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The interest in terbium radionuclides, which can be used in nuclear medicine, has increased tremendously over the last decade. Several research studies have shown the potential of four terbium radionuclides 149,152,155,161Tb both for cancer diagnosis as well as therapy. The comparison of 161Tb and 177Lu showed 161Tb as the preferred candidate not only for standard radiotherapy, but also for the treatment of minimal residual disease. Nevertheless, among the terbium sisters, currently, only 161Tb has an established production protocol where its nocarrier-added form is obtained via neutron irradiation of enriched 160Gd targets. The other terbium radioisotopes face challenges related to production capacity and production yield, which currently restricts their use in nuclear medicine. The purpose of this review is to report on recent research on the production and separation of terbium sisters and to assess the prospects for upscaling their production for nuclear medicine applications. [ABSTRACT FROM AUTHOR]

Introduction: Poly(ADP-ribose) polymerase 1 (PARP1) inhibition has become a major target in anticancer therapy. While PARP inhibitors (PARPi) are approved for homologous recombination (HR) deficient cancers, therapeutic resistance is a challenge and PARPi are now being investigated in cancers lacking HR deficiencies. This creates a need to develop molecular and imaging biomarkers of PARPi response to improve patient selection and circumvent therapeutic resistance. Areas covered: PubMed and clinicaltrials.gov were queried for studies on PARPi resistance and imaging. This review summarizes established and emerging resistance mechanisms to PARPi, and the current state of imaging and theragnostic probes for PARPi, including fluorescently labeled and radiolabeled probes. Expert opinion: While progress has been made in understanding PARPi therapeutic resistance, clinical evidence remains lacking and relatively little is known regarding PARPi response outside of HR deficiencies. Continued research will clarify the importance of known biomarkers and resistance mechanisms in patient cohorts and the broader utility of PARPi. Progress has also been made in PARPi imaging, particularly with radiolabeled probes, and both imaging and theragnostic probes have now reached clinical validation. Reducing abdominal background signal from probe clearance will broaden their applicability, and improvements to molecular synthesis and radiation delivery will increase their utility. [ABSTRACT FROM AUTHOR]

Background: Differentiated thyroid cancer (DTC) patients have an outstanding overall long-term survival rate, and certain subsets of DTC patients have a very high likelihood of disease recurrence. Radioactive iodine (RAI) therapy is a cornerstone in DTC management, but cancer cells can eventually develop resistance to RAI. Radioactive iodine-refractory DTC (RAIR-DTC) is a condition defined by ATA 2015 guidelines when DTC cannot concentrate RAI ab initio or loses RAI uptake ability after the initial therapy. The RAIR condition implies that RAI cannot reveal new met-astatic foci, so RAIR-DTC metabolic imaging needs new tracers. 18F-FDG PET/CT has been widely used and has demonstrated prognostic value, but 18F-FDG DTC avidity may remain low. Fibroblast activation protein inhibitors (FA-Pi)s, prostatic-specific membrane antigen (PSMA), and somatostatin receptor (SSTR) tracers have been proposed as theragnostic agents in experimental settings and Arg-Gly-Asp (RGD) peptides in the diagnostic trial field. Multi-targeted tyrosine kinase inhibitors are relatively new drugs approved in RAIR-DTC therapy. Despite the promising targeted setting, they relate to frequent adverse-event onset. Sorafenib and trametinib have been included in re-differentiation protocols aimed at re-inducing RAI accumulation in DTC cells. Results appear promising, but not excellent. Conclusions: RAIR-DTC remains a challenging nosological entity. There are still controversies on RAIR-DTC definition and post-RAI therapy evaluation, with post-therapy whole-body scan (PT-WBS) the only validated criterion of response. The recent introduction of multiple diagnostic and therapeutic agents obliges physicians to pursue a multidisciplinary approach aiming to correct drug introduction and timing choice.

Breast cancer remains the most prevalent cancer among women worldwide, driving the urgent need for innovative approaches to diagnosis and treatment. This review highlights the pivotal role of nanoparticles in revolutionizing breast cancer management through advancements of interconnected approaches including targeted therapy, imaging, and personalized medicine. Nanoparticles, with their unique physicochemical properties, have shown significant promise in addressing current treatment limitations such as drug resistance and nonspecific systemic distribution. Applications range from enhancing drug delivery systems for targeted and sustained release to developing innovative diagnostic tools for early and precise detection of metastases. Moreover, the integration of nanoparticles into photothermal therapy and their synergistic use with existing treatments, such as immunotherapy, illustrate their transformative potential in cancer care. However, the journey towards clinical adoption is fraught with challenges, including the chemical feasibility, biodistribution, efficacy, safety concerns, scalability, and regulatory hurdles. This review delves into the current state of nanoparticle research, their applications in breast cancer therapy and diagnosis, and the obstacles that must be overcome for clinical integration. [ABSTRACT FROM AUTHOR]

Background: Differentiated thyroid cancer (DTC) patients have an outstanding overall long-term survival rate, and certain subsets of DTC patients have a very high likelihood of disease recurrence. Radioactive iodine (RAI) therapy is a cornerstone in DTC management, but cancer cells can eventually develop resistance to RAI. Radioactive iodine-refractory DTC (RAIR-DTC) is a condition defined by ATA 2015 guidelines when DTC cannot concentrate RAI ab initio or loses RAI uptake ability after the initial therapy. The RAIR condition implies that RAI cannot reveal new met-astatic foci, so RAIR-DTC metabolic imaging needs new tracers. 18F-FDG PET/CT has been widely used and has demonstrated prognostic value, but 18F-FDG DTC avidity may remain low. Fibroblast activation protein inhibitors (FA-Pi)s, prostatic-specific membrane antigen (PSMA), and somatostatin receptor (SSTR) tracers have been proposed as theragnostic agents in experimental settings and Arg-Gly-Asp (RGD) peptides in the diagnostic trial field. Multi-targeted tyrosine kinase inhibitors are relatively new drugs approved in RAIR-DTC therapy. Despite the promising targeted setting, they relate to frequent adverse-event onset. Sorafenib and trametinib have been included in re-differentiation protocols aimed at re-inducing RAI accumulation in DTC cells. Results appear promising, but not excellent. Conclusions: RAIR-DTC remains a challenging nosological entity. There are still controversies on RAIR-DTC definition and post-RAI therapy evaluation, with post-therapy whole-body scan (PT-WBS) the only validated criterion of response. The recent introduction of multiple diagnostic and therapeutic agents obliges physicians to pursue a multidisciplinary approach aiming to correct drug introduction and timing choice. [ABSTRACT FROM AUTHOR]

Molecular imaging with positron emission tomography (PET) offers significant potential for improving diagnostic accuracy, staging and treatment monitoring in paediatric solid tumours, by using radiopharmaceuticals more specific than [18F]fluorodeoxyglucose ([18F]FDG). While non-[18F]FDG tracers have already improved diagnostic abilities in adult solid cancers such as prostate and neuroendocrine tumours, their use in the paediatric population has been underexplored. This narrative review summarises clinical evidence regarding the use, advantages, and limitations of these more specific PET tracers in paediatric patients. In neuroblastoma, [18F]mFBG, [18F]F-DOPA, and SSTR-targeting peptides stand out as the most evolved and promising tracers for the clinical setting, with encouraging results regarding feasibility, safety and detection rates. SSTR-targeting peptides have also consistently outperformed other imaging methods (both conventional and functional) and carry the benefits of theragnostic applications. For brain tumours, amino acid-based tracers in general stand out due to their ability to surpass the blood-brain barrier/blood-tumour barrier (BBB/BTB) and their specific accumulation in malignant tissue. Other paediatric solid tumours, such as sarcoma and bone tumours, suffer from a clear lack of clinical evidence that should be addressed in the near future. The studies performed to date show high accuracy, evident prognostic value, and significant clinical impact of non-[18F]FDG tracers in paediatric patients with solid tumours. However, prospective studies with longer follow-up times are warranted to provide high-level evidence regarding the impact of these tracers on patient management and prognosis, to consolidate the encouraging results obtained so far. Further research and international collaboration will be essential to overcome current challenges related to low incidence of paediatric solid tumours, logistical barriers and concerns about radiation exposure.

The interest in terbium radionuclides, which can be used in nuclear medicine, has increased tremendously over the last decade. Several research studies have shown the potential of four terbium radionuclides 149,152,155,161Tb both for cancer diagnosis as well as therapy. The comparison of 161Tb and 177Lu showed 161Tb as the preferred candidate not only for standard radiotherapy, but also for the treatment of minimal residual disease. Nevertheless, among the terbium sisters, currently, only 161Tb has an established production protocol where its no-carrier-added form is obtained via neutron irradiation of enriched 160Gd targets. The other terbium radioisotopes face challenges related to production capacity and production yield, which currently restricts their use in nuclear medicine. The purpose of this review is to report on recent research on the production and separation of terbium sisters and to assess the prospects for upscaling their production for nuclear medicine applications.

Hepatocellular carcinoma (HCC) is a major global health problem. Theragnostic is a term that refers to the integration of diagnostic and therapeutic modalities into a single system for personalized medicine. Theragnostic care in HCC involves the use of imaging techniques to diagnose the cancer and assess its characteristics, such as size, location, and extent of spread. Theragnostics involves the use of molecular and genetic tests to identify specific biomarkers that can help guide treatment decisions and, post-treatment, assess the dosimetry and localization of the treatment, thus guiding future treatment. This can be done through either positron emission tomography (PET) scanning or single photon emission tomography (SPECT) using radiolabeled tracers that target specific molecules expressed by HCC cells or radioembolization. This technique can help identify the location and extent of the cancer, as well as provide information on the tumor's metabolic activity and blood supply. In summary, theragnostics is an emerging field that holds promise for improving the diagnosis and treatment of HCC. By combining diagnostic and therapeutic modalities into a single system, theragnostics can help guide personalized treatment decisions and improve patient outcomes. [ABSTRACT FROM AUTHOR]

X-ray luminescent nanoparticles have gained significant attention as promising tools for implementing multimodal imaging and radiation-based treatments in theragnostics. The intricate comprehension of their properties and the underlying mechanisms driving the conversion of X-rays into light is critical for their success in various applications. LaPO 4 nanoparticles doped with various individual luminescence centers, gadolinium (Gd3+), europium (Eu3+), dysprosium (Dy3+), and terbium (Tb3+), were produced via co-precipitation and investigated for their behavior upon X-ray excitation using energies of up to 225 kV. These materials evidenced a radioluminescent response dependent on the dopant concentrations, with emission lines from 300 to 700 nm, providing insights into the luminescence quenching effect in these structures. The luminescent characteristics of the nanoparticles were studied under continuous irradiation, evidencing the materials' ability to withstand high absorbed doses and preserve their properties. Furthermore, the influence of dopant concentrations on crystallite size and the dependence of luminescence on thermal treatments was investigated. The assessment of nanoparticle stability in aqueous suspension was evaluated over a broad pH range, revealing a tendency of the LaPO 4 surface to selectively interact with electropositive species. This insight enhances our comprehension of the colloidal stability of the material, positioning it for extended applications and in vitro evaluations, along with further surface functionalization. [ABSTRACT FROM AUTHOR]

Theragnostics has become a popular term nowadays, since it enables both diagnosis and therapy at the same time while only using one carrier platform. Therefore, formulating a nanocarrier system that could serve as theragnostic agent by using simple techniques would be an advantage during production. In this project, we aimed to develop a nanocarrier that can be loaded with the chemotherapeutic medication chlorambucil and magnetic resonance imaging agents (e.g., iron oxide nanoparticles and near-infrared fluorophore IR780) for theragnostics. Poly(lactic-co-glycolic acid) was combined with the aforementioned ingredients to generate poly(vinyl alcohol)-based nanoparticles (NPs) using the single emulsion technique. Then the NPs were coated with F127 and F127-folate by simple incubation for five days. The nanoparticles have the hydrodynamic size of approx. 250 nm with negative charge. Similar to chlorambucil and IR780, iron oxide loadings were observed for all three kinds of NPs. The release of chlorambucil was quicker at pH 5.4 than at pH 7.4 at 37 °C. The F127@NPs and F127-folate@NPs demonstrated much greater cell uptake and toxicity up to 72 h after incubation. Our in vitro results of F127@NPs and F127-folate@NPs have demonstrated the ability of these systems to serve as medication and imaging agent carriers for cancer treatment and diagnostics, respectively.

Turner syndrome (45,X) is caused by a complete or partial absence of a single X chromosome. Vascular malformations occur due to abnormal development of blood and/or lymphatic vessels. They arise from either somatic or germline pathogenic variants in the genes regulating growth and apoptosis of vascular channels. Aortic abnormalities are a common, known vascular anomaly of Turner syndrome. However, previous studies have described other vascular malformations as a rare feature of Turner syndrome and suggested that vascular abnormalities in individuals with Turner syndrome may be more generalized. In this study, we describe two individuals with co‐occurrence of Turner syndrome and vascular malformations with a lymphatic component. In these individuals, genetic testing of the lesional tissue revealed a somatic pathogenic variant in PIK3CA—a known and common cause of lymphatic malformations. Based on this finding, we conclude that the vascular malformations presented here and likely those previously in the literature are not a rare part of the clinical spectrum of Turner syndrome, but rather a separate clinical entity that may or may not co‐occur in individuals with Turner syndrome. [ABSTRACT FROM AUTHOR]

Neuroendocrine tumor (NET) metastasis to the thyroid is rare, and its presentation as the first manifestation of primary malignancy elsewhere is even more uncommon. We present a case of a 41-year-old female who underwent biopsy of enlarging thyroid nodules with findings suspicious for medullary thyroid cancer (MTC). Subsequent thyroidectomy demonstrated NET of unknown primary in the left lower lobe. Immediate workup with 68Ga-DOTATATE-PET/CT revealed abnormal somatostatin receptor (SR) expressing lesions in the liver, right cervical nodes, thoracic paravertebral soft tissue, precoccygeal soft tissue, and right acetabulum concerning for sites of neuroendocrine malignancy. Due to disease progression while on octreotide injections, a decision was made at the multidisciplinary NET board for the patient to receive peptide receptor radionuclide therapy (PRRT) which includes 4 cycles of 77Lu-DOTATATE (Lutathera). The patient had no side effects nor toxicities during the 8 months of PRRT and achieved a partial treatment response in the early post-treatment scan at 6 weeks. This case illustrates the importance of distinguishing NET metastasis to the thyroid from MTC to ensure appropriate workup and treatment as well as predict the response of neuroendocrine malignancies to PRRT based on the visualized overexpression of SR in the SR-PET scans, despite the organ of origin.

Abstract Background Selective internal radiation therapy with 90Y radioembolization aims to selectively irradiate liver tumours by administering radioactive microspheres under the theragnostic assumption that the pre-therapy injection of 99mTc labelled macroaggregated albumin (99mTc-MAA) provides an estimation of the 90Y microspheres biodistribution, which is not always the case. Due to the growing interest in theragnostic dosimetry for personalized radionuclide therapy, a robust relationship between the delivered and pre-treatment radiation absorbed doses is required. In this work, we aim to investigate the predictive value of absorbed dose metrics calculated from 99mTc-MAA (simulation) compared to those obtained from 90Y post-therapy SPECT/CT. Results A total of 79 patients were analysed. Pre- and post-therapy 3D-voxel dosimetry was calculated on 99mTc-MAA and 90Y SPECT/CT, respectively, based on Local Deposition Method. Mean absorbed dose, tumour-to-normal ratio, and absorbed dose distribution in terms of dose-volume histogram (DVH) metrics were obtained and compared for each volume of interest (VOI). Mann–Whitney U-test and Pearson’s correlation coefficient were used to assess the correlation between both methods. The effect of the tumoral liver volume on the absorbed dose metrics was also investigated. Strong correlation was found between simulation and therapy mean absorbed doses for all VOIs, although simulation tended to overestimate tumour absorbed doses by 26%. DVH metrics showed good correlation too, but significant differences were found for several metrics, mostly on non-tumoral liver. It was observed that the tumoral liver volume does not significantly affect the differences between simulation and therapy absorbed dose metrics. Conclusion This study supports the strong correlation between absorbed dose metrics from simulation and therapy dosimetry based on 90Y SPECT/CT, highlighting the predictive ability of 99mTc-MAA, not only in terms of mean absorbed dose but also of the dose distribution.

Simple Summary: Precision medicine is a new approach to the diagnosis and treatment of cancer that considers individual patient differences and avoids a one-size-fits-all approach to treatment. Lung neuroendocrine tumors are increasingly common cancers with a wide spectrum of clinical behaviors. Lung neuroendocrine tumors have lagged behind other cancers in the incorporation of precision medicine approaches to treatment. However, this is beginning to change as our understanding of the molecular underpinnings of neuroendocrine tumor carcinogenesis expands and our clinical trial repertoire increases. In particular, advances in radiotheragnostics hold promise for yielding new personalized approaches to treatment. In this review, we summarize established and emerging precision medicine approaches to the treatment of lung neuroendocrine tumors. Well-differentiated lung neuroendocrine tumors (LNETs) are heterogeneous cancers that are increasing in incidence. Treatment options for LNETs have expanded in recent years, and our knowledge of the molecular subtypes has also advanced. Multidisciplinary teams have an established role in personalizing the best treatment for individual patients. Other precision medicine approaches for the treatment of LNETs have lagged behind those for non-small-cell lung cancer, with only rare actionable molecular alterations identified and few established predictive factors to guide therapy selection. However, as summarized in this review, there is increasing potential for personalized treatment of patients with LNETs. In particular, advances in radiotheragnostics may allow us to tailor the treatment of individual patients with NETs in the coming years. These advances may soon deliver the promise of more effective, less toxic treatments and better outcomes for patients with these increasingly common cancers. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is a prevalent malignancy with increasing incidence in middle-aged and older men. Despite various treatment options, advanced metastatic PCa remains challenging with poor prognosis and limited effective therapies. Nanomedicine, with its targeted drug delivery capabilities, has emerged as a promising approach to enhance treatment efficacy and reduce adverse effects. Prostate-specific membrane antigen (PSMA) stands as one of the most distinctive and highly selective biomarkers for PCa, exhibiting robust expression in PCa cells. In this review, we explore the applications of PSMAtargeted nanomedicines in advanced PCa management. Our primary objective is to bridge the gap between cutting-edge nanomedicine research and clinical practice, making it accessible to the medical community. We discuss mainstream treatment strategies for advanced PCa, including chemotherapy, radiotherapy, and immunotherapy, in the context of PSMA-targeted nanomedicines. Additionally, we elucidate novel treatment concepts such as photodynamic and photothermal therapies, along with nano-theragnostics. We present the content in a clear and accessible manner, appealing to general physicians, including those with limited backgrounds in biochemistry and bioengineering. The review emphasizes the potential benefits of PSMA-targeted nanomedicines in enhancing treatment efficiency and improving patient outcomes. While the use of PSMA-targeted nano-drug delivery has demonstrated promising results, further investigation is required to comprehend the precise mechanisms of action, pharmacotoxicity, and long-term outcomes. By meticulous optimization of the combination of nanomedicines and PSMA ligands, a novel horizon of PSMA-targeted nanomedicine-based combination therapy could bring renewed hope for patients with advanced PCa. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is a global public health issue. The development and use of in vitro cellular models with pre-clinical animal models are essential to elucidate the complex biology of cancer and test new diagnostic and therapeutic options. Three-dimensional (3D) tumor models are particularly important as they can accurately mimic the behavior of solid tumors. This review article critically discusses the suitability of 3D spheroid models in oncological research. Advanced tissue engineering processes and regenerative medicine provide modern strategies for fabricating 3D spheroids. Several different 3D cancer models are being developed to study a variety of cancers. Three-dimensional spheroids can correctly replicate some features of solid tumors (such as the secretion of soluble mediators, drug resistance mechanisms, gene expression patterns and physiological responses) better than 2D cell cultures or animal models. Tumor spheroids are also helpful for precisely reproducing the three-dimensional organization and microenvironmental factors of tumors. Because of these unique properties, the potential of 3D cell aggregates has been emphasized, and they have been utilized in in vitro models for the detection of novel anticancer drugs. This review discusses applications of 3D spheroid models in nuclear medicine for diagnosis and therapy, immunotherapy, and stem cell and photodynamic therapy and also discusses the establishment of the anticancer activity of nanocarriers. [ABSTRACT FROM AUTHOR]

Cancer theragnostics is a novel approach that combines diagnostic imaging and radionuclide therapy. It is based on the use of a pair of radiopharmaceuticals, one optimized for positron emission tomography imaging through linkage to a proper radionuclide, and the other bearing an alpha- or beta-emitter isotope that can induce significant damage to cancer cells. In recent years, the use of theragnostics in nuclear medicine clinical practice has increased considerably, and thus investigation has focused on the identification of novel radionuclides that can bind to molecular targets that are typically dysregulated in different cancers. The major advantages of the theragnostic approach include the elimination of multi-step procedures, reduced adverse effects to normal tissues, early diagnosis, better predictive responses, and personalized patient care. This review aims to discuss emerging theragnostic molecules that have been investigated in a series of human malignancies, including gliomas, thyroid cancer, neuroendocrine tumors, cholangiocarcinoma, and prostate cancer, as well as potent and recently introduced molecular targets, like cell-surface receptors, kinases, and cell adhesion proteins. Furthermore, special reference has been made to copper radionuclides as theragnostic agents and their radiopharmaceutical applications since they present promising alternatives to the well-studied gallium-68 and lutetium-177. [ABSTRACT FROM AUTHOR]

Nuclear medicine has acquired a crucial role in the management of patients with neuroendocrine neoplasms (NENs) by improving the accuracy of diagnosis and staging as well as their risk stratification and personalized therapies, including radioligand therapies (RLT). Artificial intelligence (AI) and radiomics can enable physicians to further improve the overall efficiency and accuracy of the use of these tools in both diagnostic and therapeutic settings by improving the prediction of the tumor grade, differential diagnosis from other malignancies, assessment of tumor behavior and aggressiveness, and prediction of treatment response. This systematic review aims to describe the state-of-the-art AI and radiomics applications in the molecular imaging of NENs. [ABSTRACT FROM AUTHOR]

Background: Selective internal radiation therapy with 90Y radioembolization aims to selectively irradiate liver tumours by administering radioactive microspheres under the theragnostic assumption that the pre-therapy injection of 99mTc labelled macroaggregated albumin (99mTc-MAA) provides an estimation of the 90Y microspheres biodistribution, which is not always the case. Due to the growing interest in theragnostic dosimetry for personalized radionuclide therapy, a robust relationship between the delivered and pre-treatment radiation absorbed doses is required. In this work, we aim to investigate the predictive value of absorbed dose metrics calculated from 99mTc-MAA (simulation) compared to those obtained from 90Y post-therapy SPECT/CT. Results: A total of 79 patients were analysed. Pre- and post-therapy 3D-voxel dosimetry was calculated on 99mTc-MAA and 90Y SPECT/CT, respectively, based on Local Deposition Method. Mean absorbed dose, tumour-to-normal ratio, and absorbed dose distribution in terms of dose-volume histogram (DVH) metrics were obtained and compared for each volume of interest (VOI). Mann–Whitney U-test and Pearson's correlation coefficient were used to assess the correlation between both methods. The effect of the tumoral liver volume on the absorbed dose metrics was also investigated. Strong correlation was found between simulation and therapy mean absorbed doses for all VOIs, although simulation tended to overestimate tumour absorbed doses by 26%. DVH metrics showed good correlation too, but significant differences were found for several metrics, mostly on non-tumoral liver. It was observed that the tumoral liver volume does not significantly affect the differences between simulation and therapy absorbed dose metrics. Conclusion: This study supports the strong correlation between absorbed dose metrics from simulation and therapy dosimetry based on 90Y SPECT/CT, highlighting the predictive ability of 99mTc-MAA, not only in terms of mean absorbed dose but also of the dose distribution. [ABSTRACT FROM AUTHOR]

Theragnostics is a promising approach that integrates diagnostics and therapeutics into a single personalized strategy. To conduct effective theragnostic studies, it is essential to create an in vitro environment that accurately reflects the in vivo conditions. In this review, we discuss the importance of redox homeostasis and mitochondrial function in the context of personalized theragnostic approaches. Cells have several ways to respond to metabolic stress, including changes in protein localization, density, and degradation, which can promote cell survival. However, disruption of redox homeostasis can lead to oxidative stress and cellular damage, which are implicated in various diseases. Models of oxidative stress and mitochondrial dysfunction should be developed in metabolically conditioned cells to explore the underlying mechanisms of diseases and develop new therapies. By choosing an appropriate cellular model, adjusting cell culture conditions and validating the cellular model, it is possible to identify the most promising therapeutic options and tailor treatments to individual patients. Overall, we highlight the importance of precise and individualized approaches in theragnostics and the need to develop accurate in vitro models that reflect the in vivo conditions. [ABSTRACT FROM AUTHOR]

Mesfin Dessale, Getachew Mengistu, Hylemariam Mihiretie Mengist Department of Medical Laboratory Sciences, Debre Markos University, Debre Markos, Amhara, EthiopiaCorrespondence: Hylemariam Mihiretie Mengist, Email hylemariam@gmail.comAbstract: Cancer remains the most devastating disease and the major cause of mortality worldwide. Although early diagnosis and treatment are the key approach in fighting against cancer, the available conventional diagnostic and therapeutic methods are not efficient. Besides, ineffective cancer cell selectivity and toxicity of traditional chemotherapy remain the most significant challenge. These limitations entail the need for the development of both safe and effective cancer diagnosis and treatment options. Due to its robust application, nanotechnology could be a promising method for in-vivo imaging and detection of cancer cells and cancer biomarkers. Nanotechnology could provide a quick, safe, cost-effective, and efficient method for cancer management. It also provides simultaneous diagnosis and treatment of cancer using nano-theragnostic particles that facilitate early detection and selective destruction of cancer cells. Updated and recent discussions are important for selecting the best cancer diagnosis, treatment, and management options, and new insights on designing effective protocols are utmost important. This review discusses the application of nanotechnology in cancer diagnosis, therapeutics, and theragnosis and provides future perspectives in the field.Keywords: cancer, nanotechnology, diagnosis, treatment, theragnostics

Lately, there has been an increasing demand for materials that could improve tissue regenerative therapies and provide antimicrobial effects. Similarly, there is a growing need to develop or modify biomaterials for the diagnosis and treatment of different pathologies. In this scenario, hydroxyapatite (HAp) appears as a bioceramic with extended functionalities. Nevertheless, there are certain disadvantages related to the mechanical properties and lack of antimicrobial capacity. To circumvent them, the doping of HAp with a variety of cationic ions is emerging as a good alterative due to the different biological roles of each ion. Among many elements, lanthanides are understudied despite their great potential in the biomedical field. For this reason, the present review focuses on the biological benefits of lanthanides and how their incorporation into HAp can alter its morphology and physical properties. A comprehensive section of the applications of lanthanides-substituted HAp nanoparticles (HAp NPs) is presented to unveil the potential biomedical uses of these systems. Finally, the need to study the tolerable and non-toxic percentages of substitution with these elements is highlighted. [ABSTRACT FROM AUTHOR]

Gold nanoparticles (AuNPs) are cutting-edge platforms for combined diagnostic and therapeutic approaches due to their exquisite physicochemical and optical properties. Using the AuNPs physically produced by femtosecond pulsed laser ablation of bulk Au in deionized water, with a capping agent-free surface, the conjugation of functional ligands onto the AuNPs can be tunable between 0% and 100% coverage. By taking advantage of this property, AuNPs functionalized by two different types of active targeting ligands with predetermined ratios were fabricated. The quantitatively controllable conjugation to construct a mixed monolayer of multiple biological molecules at a certain ratio onto the surface of AuNPs was achieved and a chelator-free 64Cu-labeling method was developed. We report here the manufacture, radiosynthesis and bioevaluation of three different types of dual-ligand AuNPs functionalized with two distinct ligands selected from glucose, arginine–glycine–aspartate (RGD) peptide, and methotrexate (MTX) for tumor theragnosis. The preclinical evaluation demonstrated that tumor uptakes and retention of two components AuNP conjugates were higher than that of single-component AuNP conjugates. Notably, the glucose/MT- modified dual-ligand AuNP conjugates showed significant improvement in tumor uptake and retention. The novel nanoconjugates prepared in this study make it possible to integrate several modalities with a single AuNP for multimodality imaging and therapy, combining the power of chemo-, thermal- and radiation therapies together. [ABSTRACT FROM AUTHOR]

Abstract In prostate cancer (PCa), the use of new radiopharmaceuticals has improved the accuracy of diagnosis and staging, refined surveillance strategies, and introduced specific and personalized radioreceptor therapies. Nuclear medicine, therefore, holds great promise for improving the quality of life of PCa patients, through managing and processing a vast amount of molecular imaging data and beyond, using a multi-omics approach and improving patients’ risk-stratification for tailored medicine. Artificial intelligence (AI) and radiomics may allow clinicians to improve the overall efficiency and accuracy of using these “big data” in both the diagnostic and theragnostic field: from technical aspects (such as semi-automatization of tumor segmentation, image reconstruction, and interpretation) to clinical outcomes, improving a deeper understanding of the molecular environment of PCa, refining personalized treatment strategies, and increasing the ability to predict the outcome. This systematic review aims to describe the current literature on AI and radiomics applied to molecular imaging of prostate cancer.

Asthma is a heterogeneous disease sharing airway instability but with different biology, risk factors, and response-to-therapy patterns. Biologics have revolutionized the one-size-fits-to-all approach to personalized medicine in severe asthma (SA), which relies on the identification of biomarkers that define distinct endotypes. Thus, blood eosinophils and, to some extent, exhaled nitric oxide (FeNO) can predict the response to approved anti-type 2 (T2) biologics (anti-IgE, anti–IL-5, and anti–IL-4R alpha), whereas age at onset and comorbidities such as anxiety/depression, obesity, reflux, and upper airway disease (UAD) also influence therapeutic responses in SA. In this article, focusing on the predictive value of biomarkers for the therapeutic response to biologics in SA, we first summarize the level of prediction achieved by T2 biomarkers (blood eosinophils, FeNO) and then review whether data support the predictive value of upper airway diagnosis on such outcomes. Post hoc analysis of most studies with T2 biologics suggests that chronic rhinosinusitis with nasal polyps (CRSwNP) and, to a lower extent, allergic rhinitis may help in predicting clinical response. Considering that T2 biologics are now also approved for the treatment of severe CRSwNP, diagnosis of upper airway disease is a key step in determining eligibility for such therapy.

Colorectal Cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Despite the notable advances achieved over the last few decades, CRC remains a hard-to-treat deadly disease in many patients. This is attributed mainly to chemo- and immuno-resistance, which frequently emerge soon after treatment with conventional therapeutics. Systemic treatments are also constrained by their many undesired and serious side effects. More recently, nanomedicine has emerged as an attractive modality that can overcome issues of therapeutic resistance, improper delivery, or suboptimal targeting of tumor cells. Many nanomaterials, having already been examined in pre-clinical and clinical studies, are now considered biocompatible and relatively safe. Indeed, around 50 nano-formulations have so far been approved as diagnostic and therapeutic agents in humans. Here, in this review, we describe a set of imperative nanoparticles (NPs) involved in diagnosing and treating CRC. In particular, we discuss the theragnostic roles of quantum dots, iron oxide NPs, Polylactide-co-glycolic acid (PLGA) NPs, dendrimer NPs, carbon nanotubes, liposomes, and gold NPs. We dissect the molecular and clinical evidence supporting the use of these NPs in CRC. We also highlight their implications in targeted drug delivery as well as their anti-tumorigenic properties and effects on the cardinal hallmarks of CRC. We conclude by highlighting the notion that nanomedicine is emerging as an attractive approach to address the unmet needs in managing several diseases, including CRC. [ABSTRACT FROM AUTHOR]

Molecular imaging is the visual representation of biological processes that take place at the cellular or molecular level in living organisms. To date, molecular imaging plays an important role in the transition from conventional medical practice to precision medicine. Among all imaging modalities, positron emission tomography (PET) has great advantages in sensitivity and the ability to obtain absolute imaging quantification after corrections for photon attenuation and scattering. Due to the ability to label a host of unique molecules of biological interest, including endogenous, naturally occurring substrates and drug-like compounds, the role of PET has been well established in the field of molecular imaging. In this article, we provide an overview of the recent advances in the development of PET radiopharmaceuticals and their clinical applications in oncology. [ABSTRACT FROM AUTHOR]

Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neoplasms that fall within the category of neuroendocrine tumors. In the last decade, their diagnostic algorithm has been modified to include the evaluation of molecular pathways, genotype, and biochemical phenotype, in order to correctly interpret anatomical and functional imaging results and tailor the best therapeutic choices to patients. More specifically, the identification of germline mutations has led to a three-way cluster classification: pseudo-hypoxic cluster, cluster of kinase receptor signaling and protein translation pathways, and cluster of Wnt-altered pathway. In this context, functional imaging gained a crucial role in the management of these patients in agreement with the ever-growing concept of personalized medicine. In this paper, we provide an overview of three specific molecular pathways targeted by positron-emitting tracers to image PCCs and PGLs: catecholamine metabolism, somatostatin receptors, and glucose uptake. Finally, we recommend different flow charts for use in the selection of tracers for specific clinical scenarios, based on sporadic/inherited tumor and known/unknown mutation status. [ABSTRACT FROM AUTHOR]

Transdermal healthcare systems have gained significant attention for their painless and convenient drug administration, as well as their ability to detect biomarkers promptly. However, the skin barrier limits the candidates of biomolecules that can be transported, and reliance on simple diffusion poses a bottleneck for personalized diagnosis and treatment. Consequently, recent advancements in transdermal transport technologies have evolved toward active methods based on external energy sources. Multiple combinations of these technologies have also shown promise for increasing therapeutic effectiveness and diagnostic accuracy as delivery efficiency is maximized. Furthermore, wearable healthcare platforms are being developed in diverse aspects for patient convenience, safety, and on-demand treatment. Herein, a comprehensive overview of active transdermal delivery technologies is provided, highlighting the combination-based diagnostics, therapeutics, and theragnostics, along with the latest trends in platform advancements. This offers insights into the potential applications of next-generation wearable transdermal medical devices for personalized autonomous healthcare., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Abstract Background Terbium-155 [T1/2 = 5.32 d, Eγ = 87 keV (32%) 105 keV (25%)] is an interesting radionuclide suitable for single photon emission computed tomography (SPECT) imaging with potential application in the diagnosis of oncological disease. It shows similar decay characteristics to the clinically established indium-111 and would be a useful substitute for the diagnosis and prospective dosimetry with biomolecules that are afterwards labeled with therapeutic radiolanthanides and pseudo-radiolanthanides, such as lutetium-177 and yttrium-90. Moreover, terbium-155 could form part of the perfect “matched pair” with the therapeutic radionuclide terbium-161, making the concept of true radiotheragnostics a reality. The aim of this study was the investigation of the production of terbium-155 via the 155Gd(p,n)155Tb and 156Gd(p,2n)155Tb nuclear reactions and its subsequent purification, in order to obtain a final product in quantity and quality sufficient for preclinical application. The 156Gd(p,2n)155Tb nuclear reaction was performed with 72 MeV protons (degraded to ~ 23 MeV), while the 155Gd(p,n)155Tb reaction was degraded further to ~ 10 MeV, as well as performed at an 18 MeV medical cyclotron, to demonstrate its feasibility of production. Result The 156Gd(p,2n)155Tb nuclear reaction demonstrated higher production yields of up to 1.7 GBq, however, lower radionuclidic purity when compared to the final product (~ 200 MBq) of the 155Gd(p,n)155Tb nuclear reaction. In particular, other radioisotopes of terbium were produced as side products. The radiochemical purification of terbium-155 from the target material was developed to provide up to 1.0 GBq product in a small volume (~ 1 mL 0.05 M HCl), suitable for radiolabeling purposes. The high chemical purity of terbium-155 was proven by radiolabeling experiments at molar activities up to 100 MBq/nmol. SPECT/CT experiments were performed in tumor-bearing mice using [155Tb]Tb-DOTATOC. Conclusion This study demonstrated two possible production routes for high activities of terbium-155 using a cyclotron, indicating that the radionuclide is more accessible than the exclusive mass-separated method previously demonstrated. The developed radiochemical purification of terbium-155 from the target material yielded [155Tb]TbCl3 in high chemical purity. As a result, initial cell uptake investigations, as well as SPECT/CT in vivo studies with [155Tb]Tb-DOTATOC, were successfully performed, indicating that the chemical separation produced a product with suitable quality for preclinical studies.

Cancer theragnostics is a novel approach that combines diagnostic imaging and radionuclide therapy. It is based on the use of a pair of radiopharmaceuticals, one optimized for positron emission tomography imaging through linkage to a proper radionuclide, and the other bearing an alpha- or beta-emitter isotope that can induce significant damage to cancer cells. In recent years, the use of theragnostics in nuclear medicine clinical practice has increased considerably, and thus investigation has focused on the identification of novel radionuclides that can bind to molecular targets that are typically dysregulated in different cancers. The major advantages of the theragnostic approach include the elimination of multi-step procedures, reduced adverse effects to normal tissues, early diagnosis, better predictive responses, and personalized patient care. This review aims to discuss emerging theragnostic molecules that have been investigated in a series of human malignancies, including gliomas, thyroid cancer, neuroendocrine tumors, cholangiocarcinoma, and prostate cancer, as well as potent and recently introduced molecular targets, like cell-surface receptors, kinases, and cell adhesion proteins. Furthermore, special reference has been made to copper radionuclides as theragnostic agents and their radiopharmaceutical applications since they present promising alternatives to the well-studied gallium-68 and lutetium-177.

Nuclear medicine has acquired a crucial role in the management of patients with neuroendocrine neoplasms (NENs) by improving the accuracy of diagnosis and staging as well as their risk stratification and personalized therapies, including radioligand therapies (RLT). Artificial intelligence (AI) and radiomics can enable physicians to further improve the overall efficiency and accuracy of the use of these tools in both diagnostic and therapeutic settings by improving the prediction of the tumor grade, differential diagnosis from other malignancies, assessment of tumor behavior and aggressiveness, and prediction of treatment response. This systematic review aims to describe the state-of-the-art AI and radiomics applications in the molecular imaging of NENs.

Simple Summary: Positron emission tomography/computed tomography (PET/CT) has an increasingly relevant role in the management of oncological patients. It consists of the administration of a radioactive molecule (tracer) which localizes in tumour cells due to specific cellular features (e.g., a receptor expressed by a specific cell population). PET/CT has a variety of applications in oncology, including staging, therapeutic response assessment and restaging in various types of tumours through the administration of different tracers. Among them, prostate-specific membrane antigen (PSMA) radioligands are a relatively novel compound widely employed in prostate cancer diagnostics and therapy. Besides their prostate cancer applications, PSMA radioligands have been shown to be a promising instrument to evaluate the stage and the aggressiveness in several types of cancer, since they allow us to study tumour neoangiogenesis. This review provides an overview of the applications of PSMA radioligand PET/CT in various types of tumours other than prostate cancer. Due to its overexpression on the surface of prostate cancer cells, prostate-specific membrane antigen (PSMA) is a relatively novel effective target for molecular imaging and radioligand therapy (RLT) in prostate cancer. Recent studies reported that PSMA is expressed in the neovasculature of various types of cancer and regulates tumour cell invasion as well as tumour angiogenesis. Several authors explored the role of diagnostic and therapeutic PSMA radioligands in various malignancies. In this narrative review, we describe the current status of the literature on PSMA radioligands' application in solid tumours other than prostate cancer to explore their potential role as diagnostic or therapeutic agents, with particular regard to the relevance of PSMA radioligand uptake as neoangiogenetic biomarker. Hence, a comprehensive review of the literature was performed to find relevant articles on the applications of PSMA radioligands in non-prostate solid tumours. Data on the general, methodological and clinical aspects of all included studies were collected. Forty full-text papers were selected for final review, 8 of which explored PSMA radioligand PET/CT performances in gliomas, 3 in salivary gland malignancies, 6 in thyroid cancer, 2 in breast cancer, 16 in renal cell carcinoma and 5 in hepatocellular carcinoma. In the included studies, PSMA radioligand PET showed promising performance in patients with non-prostate solid tumours. Further studies are needed to better define its potential role in oncological patients management, especially in those undergoing antineoangiogenic therapies, and to assess the efficacy of PSMA-RLT in this clinical context. [ABSTRACT FROM AUTHOR]

Theragnostic pairs of isotopes are used to infer radiation dosimetry for a therapeutic radiopharmaceutical from a diagnostic imaging study with the same tracer molecule labelled with an isotope better suited for the imaging task. We describe the transfer of radiation dosimetry from the diagnostic radioiodine isotope 123I, labelled for the hypoxia tracer molecule iodoazomycin arabinoside ([123I]IAZA), to isotopes 131I (therapeutic) and 124I (PET imaging). Uncertainties introduced by the dissimilar isotope half-lives are discussed in detail. Radioisotope dosimetries for [123I]IAZA were obtained previously. These data are used here to calculate residence times for 131I and 124I and their uncertainties. We distinguish two cases when extrapolating to infinity: purely physical decay (case A) and physical decay plus biological washout (case B). Organ doses were calculated using the MIRD schema with the OLIDNA/EXM code. Significant increases in some organ doses (in mSv per injected activity) were found for 131I and 124I. The most affected organs were the intestinal walls, thyroid, and urinary bladder wall. Uncertainty remained similar to 123I for case A but considerably greater for case B, especially for long biological half-lives (GI tract). Normal tissue dosimetries for IAZA must be considered carefully when substituting isotope species. A long biological half-life can significantly increase dosimetric uncertainties. These findings are relevant when considering PET imaging studies with [124I]IAZA or therapeutic administration of [131I]IAZA. [ABSTRACT FROM AUTHOR]

There has been tremendous growth in the development of theragnostics for personalized cancer diagnosis and treatment over the past two decades. In prostate cancer, the new generation of prostate specific membrane antigen (PSMA) small molecular inhibitor-based imaging agents achieve extraordinary tumor to background ratios and allow their therapeutic counterparts to deliver effective tumor doses while minimizing normal tissue toxicity. The PSMA targeted small molecule positron emission tomography (PET) agents 18F-DCFPyL (2-(3-{1-carboxy-5-((6-(18)F-fluoro-pyridine-3-carbonyl)-amino)-pentyl}-ureido)-pentanedioic acid) and Gallium-68 (68Ga)-PSMA-11 have been approved by the United States Food and Drug Administration (FDA) for newly diagnosed high risk prostate cancer patients and for patients with biochemical recurrence. More recently, the Phase III VISION trial showed that Lutetium-177 (177Lu)-PSMA-617 treatment increases progression-free survival and overall survival in patients with heavily pre-treated advanced PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). Here, we review the PSMA targeted theragnostic pairs under clinical investigation for detection and treatment of metastatic prostate cancer.

Theragnostics is a promising approach that integrates diagnostics and therapeutics into a single personalized strategy. To conduct effective theragnostic studies, it is essential to create an in vitro environment that accurately reflects the in vivo conditions. In this review, we discuss the importance of redox homeostasis and mitochondrial function in the context of personalized theragnostic approaches. Cells have several ways to respond to metabolic stress, including changes in protein localization, density, and degradation, which can promote cell survival. However, disruption of redox homeostasis can lead to oxidative stress and cellular damage, which are implicated in various diseases. Models of oxidative stress and mitochondrial dysfunction should be developed in metabolically conditioned cells to explore the underlying mechanisms of diseases and develop new therapies. By choosing an appropriate cellular model, adjusting cell culture conditions and validating the cellular model, it is possible to identify the most promising therapeutic options and tailor treatments to individual patients. Overall, we highlight the importance of precise and individualized approaches in theragnostics and the need to develop accurate in vitro models that reflect the in vivo conditions.

In prostate cancer (PCa), the use of new radiopharmaceuticals has improved the accuracy of diagnosis and staging, refined surveillance strategies, and introduced specific and personalized radioreceptor therapies. Nuclear medicine, therefore, holds great promise for improving the quality of life of PCa patients, through managing and processing a vast amount of molecular imaging data and beyond, using a multi-omics approach and improving patients' risk-stratification for tailored medicine. Artificial intelligence (AI) and radiomics may allow clinicians to improve the overall efficiency and accuracy of using these "big data" in both the diagnostic and theragnostic field: from technical aspects (such as semi-automatization of tumor segmentation, image reconstruction, and interpretation) to clinical outcomes, improving a deeper understanding of the molecular environment of PCa, refining personalized treatment strategies, and increasing the ability to predict the outcome. This systematic review aims to describe the current literature on AI and radiomics applied to molecular imaging of prostate cancer. [ABSTRACT FROM AUTHOR]