Targeted radionuclide therapy : targeted radionuclide therapy has the potential to selectively deliver radiation to diseased cells with minimal toxicity to surrounding tissues

The goal of targeted radionuclide therapy is to selectively deliver radiation to cancer cells and/or diseased tissue with minimal toxicity to surrounding normal tissues. The basis for successful radionuclide therapy is a theranostic approach that integrates diagnostic testing for the presence of a molecular target for which a specific treatment/drug is intended (Fig. 1). Theranostics is a revolutionary approach that promises improved therapy selection on the basis of specific molecular features of disease, greater predictive power for adverse effects due to improved patient-specific absorbed dose estimates, and new ways to objectively monitor therapy response. Currently, radionuclide therapy remains an important treatment option because ionising radiation from radionuclides can kill cells and inhibit growth in the benign and cancerous lesions that result from proliferative diseases. Radiation kills cells by damaging the DNA in the cell nucleus, thereby inhibiting cellular reproduction. Rapidly developing studies also demonstrate the beneficial effect of combining radionuclide therapy with chemotherapy.http://www.cmej.org.za/index.php/cmejam201

Dual time-point FDG PET/CT for differentiating benign from malignant solitary pulmonary nodules in a TB endemic area

Objective. Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is an accurate non-invasive imaging test for differentiating benign from malignant solitary pulmonary nodules (SPNs). We aimed to assess its diagnostic accuracy for differentiating benign from malignant SPNs in a tuberculosis (TB)-endemic area. Methods. Thirty patients, 22 men and 8 women, mean age 60 years, underwent dual time point FDG-PET/computed tomography (CT) imaging, followed by histological examination of the SPN. Maximum standard uptake values (SUVmax) with the greatest uptake in the lesion were calculated for two time points (SUV1 and SUV2), and the percentage change over time per lesion was calculated (%DSUV). Routine histological findings served as the gold standard. Results. Histological examination showed that 14 lesions were malignant and 16 benign, 12 of which were TB. SUVmax for benign and malignant lesions were 11.02 (standard deviation (SD) 6.6) v. 10.86 (SD 8.9); however, when tuberculomas were excluded from the analysis, a significant difference in mean SUV1max values between benign and malignant lesions was observed (p=0.0059). Using an SUVmax cut-off value of 2.5, a sensitivity of 85.7% and a specificity of 25% was obtained. Omitting the TB patients from analysis resulted in a sensitivity of 85.7% and a specificity of 100%. Mean %DSUV of benign lesions did not differ significantly from mean %DSUV of malignant lesions (17.1% (SD 16.3%) v. 19.4% (SD 23.7%)). Using a cut-off of %DSUV >10% as indicative of malignancy, a sensitivity of 85.7% and a specificity of 50% was obtained. Omitting the TB patients from the analysis yielded a sensitivity of 85.7% and a specificity of 75%. Conclusion. Our findings suggest that FDG-PET cannot distinguish malignancy from tuberculoma and therefore cannot reliably be used to reduce futile biopsy/thoracotomy

Advances in PSMA alpha theragnostics

Alpha theranostics offer an attractive alternative form of therapy, which has best been investigated and documented with 225Ac-PSMA in patients with prostate cancer. Advantages offered by targeted alpha therapy include overcoming radiation resistance, oxygen independence, effecting double-stranded DNA breakages within the tumors with anticipated improved clinical outcomes and an acceptable side effect profile. The previous Seminars article on this topic, published in 2020, had to rely mostly on published case reports and small observational studies. In the last few years, however, several meta-analyses have emerged that evaluate the safety and efficacy of 225Ac-PSMA in prostate cancer patients, followed most recently by a multi-center retrospective study initiated by WARMTH. The findings of these publications, together with the exploration of TAT offered in clinical conditions other than as a last resort, is the focus of this updated overview. Unresolved clinical issues that remain, include the appropriate selection of patients that would benefit most from treatment with 225Ac-PSMA, treatment timing within the disease landscape, optimal dosing schedule, dosimetry, when and how to best use combination therapies and minimization and treatment of side effects, particularly that of xerostomia.https://www.seminarsinnuclearmedicine.comhj2024Nuclear MedicineSDG-03:Good heatlh and well-bein

Blood-brain barrier transport kinetics of NOTA-modified proteins : the somatropin case

BACKGROUND: Chemical modifications such as PEG, polyamine and radiolabeling on proteins can alter their pharmacokinetic behaviour and their blood-brain barrier (BBB) transport characteristics. NOTA, i.e. 1,4,7-triazacyclononane-1,4,7-triacetic acid, is a bifunctional chelating agent that has attracted the interest of the scientific community for its high complexation constant with metals like gallium. Until now, the comparative BBB transport characteristics of NOTA-modified proteins versus unmodified proteins are not yet described. METHODS: Somatropin (i.e. recombinant human growth hormone), NOTA-conjugated somatropin and gallium-labelled NOTA-conjugated somatropin were investigated for their brain penetration characteristics (multiple time regression and capillary depletion) in an in vivo mice model to determine the blood-brain transfer properties. RESULTS: The three compounds showed comparable initial brain influx, with Kin = 0.38 ± 0.14 µL/(g×min), 0.36 ± 0.16 µL/(g×min) and 0.28 ± 0.18 µL/(g×min), respectively. Capillary depletion indicated that more than 80% of the influxed compounds reached the brain parenchyma. All three compounds were in vivo stable in serum and brain during the time frame of the experiments. CONCLUSIONS: Our results show that modification of NOTA as well as gallium chelation onto proteins, in casu somatropin, does not lead to a significantly changed pharmacokinetic profile at the blood-brain barrier

Theranostics in breast cancer

INTRODUCTION : Breast cancer is a complex disease and constitutes the leading cause of cancer in women globally. Conventional treatment modalities include surgery, chemotherapy, radiation therapy, and hormonal therapy; all of these have their limitations and often result in significant side effects or toxicity. Targeted radionuclide therapy based on a theranostic approach has been successfully applied in several malignancies, such as prostate cancer, thyroid cancer, and neuro-endocrine tumours. Several studies have also highlighted the potential of theranostic applications in breast cancer. AIM : This review aims to provide an overview of the most promising current and future theranostic approaches in breast cancer. DISCUSSION : The discussion includes pre-clinical as well as clinical data on some of the most successful targets used to date. Examples of potential theranostic approaches include those targeting the Human epidermal growth factor receptor 2 (HER2) expression, angiogenesis, aspects of the tumour microenvironment, Gastrin-releasing peptide receptor (GRPR), Prostate-specific membrane antigen (PSMA) and Chemokine receptor 4 (CXCR-4) expression. Several challenges to widespread clinical implementation remain, which include regulatory approval, access to the various radiopharmaceuticals and imaging technology, cost-effectiveness, and the absence of robust clinical data. CONCLUSION : Theranostic approaches have the potential to greatly improve diagnosis, treatment, and outcomes for patients with breast cancer. More research is needed to fully explore the potential of such approaches and to identify the best potential targets, considering feasibility, costs, efficacy, side effects and outcomes.https://www.frontiersin.org/journals/nuclear-medicineam2024Nuclear MedicineSDG-03:Good heatlh and well-bein

Preclinical research highlighting contemporary targeting mechanisms of radiolabelled compounds for PET based infection imaging

It is important to constantly monitor developments in the preclinical imaging arena of infection. Firstly, novel radiopharmaceuticals with the correct characteristics must be identified to funnel into the clinic. Secondly, it must be evaluated if enough innovative research is being done and adequate resources are geared towards the development of radiopharmaceuticals that could feed into the Nuclear Medicine Clinic in the near future. It is proposed that the ideal infection imaging agent will involve PET combined with CT but more ideally MRI. The radiopharmaceuticals currently presented in preclinical literature have a wide selection of vectors and targets. Ionic formulations of PET-radionuclides such 64CuCl2 and 68GaCl2 are evaluated for bacterial infection imaging. Many small molecule based radiopharmaceuticals are being investigated with the most prominent targets being cell wall synthesis, maltodextrin transport (such as [18F] F-maltotriose), siderophores (bacterial and fungal infections), the folate synthesis pathway (such as [18F]F-PABA) and protein synthesis (radiolabelled puromycin). Mycobacterial specific antibiotics, antifungals and antiviral agents are also under investigation as infection imaging agents. Peptide based radiopharmaceuticals are developed for bacterial, fungal and viral infections. The radiopharmaceutical development could even react quickly enough on a pandemic to develop a SARS-CoV-2 imaging agent in a timely fashion ([64Cu]Cu-NOTA-EK1). New immuno- PET agents for the imaging of viruses have recently been published, specifically for HIV persistence but also for SARS-CoV2. A very promising antifungal immuno-PET agent (hJ5F) is also considered. Future technologies could include the application of aptamers and bacteriophages and even going as far as the design of theranostic infection. Another possibility would be the application of nanobodies for immuno-PET applications. Standardization and optimization of the preclinical evaluation of radiopharmaceuticals could enhance clinical translation and reduce time spent in pursuing less than optimal candidates.https://www.seminarsinnuclearmedicine.comam2024Nuclear MedicineNon

Advances in imaging of tuberculosis: the role of 18 F-FDG PET and PET/CT

PURPOSE OF REVIEW : To review the main applications, advantages and limitations of 18F-FDG PET and PET/computed tomography (CT), and some other tracers in imaging of tuberculosis (TB). RECENT FINDINGS : In pulmonary TB, granulomas typically demonstrate increased 18F-FDG uptake, and areas of active TB can be differentiated from old or inactive disease by dual time point imaging. However, standardized uptake value measurements are high in both TB and malignant lesions, with significant overlap that limits their usefulness. In extrapulmonary TB, 18F-FDG PET detects more tuberculous lesions than CT, is of value in assessing response to tuberculostatic treatment, and helps in diagnosing spinal infection and identifying TB-related spondylitis; however, again, differentiation of malignant versus TB lymph node involvement is problematic. 18F-FDG PET can also be considered a marker of disease status in patients with HIV and TB co-infection. Overall, evaluation of treatment response is potentially the most important clinical application of 18F-FDG PET in TB, owing to its ability to distinguish active from inactive disease. SUMMARY : 18F-FDG PET and PET/CT may assist early diagnosis and facilitate differentiation between malignancies and TB, identification of extrapulmonary TB, staging of TB, and assessment of treatment response.http://journals.lww.com/co-pulmonarymedicinehb201

Antimicrobial Peptides: Their Role as Infection-Selective Tracers for Molecular Imaging

Antimicrobial peptides (AMPs) are a heterogeneous class of compounds found in a variety of organisms including humans and, so far, hundreds of these structures have been isolated and characterised. They can be described as natural microbicide, selectively cytotoxic to bacteria, whilst showing minimal cytotoxicity towards the mammalian cells of the host organism. They act by their relatively strong electrostatic attraction to the negatively charged bacterial cells and a relatively weak interaction to the eukaryote host cells. The ability of these peptides to accumulate at sites of infection combined with the minimal host’s cytotoxicity motivated for this review to highlight the role and the usefulness of AMPs for PET with emphasis on their mechanism of action and the different interactions with the bacterial cell. These details are key information for their selective properties. We also describe the strategy, design, and utilization of these peptides as potential radiopharmaceuticals as their combination with nuclear medicine modalities such as SPECT or PET would allow noninvasive whole-body examination for detection of occult infection causing, for example, fever of unknown origin.National Research Foundation (NRF), the Institute of Cellular and Molecular Medicine and the Nuclear Technologies in Medicine and the Biosciences Initiative (NTeMBI), a national technology platform developed and managed by the South African Nuclear Energy Corporation (Necsa) and funded by the Department of Science and Technology (DST).http://www.hindawi.com/journals/bmrihb201

Tuberculosis : role of nuclear medicine and molecular imaging with potential impact of neutrophil-specific tracers

With Tuberculosis (TB) affecting millions of people worldwide, novel imaging modalities and tools, particularly nuclear medicine and molecular imaging, have grown with greater interest to assess the biology of the tuberculous granuloma and evolution thereof. Much early work has been performed at the pre-clinical level using gamma single photon emission computed tomography (SPECT) agents exploiting certain characteristics of Mycobacterium tuberculosis (MTb). Both antituberculous SPECT and positron emission tomography (PET) agents have been utilised to characteriseMTb. Other PET tracers have been utilised to help to characterise the biology of MTb (including Gallium-68-labelled radiopharmaceuticals). Of all the tracers, 2-[18F]FDG has been studied extensively over the last two decades in many aspects of the treatment paradigm of TB: at diagnosis, staging, response assessment, restaging, and in potentially predicting the outcome of patients with latent TB infection. Its lower specificity in being able to distinguish different inflammatory cell types in the granuloma has garnered interest in reviewing more specific agents that can portend prognostic implications in the management of MTb. With the neutrophil being a cell type that portends this poorer prognosis, imaging this cell type may be able to answer more accurately questions relating to the tuberculous granuloma transmissivity and may help in characterising patients who may be at risk of developing active TB. The formyl peptide receptor 1(FPR1) expressed by neutrophils is a key marker in this process and is a potential target to characterise these areas. The pre-clinical work regarding the role of radiolabelled N-cinnamoyl –F-(D) L – F – (D) –L F (cFLFLF) (which is an antagonist for FPR1) using Technetium 99m-labelled conjugates and more recently radiolabelled with Gallium-68 and Copper 64 is discussed. It is the hope that further work with this tracer may accelerate its potential to be utilised in responding to many of the current diagnostic dilemmas and challenges in TB management, thereby making the tracer a translatable option in routine clinical care.The Wellcome Trust, Bill and Melinda Gates Foundation and SA Medical Research Council (SAMRC) with funding from the SA Department of Health.https://www.frontiersin.org/journals/medicine#am2022Nuclear Medicin