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Giovanni Baldi,1 Costanza Ravagli,1 Filippo Mazzantini,1 George Loudos,2 Jaume Adan,3 Marc Masa,3 Dimitrios Psimadas,2 Eirini A Fragogeorgi,2 Erica Locatelli,4 Claudia Innocenti,5,6 Claudio Sangregorio,5,7 Mauro Comes Franchini4 1CERICOL, Sovigliana-Vinci, Italy; 2Technological Educational Institute of Athens, Athens, Greece; 3Leitat Technological Center, Barcelona, Spain; 4Department of Industrial Chemistry Toso Montanari, University of Bologna, Bologna, 5Consorzio Interuniversitario Nazionale per la Scienza e Tecnologia dei Materiali (INSTM), 6Dipartimento di Chimica U Schiff, Università di Firenze, Firenze, 7Centro Nazionale delle Ricerche (ICCOM – CNR), Firenze, Italy Abstract: Polymeric nanoparticles with targeting moieties containing magnetic nanoparticles as theranostic agents have considerable potential for the treatment of cancer. Here we report the chemical synthesis and characterization of a poly(D,L-lactide-co-glycolide)-b-poly(ethylene glycol)-based nanocarrier containing iron oxide nanoparticles and human epithelial growth factor receptor on the outer shell. The nanocarrier was also radiolabeled with 99mTc and tested as a theranostic nanomedicine, ie, it was investigated for both its diagnostic ability in vivo and its therapeutic hyperthermic effects in a standard A431 human tumor cell line. Following radiolabeling with 99mTc, the biodistribution and therapeutic hyperthermic effects of the nanosystem were studied noninvasively in vivo in tumor-bearing mice. A substantial decrease in tumor size correlated with an increase in both nanoparticle concentration and local temperature was achieved, confirming the possibility of using this multifunctional nanosystem as a therapeutic tool for epidermoid carcinoma. Keywords: magnetic nanoparticles, polymeric nanocarriers, skin cancer, hyperthermia, single-photon emission computed tomography, imaging

Metal oxide nanoparticles, hybridized with various polymeric chemicals, represent a novel and breakthrough application in drug delivery, hyperthermia treatment and imaging techniques. Radiolabeling of these nanoformulations can result in new and attractive dual-imaging agents as well as provide accurate in vivo information on their biodistribution profile. In this paper a comparison study has been made between two of the most promising hybrid core–shell nanosystems, bearing either magnetite (Fe3O4) or cobalt ferrite (CoFe2O4) cores, regarding their magnetic, radiolabeling, hyperthermic and biodistribution properties. While hyperthermic properties were found to be affected by the metal-core type, the radiolabeling ability and the in vivo fate of the nanoformulations seem to depend critically on the size and the shell composition. [ABSTRACT FROM AUTHOR]

Abstract: In the initial stages of tumor formation, overexpression of integrins identifying the RGD sequence (Arg–Gly–Asp) is observed. The aim of the present study was the synthesis and labeling of two novel RGD derivatives, via the precursor [99mTc(H2O)3(CO)3]+, as well as the radiochemical and radiopharmacological evaluation of the labeled products. The labeling led to the formation of a single product in each case (>98%), with noteworthy in vitro stability, fast blood clearance and elimination by the hepatobiliary and the urinary systems. [Copyright &y& Elsevier]

Background and Objectives : Automated methods for the analysis of myocardial perfusion studies have been incorporated into clinical practice, but they are currently used as adjuncts to the visual interpretation. We aimed to investigate the role of automated measurements of summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) as long-term prognostic markers of morbidity and mortality, in comparison to the prognostic value of expert reading. Materials and Methods : The study was conducted at the Nuclear Medicine Laboratory of the University of Thessaly, in Larissa, Greece. A total of 378 consecutive patients with known or suspected coronary artery disease were enrolled in the study. All participants were referred to our laboratory for the performance of stress/rest myocardial perfusion single photon emission computed tomography. Automated measurements of SSS, SRS, and SDS were obtained by Emory Cardiac Toolbox (ECTb (Version 3.0), Emory University, Atlanta, GA, USA), Myovation (MYO, Xeleris version 3.05, GE Healthcare, Chicago, IL, USA), and Quantitative Perfusion SPECT (QPS (Version 4.0), Cedars-Sinai Medical Center, Los Angeles, CA, USA) software packages. Follow-up data were recorded after phone contacts, as well as through review of hospital records. Results : Expert scoring of SSS and SDS had significantly greater prognostic ability in comparison to all software packages ( p < 0.001 for all comparisons). Similarly, ECTb-obtained SRS measurements had significantly lower prognostic ability in comparison to expert scoring ( p < 0.001), while expert scoring of SRS showed significantly higher prognostic ability compared to MYO ( p = 0.018) and QPS ( p < 0.001). Conclusions : Despite the useful contribution of automated analyses in the interpretation of myocardial perfusion studies, expert reading should continue to have a crucial role, not only in clinical decision making, but also in the assessment of prognosis.

Background and Objectives : Myocardial perfusion imaging (MPI) has an important role in the non-invasive investigation of coronary artery disease. The interpretation of MPI studies is mainly based on the visual evaluation of the reconstructed images, while automated quantitation methods may add useful data for each patient. However, little evidence is currently available regarding the actual incremental clinical diagnostic performance of automated MPI analysis. In the present study, we aimed to assess the correlation between automated measurements of Summed Stress Score (SSS), Summed Rest Score (SRS) and Summed Difference Score (SDS), with the corresponding expert reading values, using coronary angiography as the gold standard. Materials and Methods : The study was conducted at the Nuclear Medicine Laboratory of the University Hospital of Larissa, Larissa, Greece, οver an one-year period (January 2019-January 2020). 306 patients, with known or suspected coronary artery disease, were enrolled in the study. Each participant underwent a coronary angiography, prior to or after the scintigraphic study (within a three-month period). Either symptom-limited treadmill test, or pharmacologic testing using adenosine or regadenoson, was performed in all participants, and the scintigraphic studies were carried out using technetium 99m (99mTc) tetrofosmin (one-day stress/rest protocol). Coronary angiographies were scored according to a 4-point scoring system (angiographic score; O: normal study, 1: one-vessel disease, 2: two-vessel disease, 3: three-vessel disease). Moreover, automated measurements of SSS, SRS and SDS were derived by three widely available software packages (Emory Cardiac Toolbox, Myovation, Quantitative Perfusion SPECT). Results : Interclass Correlation Coefficients of SSS, SRS and SDS between expert reading and software packages were moderate to excellent. Visually defined SSS, SRS and SDS were significantly correlated with the corresponding results of all software packages. However, visually defined SSS, SRS and SDS were more strongly correlated with the angiographic score, indicating a better performance of expert reading when compared to automated analysis. Conclusions : Based on our results, visual evaluation continues to have a crucial role for the interpretation of MPI images. Software packages can provide automated measurements of several parameters, particularly contributing to the investigation of cases with ambiguous scintigraphic findings.

(1) Background: Considerable inconsistency exists regarding the neural substrates of anosognosia in dementia in previous neuroimaging studies. The purpose of this study was the evaluation of anosognosia perfusion correlates across various types of dementia using automated Brodmann areas (BAs) analysis and comparison with a database of normal subjects. (2) Methods: We studied 72 patients: 32 with Alzheimer's disease, 26 with frontotemporal dementia-FTD (12 behavioral FTD, 9 semantic FTD, 5 Progressive Non-Fluent Aphasia), 11 with corticobasal syndrome, and 3 with progressive supranuclear palsy. Addenbrook's Cognitive Examination-Revised (ACE-R) mean(±SD) was 55.6(±22.8). For anosognosia measurement, the Anosognosia Questionnaire-Dementia was used. Total anosognosia score mean(±SD) was 22.1(±17.9), cognitive anosognosia score mean(±SD) was 18.1(±15.1) and behavioral-mood anosognosia score mean(±SD) was 3.3(±4.7). (3) Results: Higher anosognosia total score was associated with hypoperfusion in the inferior temporal, anterior cingulate, and inferior frontal cortices of the right hemisphere (BAs 20R, 24R, 32R, 45R). Higher anosognosia cognitive score was correlated with hypoperfusion in the left middle and anterior temporal cortices, and right dorsal anterior cingulate cortex (BAs 21L, 22L, 32R). No association was found with behavioral-mood anosognosia. (4) Conclusions: Automated analysis of brain perfusion Single Photon Emission Computed Tomography could be useful for the investigation of anosognosia neural correlates in dementia.

Objectives: To explore differences of apathy perfusion correlates between Alzheimer's disease (AD) and Frontotemporal dementia (FTD) using perfusion SPECT., Methods: We studied 75 FTD and 66 AD patients. We evaluated apathy using Neuropsychiatric Inventory (NPI). We compared perfusion of BAs on left (L) and right (R) hemisphere in AD and FTD., Results: Apathy in AD was significantly and negatively correlated with dorsolateral prefrontal cortex bilaterally, right anterior prefrontal cortex, inferior frontal cortex bilaterally, especially on the right, orbital part of inferior frontal gyrus bilaterally, left dorsal anterior cingulate cortex, right primary and secondary visual cortex, and with bilateral anterior and dorsolateral prefrontal cortex, inferior frontal cortex and orbital part of inferior frontal gyrus, bilaterally, bilateral anterior -ventral and dorsal- cingulate cortex, left posterior ventral cingulate cortex, right inferior, middle and anterior temporal gyri, entorhinal and parahippocampal cortex in FTD., Conclusions: Significant overlapping of apathy perfusion correlates between AD and FTD is seen in frontal areas and anterior cingulate. Right occipital cortex is also involved in AD, while right temporal cortex and left posterior cingulate are involved in FTD. Nuclear imaging could be a useful biomarker for revealing apathy underlying mechanisms, resulting in directed treatments.KEYPOINTSUnderlying neural networks and clinical manifestation of apathy may differ between AD and FTD.Apathy in AD is correlated with hypoperfusion in bilateral frontal areas, more prominent on the right, left anterior cingulate and right occipital cortex.Apathy in FTD is correlated with hypoperfusion in bilateral frontal areas, bilateral anterior cingulate, left posterior cingulate and right temporal cortex.Brain perfusion SPECT with automated BAs analysis and comparison with normal healthy subjects may provide significant information for apathy mechanisms in neurodegenerative disorders, affecting patients' treatment.

Background: Eating disorders (ED) in dementia represent a significant impairment affecting patients' and caregivers' lives. In frontotemporal dementia (FTD), ED include overeating, sweet food preference, stereotypical eating, and hyperorality, while in Alzheimer's disease (AD), anorexia and appetite loss are the most common ED., Objective: The aim of our study was to highlight Brodmann areas (BAs) implicated specifically in the appearance of ED in FTD and AD., Methods: We studied 141 patients, 75 with FTD and 66 with AD. We used the NeuroGamTM software on the reconstructed single photon emission computed tomography-SPECT data for the automated comparison of BAs perfusion on the left (L) and right (R) hemisphere with perfusion in corresponding BAs of a normal database., Results: The FTD group included 27 men and 48 women, age (mean±SD) 65.8±8.5 years, duration of disease 3.4±3.3 years, Mini-Mental State Examination (MMSE) 17.9±8.6, ED score on Neuropsychiatric Inventory (NPI) 4.7±8.5. ED in FTD were correlated with hypoperfusion in right anterior and dorsolateral prefrontal cortices (BAs 10R, 46R), left orbitofrontal cortex (BA 12L), orbital part of the right inferior frontal gyrus (BA 47R), and left parahippocampal gyrus (BA 36L). The AD group included 21 men and 45 women, age (mean±SD) 70.2±8.0 years, duration of disease 3.3±2.4 years, MMSE 20.2±6, ED-NPI score 2.7±3.9. ED in AD were correlated with hypoperfusion in left inferior temporal cortex (BA 20L)., Conclusion: SPECT imaging with automated mapping of brain cortex could contribute to the understanding of the neural networks involved in the manifestation of ED in dementia.

Background: Neuropsychiatric symptoms (NPSs) are common in dementia. Their evaluation is based on Neuropsychiatric Inventory (NPI). Neuroimaging studies have tried to elucidate the underlying neural circuits either in isolated NPSs or in specific forms of dementia., Objective: The objective of this study is to evaluate the correlation of NPS in the NPI with Brodmann areas (BAs) perfusion, for revealing BAs involved in the pathogenesis of NPSs in dementia of various etiologies., Methods: We studied 201 patients (82 with Alzheimer's disease, 75 with Frontotemporal dementia, 27 with Corticobasal Syndrome, 17 with Parkinson Disease/Lewy Body Dementia). Exploratory factor analysis was carried out to evaluate underlying groups of BAs, and Principal Component analysis was chosen as extraction method using Varimax rotation. Partial correlation coefficients were computed to explore the association of factors obtained from analysis and NPI items controlling for age, educational yeas, and ACE-R., Results: We found 6 BAs Factors(F); F1 (BAs 8,9,10,11,24,32,44,45,46,47, bilaterally), F2 (BAs 4,5,6,7,23,31, bilaterally), F3 (BAs 19,21,22,37,39,40, bilaterally), F4 (BAs 20,28,36,38, bilaterally), F5 (BAs 25, bilaterally) and F6 (BAs 17,18, bilaterally). Significant and negative correlation was found between NPI1 (delusions) and F3,F6, NPI2 (hallucinations) and F6, NPI7 (apathy) and F1,F4,F5, NPI3 (agitation) - NPI10 (aberrant motor behavior) - NPI12 (eating disorders) and F1. We did not find any significant correlation for NPI4,5,6,8,9,11 (depression, anxiety, euphoria, disinhibition, irritability, sleep disorders, respectively)., Conclusion: Several NPSs share the same BAs among different types of dementia, while the manifestation of the rest may be attributed to different neural networks. These findings may have an impact on patients' treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A 50-year-old man with beta-thalassemia major underwent Tc-99m sestamibi parathyroid scintigraphy due to elevated parathyroid hormone and calcium serum levels. Single-photon emission computed tomography imaging of neck and thorax revealed a parathyroid adenoma, as well as increased tracer uptake in a paraspinal region in the right hemithorax, where X-ray and computed tomography of the thorax had shown previously a mass compatible with extramedullary hematopoietic tissue., Competing Interests: There are no conflicts of interest., (Copyright: © 2019 Indian Journal of Nuclear Medicine.)

Background: Renin-angiotensin-aldosterone system (RAAS) has an important role in atherosclerosis. We investigated the effects of six RAAS gene polymorphisms on myocardial perfusion., Methods and Results: We examined 810 patients with known or suspected coronary artery disease (CAD) using stress-rest myocardial single-photon emission computed tomography. Summed stress score (SSS), summed rest score (SRS), summed difference score (SDS), transient ischemic dilation (TID), and lung/heart ratio (LHR) were recorded. The following gene polymorphisms were investigated: angiotensin-converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen (AGT) M235T and T174M, angiotensin II type 1 receptor (AT1R) A1166C, renin (REN) C5312T, and angiotensin II type 2 receptor (AT2R) C3123A. The heterozygotes or homozygotes on ACE D allele were 7.54 times more likely to have abnormal SSS, while the AGT (T174M) heterozygotes were 5.19 times more likely to have abnormal SSS. The homozygotes of ACE D had significantly higher values on TID and LHR, while the AGT (T174M) heterozygotes had higher values on TID. The AT1R heterozygotes had greater odds for having SSS ≥ 3. The patients carried AT1R homozygosity of C allele had significantly higher values on TID, while heterozygotes of AT1R had significantly higher values on LHR., Conclusions: Among the polymorphisms investigated, ACE D allele had the strongest association with abnormal myocardial perfusion.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. Beta-amyloid (Aβ) deposition and neurofibrillary tangles (NFTs) of abnormal hyperphosphorylated tau protein are the pathological hallmarks of the disease, accompanied by other pathological processes such as microglia activation. Functional and molecular nuclear medicine imaging with single-photon emission computed tomography (SPECT) and positron emission tomography (PET) techniques provides valuable information about the underlying pathological processes, many years before the appearance of clinical symptoms. Nuclear neuroimaging in AD has made great progress in the past two decades and has extended beyond the traditional role of brain perfusion and glucose metabolism evaluation. Intense efforts in radiopharmaceuticals research have led to the development of various probes able to detect Aβ deposits, tau protein accumulation, microglia activation and neuroinflammation. As a result, SPECT and PET have proposed to serve as biomarkers in recently revised diagnostic clinical criteria for the early diagnosis of AD and the prediction of progression to AD in mild cognitive impairment (MCI) subjects.

Superparamagnetic iron oxide nanoparticles with well-integrated multimodality imaging properties have generated increasing research interest in the past decade, especially when it comes to the targeted imaging of tumors. Bevacizumab (BCZM) on the other hand is a well-known and widely applied monoclonal antibody recognizing VEGF-A, which is overexpressed in angiogenesis. The aim of this proof-of-concept study was to develop a dual-modality nanoplatform for in vivo targeted single photon computed emission tomography (SPECT) and magnetic resonance imaging (MRI) of tumor vascularization. Iron oxide nanoparticles (IONPs) have been coated with dimercaptosuccinic acid (DMSA), for consequent functionalization with the monoclonal antibody BCZM radiolabeled with 99m Tc, via well-developed surface engineering. The IONPs were characterized based on their size distribution, hydrodynamic diameter and magnetic properties. In vitro cytotoxicity studies showed that our nanoconstruct does not cause toxic effects in normal and cancer cells. Fe 3 O 4 -DMSA-SMCC-BCZM- 99m Tc were successfully prepared at high radiochemical purity (>92%) and their stability in human serum and in PBS were demonstrated. In vitro cell binding studies showed the ability of the Fe 3 O 4 -DMSA-SMCC-BCZM- 99m Tc to bind to the VEGF-165 isoform overexpressed on M-165 tumor cells. The ex vivo biodistribution studies in M165 tumor-bearing SCID mice showed high uptake in liver, spleen, kidney and lungs. The Fe 3 O 4 -DMSA-SMCC-BCZM- 99m Tc demonstrated quick tumor accumulation starting at 8.9 ± 1.88%ID/g at 2 h p.i., slightly increasing at 4 h p.i. (16.21 ± 2.56%ID/g) and then decreasing at 24 h p.i. (6.01 ± 1.69%ID/g). The tumor-to-blood ratio reached a maximum at 24 h p.i. (~7), which is also the case for the tumor-to-muscle ratio (~18). Initial pilot imaging studies on an experimental gamma-camera and a clinical MR camera prove our hypothesis and demonstrate the potential of Fe 3 O 4 -DMSA-SMCC-BCZM- 99m Tc for targeted dual-modality imaging. Our findings indicate that Fe 3 O 4 -DMSA-SMCC-BCZM- 99m Tc IONPs could serve as an important diagnostic tool for biomedical imaging as well as a promising candidate for future theranostic applications in cancer.

Background: The aim of the present study was to compare Emory Cardiac Toolbox, Myovation, and Quantitative Gated SPECT software regarding the automatic measurements of perfusion and functional left ventricular (LV) quantitative parameters, summed stress score (SSS), perfusion defect score, LV ejection fraction (LVEF), end-diastolic volume, and end-systolic volume (ESV)., Methods and Results: 99 mTc-tetrofosmin gated SPECT studies were performed in 634 consecutive patients based on the one-day stress/rest protocol. Participants were divided into subgroups according to heart size (ESV cut-off value: 25 mL), perfusion (SSS >/≤3), and other patient/protocol-related factors. LVEF was categorized as normal (≥50%), mildly moderately impaired (35-49%), and severely abnormal (<35%). The concordance between the packages was good to excellent, in overall population, ESV ≤25 mL, ESV >25 mL, and SSS >3 subgroups (intraclass correlation coefficients, ICCs 0.73-0.93). In SSS ≤3 subgroup, the correlation was excellent for LV functional parameters, but suboptimal for perfusion variables (ICCs 0.30-0.83). LVEF categorization revealed similar variability (discordance 18.1 and 11.1% for stress/rest LVEF values, respectively). Pair comparisons demonstrated considerable differences concerning all parameters for all patient subgroups. The statistical significance of our findings by ESV and SSS classifications was evaluated., Conclusions: Despite the significant concordance between software packages, considerable differences in mean values of myocardial perfusion and LV functional parameters were demonstrated.

Molecular imaging and therapy is a rapidly evolving field in research and clinical medicine. The use of the exciting and attractive properties of radioisotopes for imaging and therapy has made Nuclear Medicine very significant when it comes to molecular imaging/therapy. Monoclonal Antibodies (mAbs) on the other hand are very important targeting biomolecules with high affinity that can "carry" the radioisotope of choice. Herein we make a brief overview of the radiolabeled mAbs that target prostate specific membrane antigen (PSMA) and their use in the management of patients with prostate cancer (PCa).

Early diagnosis of Alzheimer's disease (AD) based on clinical criteria alone may be problematic, while current and future treatments should be administered earlier in order to be more effective. Thus, various disease biomarkers could be used for early detection of AD. We evaluated brain perfusion with 99mTc-HMPAO single photon emission computed tomography (SPECT) and Brodmann areas (BAs) mapping in mild AD using an automated software (NeuroGam) for the semi-quantitative evaluation of perfusion in BAs and the comparison with the software's normal database. We studied 34 consecutive patients with mild AD: 9 men, 25 women, mean age 70.9 ± 8.1 years, mean Mini-Mental State Examination 22.6 ± 2.5. BAs 25L, 25R, 38L, 38R, 28L, 28R, 36L, and 36R had the lower mean perfusion values, while BAs 31L, 31R, 19R, 18L, 18R, 17L, and 17R had the higher mean values. Compared with healthy subjects of the same age, perfusion values in BAs 25L, 25R, 28R, 28L, 36L, and 36R had the greatest deviations from the healthy sample, while the lowest deviations were found in BAs 32L, 32R, 19R, 24L, 17L, 17R, 18L, and 18R. A percentage of ≥94% of patients had perfusion values more than -2SDs below the mean of healthy subjects in BAs 38R, 38L, 36L, 36R, 23L, 23R, 22L, 44L, 28L, 28R, 25L, and 25R. The corresponding proportion was less than 38% for BAs 11L, 19R, 32L, 32R, 18L, 18R, 24L, and 17R. In conclusion, brain SPECT studies with automated perfusion mapping could be useful as an ancillary tool in daily practice, revealing perfusion impairments in early AD.

In this study, a novel way of distinguishing the intrinsic relationship between ανβ3 integrin targeting and detection of tumor growth by using a radiolabeled tracer based on a cyclic Arg-Gly-Asp (RGD) peptide was provided. The potential of the in vivo scintigraphic imaging of the developing vasculature from the early stage of tumor growth was evaluated. Alongside with the scintigraphic images, biodistribution studies were performed at distinct time points to validate this noninvasive imaging approach. The ability to noninvasively assess the tumor growth of ανβ3 integrin-positive glioblastoma tumors provides a method to better understand tumor angiogenesis in vivo and allows for a direct assessment of anti-integrin treatment efficacy.

Hypothesis: Dual-modality imaging agents, such as radiolabeled iron oxide nanoparticles (IO-NPs), are promising candidates for cancer diagnosis and therapy. We developed and evaluated aminosilane coated Fe3O4 (10±2nm) as a tumor imaging agent in nuclear medicine through 3-aminopropyltriethoxysilane (APTES) functionalization. We evaluated this multimeric system of targeted (99m)Tc-labeled nanoparticles (NPs) conjugated with a new RGD derivate (cRGDfK-Orn3-CGG), characterized as NPs-RGD as a potential thermal therapy delivery vehicle., Experiments: Transmission Electron Microscopy (TEM) and spectroscopy techniques were used to characterize the IO-NPs indicating their functionalization with peptides. Radiolabeled IO-NPs (targeted, non-targeted) were evaluated with regard to their radiochemical, radiobiological and imaging characteristics. In vivo studies were performed in normal and ανβ3-positive tumor (U87MG glioblastoma) bearing mice. We also demonstrated that this system could reach ablative temperatures in vivo., Findings: Both radiolabeled IO-NPs were obtained in high radiochemical yield (>98%) and proved stable in vitro. The in vivo studies for both IO-NPs have shown significant liver and spleen uptake at all examined time points in normal and U87MG glioblastoma tumor-bearing mice, due to their colloidal nature. We have confirmed through in vivo biodistribution studies that the non-targeted (99m)Tc-NPs poorly internalized in the tumor, while the targeted (99m)Tc-NPs-RGD, present 9-fold higher tumor accumulation at 1h p.i. Accumulation of both IO-NPs in other organs was negligible. Blocking experiments indicated target specificity for integrin receptors in U87MG glioblastoma cells. The preliminary in vivo study of applied alternating magnetic field showed that the induced hyperthermia is feasible due to the aid of IO-NPs., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aim: Targeted biocompatible nanoplatforms presenting multiple therapeutic functions have great potential for the treatment of cancer., Materials & Methods: Multifunctional nanocomposites formed by polymeric nanoparticles (PNPs) containing two cytotoxic agents - the drug alisertib and silver nanoparticles - were synthesized. These PNPs have been conjugated with a chlorotoxin, an active targeting 36-amino acid-long peptide that specifically binds to MMP-2, a receptor overexpressed by brain cancer cells., Results: The individual and synergistic activity of these two cytotoxic agents against glioblastoma multiforme was tested both in vitro and in vivo. The induced cytotoxicity in a human glioblastoma-astrocytoma epithelial-like cell line (U87MG) was studied in vitro through a trypan blue exclusion test after 48 and 72 h of exposure. Subsequently, the PNPs' biodistribution in healthy animals and their effect on tumor reduction in tumor-bearing mice were studied using PNPs radiolabeled with (99m)Tc., Conclusion: Tumor reduction was achieved in vivo when using silver/alisertib@PNPs-chlorotoxin.

Liposomes radiolabelling with diagnostic radionuclides is an excellent tool for studying pharmacokinetics with the view of developing liposome-based drug delivery agents. The aim of the present study is to evaluate the in vitro and in vivo behavior of a (99m)Tc-labeled liposome by applying either a direct labeling strategy via a carboxyl group, LP-COOH, or a surface chelating method via pyridyl ethyl cysteine compound (with the intermediate [⁹⁹mTc(I)(CO)₃(H₂O)(3)](+)), LP-PEC. ⁹⁹mTc-LP-COOH was obtained in high radiolabelling yield and radiochemical purity, while ⁹⁹mTc(I)(CO)₃-LP-PEC was initially purified before being in vitro and in vivo evaluated. ⁹⁹mTc-LP-COOH was less stable in the presence of competitive for ⁹⁹mTc ligands than ⁹⁹mTc(I)(CO)₃-LP-PEC. According to DLS measurements, the presence of serum as well as the applied radiolabelling conditions did not affect the liposomes' size. The different radiolabelling methods seemed to exert an influence on the biodistribution pattern of the liposomes with the ⁹⁹mTc(I)(CO)₃-LP-PEC showing slow blood clearance, which was also confirmed by in vivo scintigraphic imaging. Nevertheless, passive tumor targeting was attained at a similar extent no matter which radiolabelling technique was followed., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The application of combined diagnosis and therapy through nanotechnology applications is attracting increasing attention worldwide. Polymeric self-assembled nanoparticles (NPs) have been studied for this purpose. Micelles and vesicles with or without a magnetic core can efficiently carry diagnostic and/or therapeutic agents to a desired target. The biological behavior of these NPs has been evaluated in this study, after radiolabeling with (99m)Tc. In vitro stability, in media that mimic the environment of the living body, was better for vesicles than for micelles at 1 h and decreased for both as time passed. After administration to healthy animals, all NPs presented major uptake at liver and spleen as expected. Biodistribution and imaging studies confirmed the higher uptake in these organs for the hybrid NPs and at higher extent for the ones with larger size, indicating that the magnetic load and size play an important role on in vivo distribution.

Despite the known validity of clinical diagnostic criteria, significant overlap of clinical symptoms between Frontotemporal dementia (FTD) subtypes exists in several cases, resulting in great uncertainty of the diagnostic boundaries. We evaluated the perfusion between FTD subtypes using brain perfusion (99m)Tc-HMPAO SPECT with Brodmann areas (BA) mapping. NeuroGam software was applied on single photon emission computed tomographic (SPECT) studies for the semi-quantitative evaluation of perfusion in BA and the comparison with the software's normal database. We studied 91 consecutive FTD patients: 21 with behavioural variants (bvFTD), 39 with language variants (lvFTD) [12 with progressive non-fluent aphasia (PNFA), 27 with semantic dementia (SD)], and 31 patients with progressive supranuclear palsy (PSP)/corticobasal degeneration (CBD). Stepwise logistic regression analyses showed that the BA 28L and 32R could independently differentiate bvFTD from lvFTD, while the BA 8R and 25R could discriminate bvFTD from SD and PNFA, respectively. Additionally, BA 7R and 32R were found to discriminate bvFTD from CBD/PSP. The only BA that could differentiate SD from PNFA was 6L. BA 6R and 20L were found to independently differentiate CBD/PSP from lvFTD. Moreover, BA 20L and 22R could discriminate CBD/PSP from PNFA, while BA 6R, 20L and 45R were found to independently discriminate CBD/PSP from SD. Brain perfusion SPECT with BA mapping can be a useful additional tool in differentiating FTD variants by improving the definition of brain areas that are specifically implicated, resulting in a more accurate differential diagnosis in atypical or uncertain forms of FTD.

Bombesin is a neuropeptide widely studied due to its ability to target various types of cancers. Technetium-99m on the other hand is ideal for diagnostic tumor targeting. The aim of the present study is the investigation of the coupling of the ligand (S)-(2-(2'-pyridyl)ethyl)-d,l-cysteine with the BN-peptide Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met(CONH2) through the spacer aminohexanoic acidand the labeling of the resulting derivative MBN with the synthon [M(CO)3(H2O)3](+) (M=(99m)Tc, Re). The peptide was synthesized according to the SPPS method, purified and characterized by ESI-MS. The new (99m)Tc-labeled biomolecule was stable in vitro, showed high affinity for the human GRP receptor expressed in PC3 cells and the rate of internalization was found to be time-dependent tissue distribution of the radiopeptide was evaluated in normal mice and in prostate cancer experimental models and significant radioactivity uptake was observed in the pancreas of normal mice as well as in PC3 tumors. Dynamic studies of the radiopeptide showed satisfactory tumor images., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Adiponectin, the most abundant adipose-released cytokine, has an important role in metabolism, primarily through reducing insulin resistance. Reproductive functions are known to be influenced by energy balance and adiponectin may be involved in the underlying mechanisms connecting reproduction and metabolism. Interestingly, adiponectin has been shown to exert actions in the female reproductive system, including the hypothalamic-pituitary-ovarian axis and the endometrium. The peripheral effects of this adipocytokine are mediated mainly via 2 receptors, AdipoR1 and AdipoR2. The expression of these receptors has been reported in the brain, ovaries, endometrium, and the placenta. Thus, adiponectin may influence fertility and pregnancy. Furthermore, adiponectin concentrations and effects have been assessed in some pregnancy-associated disorders and gynecological conditions. The findings may lead to the use of adiponectin or its receptors as therapeutic targets in novel treatment strategies of these disorders.

Nanomedicine applications have recently gathered great attention in terms of their revolutionary properties and multivalency. Nanoparticles (NPs) have proven useful owing to their size, surface and kinetics advantages, as well as their ability to be functionalized with targeting, imaging and therapeutic moieties. Nuclear medicine is actively involved in nano-research innovative breakthrough efforts in multiple applications, through the radiolabeling of NP structures. There are several ways that NP-radiolabeling can be approached depending on the radionuclide that is used and the NP type. The radiolabeling of NPs with the most widely and easily available radiometal, which is (99m) Tc, is the focus of this review., (Copyright © 2013 John Wiley & Sons, Ltd.)

Introduction: Radiolabeled RGD peptides that specifically target integrin α(ν)β(3) have great potential in early tumor detection through noninvasive monitoring of tumor angiogenesis. Based on previous findings of our group on radiopeptides containing positively charged aminoacids, we developed a new cyclic cRGDfK derivative, c(RGDfK)-(Orn)(3)-CGG. This new peptide availing the polar linker (Orn)(3) and the (99m)Tc-chelating moiety CGG (Cys-Gly-Gly) is appropriately designed for (99m)Tc-labeling, as well as consequent conjugation onto nanoparticles., Methods: A tumor imaging agent, c(RGDfK)-(Orn)(3)-[CGG-(99m)Tc], is evaluated with regard to its radiochemical, radiobiological and imaging characteristics., Results: The complex c(RGDfK)-(Orn)(3)-[CGG-(99m)Tc] was obtained in high radiochemical yield (>98%) and was stable in vitro and ex vivo. It presented identical to the respective, fully analytically characterized (185/187)Re complex retention time in RP-HPLC. In contrary to other RGD derivatives, we showed that the new radiopeptide exhibits kidney uptake and urine excretion due to the ornithine linker. High tumor uptake (3.87±0.48% ID/g at 60 min p.i.) was observed and was maintained relatively high even at 24 h p.i. (1.83±0.05 % ID/g), thus providing well-defined scintigraphic imaging. Accumulation in other organs was negligible. Blocking experiments indicated target specificity for integrin receptors in U87MG glioblastoma cells., Conclusion: Due to its relatively high tumor uptake, renal elimination and negligible abdominal localization, the new (99m)Tc-RGD peptide is considered promising in the field of imaging α(ν)β(3)-positive tumors. However, the preparation of multifunctional SPECT/MRI contrast agents (RGD-conjugated nanoparticles) for dual modality imaging of integrin expressing tumors should be further investigated., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Magnetic nanoparticles have become important tools for imaging a wide range of diseases, improving drug delivery and applying hyperthermic treatment. Iron oxide based nanoparticles have been widely examined, unlike cobalt ferrite based ones. Herein, monodisperse and stable CoFe2O4 nanoparticles have been produced, coated and further stabilized using ethyl 12-(hydroxyamino)-12-oxododecanoate, poly(lactic-co-glycolic acid) and bovine serum albumin. The final product, NBRh1, was fully characterized and has been directly radiolabeled with 99mTc using SnCl1 as the reducing agent in high yields. In vitro stability and hyperthermic properties of 99mTC-NBRh1 were encouraging for further application in low frequencies hyperthermia and biomagnetic applications. In vivo evaluation followed after injection in healthy mice. The planar and SPECT imaging data as well as the biodistribution results were in accordance, showing high liver and spleen uptake as expected starting almost immediately after administration. In conclusion the preliminary results for nanoparticles bearing a cobalt ferrite core justify further investigations towards potential hyperthermic applications, drug transportation and liver or spleen imaging.

Nanomedicine is the medical application of materials, devices, or systems in the nanometer scale and is currently undergoing explosive development. Molecular imaging of cancer using nanosized materials comprises an important part in diagnosis, therapy, and drug discovery in medical nanosciences. Radiopharmaceuticals are a key tool of molecular imaging in the field of nuclear medicine. The in vivo administration of radiolabeled nanoparticles (NPs) can provide an accurate biodistribution profile of the nanoformulations, as well as visualization of their route in vivo. Surface modifications of NPs with antibodies, peptides, or other small molecules that bind to tumor cell receptors have resulted in the development of sensitive and specific targeted imaging and diagnostic modalities for in vitro and in vivo applications. Radiometals are the most favorable of all radionuclides for labeling applications and they have the most suitable properties for single-photon emission computed tomography imaging. Indium-111((111)In), specifically, is a readily available gamma-emitting radiometal, which is widely used in clinical practice for diagnosis and/or therapy. Herein, we will overview the latest evolvement on (111)In-labeled nanoparticles for biodistribution assessment and/or imaging evaluation of nanocarriers, as well as therapy in cancer., (Copyright © 2012 Wiley Periodicals, Inc.)

During the past decade radiolabeled RGD-peptides have been extensively studied to develop site-directed targeting vectors for integrins. Integrins are heterodimeric cell-surface adhesion receptors, which are upregulated in cancer cells and neovasculature during tumor angiogenesis and recognize the RGD aminoacid sequence. In the present study, we report the synthesis and development of two derivatives of the Nε-Lys derivatized cyclic Arg-Gly-Asp-D-Phe-Lys peptide, namely of cRGDfKHis and cRGDfK-CPA (CPA: 3-L-Cysteine Propionic Acid), radiolabeled via the [(99m)Tc(H(2)O)(3)(CO)(3)](+) metal aquaion at a high yield even at low concentrations of 10-5M (>87%) for cRGDfK-10-5M (>93%) for cRGDfK-CPA. Radiolabeled peptides were characterized with regard to their stability in saline, in His/Cys solutions, as well as in plasma, serum and tissue homogenates and were found to be practically stable. Internalization and efflux assays using αvβ3-receptor-positive MDA-MB 435 breast cancer cells showed a good percentage of quick internalization (29.1 ± 9.8% for (99m)Tc-HiscRGDfK and 37.0 ± 0.7% for (99m)Tc-CPA-cRGDfK at 15 min) and no retention of radioactivity for both derivatives. Their in vivo behavior was assessed in normal mice and pathological SCID mice bearing MDA-MB 435 ανβ3 positive breast tumors. Both presented fast blood clearance and elimination via both the urinary and hepatobiliary systems, with (99m)Tc-His-cRGDfK remaining for a longer time than (99m)Tc-CPA-cRGDfK in all organs examined. Tumor uptake 30 min pi was higher for (99m)Tc-CPAcRGDfK (4.2 ± 1.5% ID/g) than for (99m)Tc-His-cRGDfK (2.8 ± 1.5% ID/g). Dynamic scintigraphic studies showed that the tumor could be visualized better between 15 and 45 min pi for both radiolabeled compounds but low delineation occurred due to high abdominal background. It was finally noticed that the accumulated activity on the tumor site was depended on the size of the experimental tumor; the smaller the size, the higher was the radioactivity concentration., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Meningiomas arise from the meningothelial cells of the arachnoid membranes. They are the most common primary intracranial neoplasms and represent about 20% of all intracranial tumors. They are usually diagnosed after the third decade of life and they are more frequent in women than in men. According to the World Health Organization (WHO) criteria, meningiomas can be classified into grade I meningiomas, which are benign, grade II (atypical) and grade III (anaplastic) meningiomas, which have a much more aggressive clinical behaviour. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are routinely used in the diagnostic workup of patients with meningiomas. Molecular Nuclear Medicine Imaging with Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) could provide complementary information to CT and MRI. Various SPECT and PET tracers may provide information about cellular processes and biological characteristics of meningiomas. Therefore, SPECT and PET imaging could be used for the preoperative noninvasive diagnosis and differential diagnosis of meningiomas, prediction of tumor grade and tumor recurrence, response to treatment, target volume delineation for radiation therapy planning, and distinction between residual or recurrent tumour from scar tissue.

Dual-modality contrast agents, such as radiolabeled nanoparticles, are promising candidates for a number of diagnostic applications, since they combine the advantages of two different imaging modalities, namely SPECT or PET imaging with MR imaging. The benefit of such a combination is to more accurately interpret disease and abnormalities in vivo, by exploiting the advantages of each imaging technique, i.e. high sensitivity for SPECT/PET, high resolution anatomical information for MRI. In this review article, we provide an overview of recent findings in the synthesis, evaluation and application of radiolabeled iron oxide nanoparticles as dual-modality SPECT/MRI and PET/MRI imaging probes.

Small animal molecular imaging is a rapidly expanding efficient tool to study biological processes non-invasively. The use of radiolabeled tracers provides non-destructive, imaging information, allowing time related phenomena to be repeatedly studied in a single animal. In the last decade there has been an enormous progress in related technologies and a number of dedicated imaging systems overcome the limitations that the size of small animal possesses. On the other hand, nanoparticles (NPs) gain increased interest, due to their unique properties, which make them perfect candidates for biological applications. Over the past 5 years the two fields seem to cross more and more often; radiolabeled NPs have been assessed in numerous pre-clinical studies that range from oncology, till HIV treatment. In this article the current status in the tools, applications and trends of radiolabeled NPs reviewed., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)