT, since it improves lesion detectability due to the significant improvement of image contrast.

The aim of this study was to develop a dual-modality PET/MR imaging probe by radiolabeling iron oxide magnetic nanoparticles (IONPs), surface functionalized with water soluble stabilizer 2,3-dicarboxypropane-1,1-diphosphonic acid (DPD), with the positron emitter Gallium-68. Magnetite nanoparticles (Fe3O4 MNPs) were synthesized via coprecipitation method and were stabilized with DPD. The Fe3O4-DPD MNPs were characterized based on their structure, morphology, size, surface charge, and magnetic properties. In vitro cytotoxicity studies showed reduced toxicity in normal cells, compared to cancer cells. Fe3O4-DPD MNPs were successfully labeled with Gallium-68 at high radiochemical purity (>91%) and their stability in human serum and in PBS was demonstrated, along with their further characterization on size and magnetic properties. The ex vivo biodistribution studies in normal Swiss mice showed high uptake in the liver followed by spleen. The acquired PET images were in accordance with the ex vivo biodistribution results. Our findings indicate that Ga68-Fe3O4-DPD MNPs could serve as an important diagnostic tool for biomedical imaging.

Introduction Gold and magnetic nanoparticles (NPs) are already used as contrast agents in CT and MRI diagnosis respectively, as well as in hyperthermia treatments. In both cases it is very important to be able to determine in vivo the distribution of the NPs. This can be done by radiolabeling the NPs or via MRI. These methods however present serious drawbacks in terms of cost and complexity. Purpose The purpose of this study is to explore and standardize a procedure of in vivo X-ray imaging for magnetic and gold NPs for diagnostic and pre-therapeutic purposes, using this low-cost, simple, readily available technology. Materials and methods The measurements were carried out on a prototype bench top x-ray system, consisting of an X-ray tube of a maximum beam energy of 80 keV and a minimum focal spot of 33 μm and of a CMOS detector with an active area of 12 × 12 cm and a spatial resolution of 0.1 mm. NPs samples of concentrations ranging between 1 and 500 mg of substance/ml were studied and compared with standard iodine solutions. Results All substances are found to present significant contrast enhancement properties and are used to create a standardized imaging procedure with respect to their concentrations. Gold nanoparticles are easily seen in lower concentrations and dual energy subtraction offers a greater differentiation in the observed attenuation properties. Localization and distribution information can be obtained in vivo through X-ray imaging. Conclusion A standardized procedure of in vivo X-ray imaging is set up for magnetic and gold NPs for diagnostic and pre-therapeutic purposes. Disclosure There is no relationship to be disclosed that may bias this presentation.