In Vitro and In Vivo Evaluation of 99mTc-Polymyxin B for Specific Targeting of Gram-Bacteria.

BACKGROUND: Infectious diseases are one of the main causes of morbidity and mortality worldwide. Nuclear molecular imaging would be of great help to non-invasively discriminate between septic and sterile inflammation through available radiopharmaceuticals, as none is currently available for clinical practice. Here, we describe the radiolabeling procedure and in vitro and in vivo studies of 99mTc-polymyxin B sulfate (PMB) as a new single photon emission imaging agent for the characterization of infections due to Gram-negative bacteria. RESULTS: Labeling efficiency was 97 ± 2% with an average molar activity of 29.5 ± 0.6 MBq/nmol. The product was highly stable in saline and serum up to 6 h. In vitro binding assay showed significant displaceable binding to Gram-negative bacteria but not to Gram-positive controls. In mice, 99mTc-HYNIC-PMB was mainly taken up by liver and kidneys. Targeting studies confirmed the specificity of 99mTc-HYNIC-PMB obtained in vitro, showing significantly higher T/B ratios for Gram-negative bacteria than Gram-positive controls. CONCLUSIONS: In vitro and in vivo results suggest that 99mTc-HYNIC-PMB has a potential for in vivo identification of Gram-negative bacteria in patients with infections of unknown etiology. However, further investigations are needed to deeply understand the mechanism of action and behavior of 99mTc-HYNIC-PMB in other animal models and in humans.

Radiopharmaceuticals for Breast Cancer and Neuroendocrine Tumors: Two Examples of How Tissue Characterization May Influence the Choice of Therapy.

Molecular medicine has gained clinical relevance for the detection and staging of oncological diseases, to guide therapy decision making and for therapy follow-up due to the availability of new highly sensitive hybrid imaging camera systems and the development of new tailored radiopharmaceuticals that target specific molecules. The knowledge of the expression of different receptors on the primary tumor and on metastases is important for both therapeutic and prognostic purposes and several approaches are available aiming to achieve personalized medicine in different oncological diseases. In this review, we describe the use of specific radiopharmaceuticals to image and predict therapy response in breast cancer and neuroendocrine tumors since they represent a paradigmatic example of the importance of tumoral characterization of hormonal receptors in order to plan a tailored treatment. The most attractive radiopharmaceuticals for breast cancer are 16α-[18F]-fluoro-17ß-estradiol for PET assessment of the estrogen expression, radiolabeled monoclonal antibody trastuzumab to image the human epidermal growth factor receptor 2, but also the imaging of androgen receptors with [18F]-fluorodihydrotestosterone.

State of the Art of Natural Killer Cell Imaging: A Systematic Review.

Natural killer (NK) cell therapy is a promising alternative to conventional T cell-based treatments, although there is a lack of diagnostic tools to predict and evaluate therapeutic outcomes. Molecular imaging can offer several approaches to non-invasively address this issue. In this study, we systematically reviewed the literature to evaluate the state of the art of NK cell imaging and its translational potential. PubMed and Scopus databases were searched for published articles on the imaging of NK cells in humans and preclinical models. Study quality was evaluated following Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) criteria. We pooled studies as follows: Optical, magnetic resonance imaging (MRI) and nuclear medicine imaging with a total of 21 studies (n = 5, n = 8 and n = 8, respectively). Considering the limitation of comparing different imaging modalities, it appears that optical imaging (OI) of NK cells is very useful in a preclinical setting, but has the least translational potential. MRI provides high quality images without ionizing radiations with lower sensitivity. Nuclear medicine is the only imaging technique that has been applied in humans (four papers), but results were not outstanding due to a limited number of enrolled patients. At present, no technique emerged as superior over the others and more standardization is required in conducting human and animal studies.

Immuno-Imaging to Predict Treatment Response in Infection, Inflammation and Oncology.

BACKGROUND: Molecular nuclear medicine plays a pivotal role for diagnosis in a preclinical phase, in genetically susceptible patients, for radio-guided surgery, for disease relapse evaluation, and for therapy decision-making and follow-up. This is possible thanks to the development of new radiopharmaceuticals to target specific biomarkers of infection, inflammation and tumour immunology. METHODS: In this review, we describe the use of specific radiopharmaceuticals for infectious and inflammatory diseases with the aim of fast and accurate diagnosis and treatment follow-up. Furthermore, we focus on specific oncological indications with an emphasis on tumour immunology and visualizing the tumour environment. RESULTS: Molecular nuclear medicine imaging techniques get a foothold in the diagnosis of a variety of infectious and inflammatory diseases, such as bacterial and fungal infections, rheumatoid arthritis, and large vessel vasculitis, but also for treatment response in cancer immunotherapy. CONCLUSION: Several specific radiopharmaceuticals can be used to improve diagnosis and staging, but also for therapy decision-making and follow-up in infectious, inflammatory and oncological diseases where immune cells are involved. The identification of these cell subpopulations by nuclear medicine techniques would provide personalized medicine for these patients, avoiding side effects and improving therapeutic approaches.

PET Radiopharmaceuticals for Specific Bacteria Imaging: A Systematic Review.

BACKGROUND: Bacterial infections are still one of the main factors associated with mortality worldwide. Many radiopharmaceuticals were developed for bacterial imaging, both with single photon emission computed tomography (SPECT) and positron emission tomography (PET) isotopes. This review focuses on PET radiopharmaceuticals, performing a systematic literature review of published studies between 2005 and 2018. METHODS: A systematic review of published studies between 2005 and 2018 was performed. A team of reviewers independently screened for eligible studies. Because of differences between studies, we pooled the data where possible, otherwise, we described separately. Quality of evidence was assessed by Quality Assessment of Diagnostic Accuracy Studies (QUADAS) approach. RESULTS: Eligible papers included 35 published studies. Because of the heterogeneity of animal models and bacterial strains, we classified studies in relation to the type of bacterium: Gram-positive, Gram-negative, Gram-positive and negative, others. CONCLUSIONS: Results highlighted the availability of many promising PET radiopharmaceuticals for bacterial imaging, despite some bias related to animal selection and index test, but few have been translated to human subjects. Results showed a lack of standardized infection models and experimental settings.

Comparison of 99mTc-UBI 29-41, 99mTc-ciprofloxacin, 99mTc-ciprofloxacin dithiocarbamate and 111In-biotin for targeting experimental Staphylococcus aureus and Escherichia coli foreign-body infections: an ex-vivo study.

BACKGROUND: Diagnosis of implant-associated infection is challenging. Several radiopharmaceuticals have been described but direct comparisons are limited. Here we compared in vitro and in an animal model 99mTc-UBI, 99mTc-ciprofloxacin, 99mTcN-CiproCS2 and 111In-DTPA-biotin for targeting E. coli (ATCC 25922) and S. aureus (ATCC 43335). METHODS: Stability controls were performed with the labelled radiopharmaceuticals during 6 hours in saline and serum. The in vitro binding to viable or killed bacteria was evaluated at 37 °C and 4 °C. For in vivo studies, Teflon cages were subcutaneously implanted in mice, followed by percutaneous infection. Biodistribution of i.v. injected radiolabelled radiopharmaceuticals were evaluated during 24 h in cages and dissected tissues. RESULTS: Labelling efficiency of all radiopharmaceuticals ranged between 94% and 98%, with high stability both in saline and in human serum. In vitro binding assays displayed a rapid but poor bacterial binding for all tested agents. Similar binding kinetic occurred also with heat-killed and ethanol-killed bacteria. In the tissue cage model, infection was detected at different time points: 99mTc-UBI and 99mTcN-CiproCS2 showed higher infected cage/sterile cage ratio at 24 hours for both E. coli and S. aureus; 99mTc-Ciprofloxacin at 24 hours for both E. coli and at 4 hours for S. aureus; 111In-DTPA-biotin accumulates faster in both E. coli and S. aureus infected cages. CONCLUSIONS: 99mTc-UBI, 99mTcN-CiproCS2 showed poor in vitro binding but good in vivo binding to E. coli only. 111In-DTPA-biotin showed poor in vitro binding but good in vivo binding to S. aureus and poor to E. coli. 99mTc-Ciprofloxacin showed poor in vitro binding but good in vivo binding to all tested bacteria. The mechanism of accumulation in infected sites remains to be elucidated.

Current Status of Molecular Imaging in Inflammatory and Autoimmune Disorders.

In the field of inflammation imaging, nuclear medicine techniques can be considered as a non-invasive tool to early detect pathophysiological changes in affected tissues. These changes usually occur before clinical onset of symptoms and before the development of anatomical changes, that are commonly detected by radiological procedures. This is particularly important for prognostic purposes, therapy decision making and for therapy follow-up. Here we review the current state-of-the art of nuclear medicine for diagnostic purposes in different conditions characterized by a chronic inflammation, such as vulnerable atherosclerotic plaques, vasculitis, rheumatoid arthritis, Sjogren syndrome, autoimmune thyroid diseases, inflammatory bowel diseases, Coeliac disease, Type 1 diabetes mellitus and other immunological diseases. Overall, we describe several different approaches based on radiolabeled cells, peptides and antibodies or FDG. It emerges the role of PET and of hybrid cameras in particular (SPECT/CT and PET/CT) for diagnosis of these disorders and for therapy decision making and followup.

Animal models for the study of inflammatory bowel diseases: a meta-analysis on modalities for imaging inflammatory lesions.

Inflammatory bowel diseases are lifelong disorders affecting the gastrointestinal tract characterized by intermittent disease flares and periods of remission with a progressive and destructive nature. Unfortunately, the exact etiology is still not completely known, therefore a causal therapy to cure the disease is not yet available. Current treatment options mainly encompass the use of non-specific anti-inflammatory agents and immunosuppressive drugs that cause significant side effects that often have a negative impact on patients' quality of life. As the majority of patients need a long-term follow-up it would be ideal to rely on a non-invasive technique with good compliance. Currently, the gold standard diagnostic tools for managing IBD are represented by invasive procedures such as colonoscopy and histopathology. Nevertheless, recent advances in imaging technology continue to improve the ability of imaging techniques to non-invasively monitor disease activity and treatment response in preclinical models of IBD. Novel and emerging imaging techniques not only allow direct visualization of intestinal inflammation, but also enable molecular imaging and targeting of specific alterations of the inflamed murine mucosa. Furthermore, molecular imaging advances allow us to increase our knowledge on the critical biological pathways involved in disease progression by characterizing in vivo processes at a cellular and molecular level and enabling significant improvements in the understanding of the etiology of IBD. This review presents a critical and updated overview on the imaging advances in animal models of IBD. Our aim is to highlight the potential beneficial impact and the range of applications that imaging techniques could offer for the improvement of the clinical monitoring and management of IBD patients: diagnosis, staging, determination of therapeutic targets, monitoring therapy and evaluation of the prognosis, personalized therapeutic approaches.

Hybrid imaging in Crohn's disease: from SPECT/CT to PET/MR and new image interpretation criteria.

Crohn's disease is a chronic relapsing disease characterized by mucosal inflammation, lymphocytes infiltration and fibrotic strictures. Usually, the assessment of location, extension, inflammatory activity and severity of intestinal lesions is complex and invasive with endoscopic methods or histological and biochemical investigations. Thus, the diagnosis remains a challenge for the management of patients. Nuclear medicine techniques, in particular hybrid and molecular imaging, might offer a valid option for the evaluation and determination of the prognosis of the disease. Indeed, imaging methods provide a non-invasive, reproducible and quantitative analysis. An overview of the currently available multimodality imaging techniques in Crohn's disease are reviewed, with particular regard to positron-emission tomography/magnetic resonance and the choice of the best evaluation Score, explaining advantages and disadvantages of each one, with particular regard to their potential role for the assessment of disease activity and extent of inflammation in order to improve the diagnosis. We propose new interpretation criteria for PET/MR images.

Molecular imaging of cancer microenvironment / Imagen molecular del microentorno del cáncer

In the last decades, researchers have been focusing on cancer cells looking for novel targets, however, tumours grow in a host environment that either contribute to or inhibit tumour expansion and metastatization. Several efforts have been focused on cancer microenvironment for diagnostic and therapeutic purposes. Nuclear medicine can contribute to understand the complexity and role of tumour microenvironment by imaging several of its components (chemokine receptors, immune cells, stromal antigens, vascular factors, etc). In a tumour, each microenvironment component offers many potential targets for several drugs or radiopharmaceuticals. Cancer may be studied using different strategies from different viewpoints: imaging tumour markers or differentiating markers for diagnostic purposes in order to plan personalized therapies (receptor agonists or superagonists); imaging tumour stroma and vascularization to monitor cell adhesion, metastases, angiogenesis and hypoxia; imaging the host response of cancer cells to monitor efficacy of immunotherapeutic strategies

En las últimas décadas los investigadores han centrado su atención en la observación de las células cancerosas, en búsqueda de nuevos sitios blanco. Sin embargo, el crecimiento del tumor se produce en un entorno que, o inhibe, o contribuye a la expansión del tumor y su metástasis. Varios esfuerzos han estado enfocados al estudio del microentorno del cáncer, con propósitos diagnósticos o terapéuticos. La Medicina Nuclear puede contribuir a la comprensión de la complejidad y del papel que juega el microentorno del tumor, mediante la obtención de las imágenes de varios de sus componentes (receptores de quimioquinas, células inmunes, antígenos del estroma, factores vasculares, etc.). En un tumor, cada componente del microentorno ofrece muchos blancos potenciales para varias drogas o radiofármacos. El cáncer puede ser estudiado mediante diferentes estrategias y enfoques: mediante la imagen de marcadores tumorales, o la diferenciación de estos, con propósitos diagnósticos a fin de planificar terapias personalizadas (receptores agonistas o superagonistas); mediante la imagen del estroma del tumor y la vascularización, para monitorear la adhesión celular, la metástasis, la angiogénesis y la hipoxia; mediante la imagen de la respuesta del huésped de las células cancerosas, con el objetivo de monitorear la eficacia de las estrategias inmunoterapéuticas