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Background/Aim: Myocardial infarction, an acute medical situation with a high mortality rate worldwide, has been extensively studied in modern cardiovascular research, using different experimental models. However, a deep understanding of myocardial activity loss has not been fully investigated. We have developed a novel experimental rat model for noninvasive assessment of myocardial ischemia based on single photon emission computed tomography (SPECT/CT), in order to further understand and evaluate myocardial activity before and after surgical induction of myocardial ischemia. Materials and Methods: Thirty adult female Wistar rats underwent open thoracotomy with (n=20) or without (n=10) surgical ligation of the left anterior descending coronary artery (LAD). The myocardial ischemia was confirmed with ECG and myocardial viability was evaluated via SPECT/CT at 7 days before as well as at 7 and 14 days post-surgery, after which animals were sacrificed and myocardial ischemic injury was further assessed histologically. Results: All animals were evaluated with anatomical and functional criteria based on the SPECT/CT imaging results. A successful surgical technique causing ischemia and loss of myocardial function in all animals undergoing a LAD ligation was established. Furthermore, evaluation of the viable myocardium with SPECT/CT confirmed the reduction of functional myocardial cells of the left ventricle post-infarction, which was also documented histologically. Conclusion: Using our technique, the validity of this animal model to induce and evaluate myocardial ischemia was demonstrated. Our choice to apply SPECT-CT qualitative and quantitative evaluation of myocardial function leads to a new approach in experimentation with an anticipated significant impact in the ongoing cardiovascular laboratory research.

PURPOSE This study proposes a novel computational platform that we refer to as IDDRRA (DNA Damage Response to Ionizing RAdiation), which uses Monte Carlo (MC) simulations to score radiation induced DNA damage. MC simulations provide results of high accuracy on the interaction of radiation with matter while scoring the energy deposition based on state-of-the-art physics and chemistry models and probabilistic methods. METHODS The IDDRRA software is based on the Geant4-DNA toolkit together with new tools that were developed for the purpose of this study, including a new algorithm that was developed in Python for the design of the DNA molecules. New classes were developed in C++ to integrate the GUI and produce the simulation's output in text format. An algorithm was also developed to analyze the simulation's output in terms of energy deposition, Single Strand Breaks (SSB), Double Strand Breaks (DSB) and Cluster Damage Sites (CDS). Finally, a new tool was developed to implement probabilistic SSB and DSB repair models using MC techniques. RESULTS This article provides the first benchmarks that the user of the IDDRRA tool can use to validate the functionality of the software as well as to provide a starting point to produce different types of DNA simulations. These benchmarks incorporate different kind of particles (e-, e+, protons, electron spectrum) and DNA molecules. CONCLUSION We have developed the IDDRRA tool and demonstrated its use to study various aspects of the modeling and simulation of a DNA irradiation experiment. The tool is expandable and can be expanded by other users with new benchmarks and applications based on the user's needs and experience. New functionality will be added over time, including the quantification of the indirect damage.

Edelfosine (ET) is a potent antitumor agent but causes severe side effects that have limited its use in clinical practice. For this reason, nanoencapsulation in lipid nanoparticles (LNs) is advantageous as it protects from ET side-effects. Interestingly, previous studies showed the efficacy of LNs containing ET in various types of tumor. In this paper, biodistribution studies of nanoencapsulated ET, administered by three routes (oral, intravenous (IV) and intraperitoneal (IP)), were tested in order to select the optimal route of administration. To do this, ET-LNs were labeled with Technetium-99 m (99mTc) and administered by the oral, IV and IP route in mice. IV admin- istration of the radiolabeled LNs led to fast elimination from the blood circulation and increased accumulation in reticulo-endothelial (RES) organs, while their oral administration could not provide any evidence on their bio- distribution since large radiocomplexes were formed in the presence of gastrointestinal fluids. However, when the LNs were administered by the IP route they could access the systemic circulation and provided more constant blood ET-LN levels compared to the IV route. These findings suggest that the IP route can be used to sustain the level of drug in the blood and avoid accumulation in RES organs.

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

In nuclear medicine, the gamma camera is one of the more used imaging devices for radionuclide imaging. Gamma camera provide an image of the target organ, with high spatial resolution and sensitivity; gamma cameras use collimators. This paper presents a simple and customizable collimator to be used in radionuclide imaging for preclinical studies, using additive manufacturing (AM) techniques. A numerical analysis, based on GATE Monte Carlo toolkit (vGate 8.2), has been conducted to simulate different configurations of an already working collimator used as reference. In addition to the standard collimator geometry with alternatives materials, we also propose a new concept of collimator to be easily 3D printed, using different 3D printing technologies. We have simulated collimators with square apertures of 1.5 mm and septa of 0.4 mm of thickness, source was Tc99m. The materials simulated were standard tungsten, a PLA doped with tungsten (Rapid 3D Shield Tungsten Filament - Virtual Foundry), a classical PLA filament and P A2200 for the new concept. The results show a similar behavior for what concern the spatial resolution, while for the sensitivity a reduction of about 45% of entries is reported. This is due mainly since the extruded pixel, made of PLA or PA2200, have higher density $(\approx$ 1.24 g/cm^3 for PLA and $\approx 0,95$ g/cm^3 for PA2200) with respect to air $(\approx$ 0,0012 g/cm^J). Further studies are necessary to explore optimization of the used design to reduce the impact of material density.

We aim to investigate the counting response variations of positron emission tomography (PET) scanners with different detector configurations in the presence of solitary pulmonary nodule (SPN). Using experimentally validated Monte Carlo simulations, the counting performance of four different scanner models with varying tumor activity, location, and patient obesity is represented using a noise equivalent count rate (NECR). NECR is a well-established quantitative metric which has positive correlation with clinically perceived image quality. The combined effect of tumor displacement and increased activity shows a linear ascending trend for NECR with slope ranges of (12.5–18.2)*10−3 (kBq/cm3)−1 for three-ring (3R) scanners and (15.3–21.5)*10−3 (kBq/cm3)−1 for four-ring (4R). The trend for the combined effect of tumor displacement and patient obesity is exponential decay with 3R configurations weakly dependent on the patient obesity if the tumor is located at the center of the field of view with exponent’s range of (6.6–33.8)*10−2cm−1. The dependence is stronger for 4R scanners (9.6–38.5)*10−2cm−1. The analysis indicates that quantitative PET data from the same SPN patient possibly examined in different time points (e.g., during staging or for the evaluation of treatment response) are affected by the different detector configurations and need to be normalized with patient weight, activity, and tumor location to reduce unwanted bias of the diagnosis. This paper provides also with a proof of concept for the ability of properly tuned simulations to provide additional insights into the counting response variability especially in tumor types where often borderline decisions have to be made regarding their characterization.

Preclinical nuclear molecular imaging speeds up the mean time from synthesis to market, in drug development process. Commercial imaging systems have in general high cost, require high-cost service contracts, special facilities and trained staff. In the current work, we present β -eye, a benchtop system for in vivo molecular screening of labeled compounds with Positron Emission Tomography (PET) isotopes. The developed system is based on a dual-head geometry, offering simplicity and decreased cost. The goal of the design is to provide 2D, real-time radionuclide images of mice, allowing the recording of fast frames and thus perform fast kinetic studies, with spatial resolution of ∼ 2 mm. Performance evaluation demonstrates the ability of β -eye to provide quantitative results for injected activities lower than 1.5 MBq, which is adequate for pharmacodynamic studies in small mice.

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.

Built on top of the Geant4 toolkit, GATE is collaboratively developed for more than 15 years to design Monte Carlo simulations of nuclear-based imaging systems. It is, in particular, used by researchers and industrials to design, optimize, understand and create innovative emission tomography systems. In this paper, we reviewed the recent developments that have been proposed to simulate modern detectors and provide a comprehensive report on imaging systems that have been simulated and evaluated in GATE. Additionally, some methodological developments that are not specific for imaging but that can improve detector modeling and provide computation time gains, such as Variance Reduction Techniques and Artificial Intelligence integration, are described and discussed.

Radiolabeled gastrin analogues have been proposed for theranostics of cholecystokinin subtype 2 receptor (CCK(2)R)-positive cancer. Peptide radioligands based on other receptor antagonists have displayed superior pharmacokinetics and higher biosafety than agonists. Here, we present DGA1, a derivative of the nonpeptidic CCK(2)R antagonist Z-360 carrying an acyclic tetraamine, for [(99m)Tc]Tc labeling. Preclinical comparison of [(99m)Tc]Tc-DGA1 with [(99m)Tc]Tc-DG2 (CCK(2)R-agonist reference) was conducted in HEK293-CCK(2)R/CCK(2i4sv)R cells and mice models, qualifying [(99m)Tc]Tc-DGA1 for further study in patients with CCK(2)R-positive tumors and single-photon emission computed tomography/CT.

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 this paper, we report for the first time on the performance of the Hamamatsu H13974 flat panel photomultiplier tube (PMT) array. This new photodetector is based on four Hamamatsu H12700A position sensitive PMTs in a $ 2 \times 2$ arrangement providing large sensitive area ( $ {100\times 100}$ mm2) for use in scintimammography or/and medium size mammals imaging. We acquired raw images from three pixellated scintillators for possible positron emission tomography and single photon emission computed tomography applications (BGO with $ {2\times 2\times 6}$ mm3, CsI:Tl with $ {2\times 2\times 4}$ mm3, and CsI:Na with $ {1.45\times 1.45\times 6}$ mm3 pixel sizes) irradiated with 511 keV (68Ga) and 140 keV (99 m Tc), respectively. Different coupling schemes involving optical grease and optical glasses of different thicknesses were used in order to find the scheme that better resolves the crystal elements of the scintillators especially in the dead areas of the flat panel PMT array. We present the results of investigating the basic properties, including energy resolution, intrinsic spatial resolution, detection efficiency, and sensitivity uniformity. The scintillation material, the coupling scheme and the analog readout circuits are the main factors that affect the performance of the detector. The proper combination of these factors should be carefully chosen so as to build a high performance imaging system.

Simultaneous PET/MR/EEG (Positron Emission Tomography – Magnetic Resonance – Electroencephalography), a new tool for the investigation of neuronal networks in the human brain, is presented here within the framework of the European Union Project TRIMAGE. The trimodal, cost-effective PET/MR/EEG imaging tool makes use of cutting edge technology both in PET and in MR fields. A novel type of magnet (1.5T, non-cryogenic) has been built together with a PET scanner that makes use of the most advanced photodetectors (i.e., SiPM matrices), scintillators matrices (LYSO) and digital electronics. The combined PET/MR/EEG system is dedicated to brain imaging and has an inner diameter of 260 mm and an axial Field-of-View of 160 mm.It enables the acquisition and assessment of molecular metabolic information with high spatial and temporal resolution in a given brain simultaneously. The dopaminergic system and the glutamatergic system in schizophrenic patients are investigated via PET, the same physiological/pathophysiological conditions with regard to functional connectivity, via fMRI, and its electrophysiological signature via EEG. In addition to basic neuroscience questions addressing neurovascular-metabolic coupling, this new methodology lays the foundation for individual physiological and pathological fingerprints for a wide research field addressing healthy aging, gender effects, plasticity and different psychiatric and neurological diseases.The preliminary performances of two components of the imaging tool (PET and MR) are discussed. Initial results of the search of possible candidates for suitable schizophrenia biomarkers are also presented as obtained with PET/MR systems available to the collaboration.

Sentinel lymph node detection (SLND) is rapidly entering common practice in the management of patients with tumors. The introduction of mannose molecules to 99mTc-labeled dextrans, so far, showed that the sentinel node could trap these agents due to their recognition by the mannose receptors of lymph node macrophages. The current study aimed to synthesize, characterize, and biologically evaluate a series of mannosylated dextran derivatives labeled with 99mTc for potential use in SLND. The compounds were designed to have a dextran with a molecular weight of 10–500 kDa as a backbone, S-derivatized cysteines, efficient SNO chelators, and mannose moieties for binding to mannose receptors. They were successfully synthesized, thoroughly characterized using NMR techniques, and labeled with the fac-[99mTc(CO)3]+ synthon. Labeling with high yields and radiochemical purities was achieved with all derivatives. In vivo biodistribution and imaging studies demonstrated high uptake in the first lymph node and low uptakes in the following node and confirmed the ability to visualize the SLN. Among the compounds studied, 99mTc-D75CM demonstrated the most attractive biological features, and in combination with the high radiochemical yield and stability of the compound, its further evaluation as a new radiopharmaceutical for sentinel lymph node detection was justified.

Prothymosin alpha (ProTα) is a highly conserved mammalian polypeptide (109 amino acids in man) exerting in vitro and in vivo immunoenhancing activities. Recently, our team has developed a 99mTc-radiolabeled derivative of the C-terminal bioactive decapeptide of ProTα ([99mTc]C1) and employed it in in vitro studies, the results of which support the existence of binding sites on human neutrophils that recognize [99mTc]C1, intact ProTα as well as the C-terminal decapeptide of ProTα and presumably involve Toll-like receptor 4. In the present work, [99mTc]C1 was administered to Swiss albino mice with experimentally-induced inflammation for in vivo biodistribution and imaging studies, in parallel with a suitable negative control, which differs from [99mTc]C1 only in bearing a scrambled version of the ProTα decapeptide. The biodistribution data obtained with [99mTc]C1 demonstrated fast clearance of radioactivity from blood, heart, lungs, normal muscle, and predominantly urinary excretion. Most importantly, slow clearance of radioactivity from the inflammation focus was observed, resulting in a high ratio of inflamed/normal muscle tissue (9.15 at 30 min post injection, which remained practically stable up to 2 h). The inflammation-targeting capacity of [99mTc]C1 was confirmed by imaging studies and might be attributed to neutrophils, which are recruited at the inflamed areas and bear binding sites for [99mTc]C1. In this respect, apart from being a valuable tool for further studies on ProTα in in vitro and in vivo systems, [99mTc]C1 merits further evaluation as a radiopharmaceutical for specific imaging of inflammation foci.

[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.

Recently, nanoparticles have emerged as promising contrast agents for various imaging applications. In this paper, we present the synthesis and characterization of a novel hybrid nano-structure, consisting of an iron oxide@gold nanoparticle, labeled with technetium-99m, for trimodal SPECT/CT/MRI imaging. The particles showed efficient capabilities as CT/MRI imaging agent and high radiochemical yield, indicating a potential single hybrid material for multimodal SPECT/CT/MRI.

State of the art data acquisition systems for small animal imaging gamma ray detectors often rely on free running Analog to Digital Converters (ADCs) and high density Field Programmable Gate Arrays (FPGA) devices for digital signal processing. In this work, a sub-sampling acquisition approach, which exploits a priori information regarding the shape of the obtained detector pulses is proposed. Output pulses shape depends on the response of the scintillation crystal, photodetector’s properties and amplifier/shaper operation. Using these known characteristics of the detector pulses prior to digitization, one can model the voltage pulse derived from the shaper (a low-pass filter, last in the front-end electronics chain), in order to reduce the desirable sampling rate of ADCs. Fitting with a small number of measurements, pulse shape estimation is then feasible. In particular, the proposed sub-sampling acquisition approach relies on a bi-exponential modeling of the pulse shape. We show that the properties of the pulse that are relevant for Single Photon Emission Computed Tomography (SPECT) event detection (i.e., position and energy) can be calculated by collecting just a small fraction of the number of samples usually collected in data acquisition systems used so far. Compared to the standard digitization process, the proposed sub-sampling approach allows the use of free running ADCs with sampling rate reduced by a factor of 5. Two small detectors consisting of Cerium doped Gadolinium Aluminum Gallium Garnet (Gd3Al2Ga3O12 : Ce or GAGG:Ce) pixelated arrays (array elements: $2\times 2\times 5~\mathrm {mm}^{3}$ and $1\times 1\times 10~\mathrm {mm}^{3}$ respectively) coupled to a Position Sensitive Photomultiplier Tube (PSPMT) were used for experimental evaluation. The two detectors were used to obtain raw images and energy histograms under 140 keV and 661.7 keV irradiation respectively. The sub-sampling acquisition technique (10 MHz sampling rate) was compared with a standard acquisition method (52 MHz sampling rate), in terms of energy resolution and image signal to noise ratio for both gamma ray energies. The Levenberg-Marquardt (LM) non-linear least-squares algorithm was used, in post processing, in order to fit the acquired data with the proposed model. The results showed that analog pulses prior to digitization are being estimated with high accuracy after fitting with the bi-exponential model.

Nuclear medicine and radiation therapy, although well established, are still rapidly evolving, by exploiting animal models, aiming to define precise dosimetry in molecular imaging protocols. The purpose of the present study was to create a dataset based on the MOBY phantom for the calculation of organ-to-organ S-values of commonly used radionuclides. S-values of most crucial organs were calculated using specific biodistributions with a whole-body heterogeneous source. In order to determine the impact of the varying organs' size on the S-values, and based on the fact that the anatomic properties of the organs are correlated with S-values, dosimetric calculations were performed by simulating the MOBY-version 2 model with different whole-body masses. The GATE Monte Carlo simulation toolkit was used for all simulations. Two mouse models of different body masses were developed to calculate the S-values of eight commonly used radioisotopes in nuclear imaging studies, namely 18F, 68Ga, 131I, 111In, 177Lu, and 99mTc, 90Y and 188Re. The impact of modified mass of the source organs in S-values was investigated with 18F, and 90Y in five different scalings of the source organs. Based on realistic preclinical exams, three mouse models, 22, 28 and 34 g, were used as input in the GATE simulator based on realistic preclinical exams to calculate the S-values of the six radioisotopes used. Whole body activity distributions were used as the source organ. The simulation procedure was validated in terms of extracting individual organ-to-organ S-values, and consequently in calculating the new S-values using a heterogeneous activity distribution as a source. The calculation was validated with 18F source in a 30 g mouse model. For the generation of the new S-values with heterogeneous activity sources, four organs were used for the calculation of a single S-value. The absorbed doses per organ were compared with previously published reports. The validation procedure of 18F indicates discrepancies, ranging from 5.32 to 7.72%. The S-values in Gy/(Bqs), with the corresponding uncertainties of all simulated cases, are given in the developed dataset. The comparison of the dosimetric calculations on the three different phantoms highlights the impact of the mouse model size on the calculated S-values. The developed dataset can be used to improve the accuracy of the absorbed dose calculations in small animal dosimetry and depict the crucial impact the mouse size has on S-values' calculation. The generated S-values dataset for different radiopharmaceuticals contributes to the estimation of radiation dose to mice in small animal PET and SPECT exams. Finally, the detailed methodology of the procedure is provided.

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.

Polymeric materials are in the epicenter of scientific research the last decade and have been used in a range of pharmaceutical and biological applications. Multifunctional polymeric materials are capable targeting agents, which can be used as controlled drug release vehicles for the enhancement of therapeutic efficacy, as well as for diagnostic purposes. A newer generation of these smart polymeric entities constitutes of smart nanocontainers (NCs), which can navigate the drug to specific areas by avoiding random distribution, and thus resulting in drug toxicity reduction. The combination of pH, thermo and redox sensitivity of the multi stimuli NCs can help to achieve specific release of the drug in the tumor area, where these sensitivity parameters can be observed. Hollow polymeric multi stimuli fluorescent tNCs based on N-(2-Hydroxypropyl)methacrylamide (HPMA) were successfully functionalized with a specific targeting moiety; folic acid, and then characterized morphologically, by scanning electron and transmission electron microscopy, as well as structurally, by Fourier-transform infrared spectroscopy. Their targeting mechanism was investigated in vitro in cervical cancer cell lines and in vivo in tumor bearing mice. According to our results the folic acid functionalized NCs targeted HeLa cells’ surface within the first 30 min of treatment. Human tumor xenografted mice (nonobese diabetic/severe combined immunodeficient) were injected with folate functionalized NCs and their tumor uptake was estimated by γ-imaging at about 3.5%. The targeting efficiency of the folate functionalized NCs was investigated directly in vivo by γ-imaging and indirectly by a tumor efficacy protocol.