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In the United States, [68Ga]Ga-DOTA-TOC has been approved by the Food and Drug Administration (FDA) in 2019 as the first 68Ga-radiopharmaceutical for imaging of somatostatin receptor (SSTR) positive gastroenteropancreatic neuroendocrine tumors while employing positron emission tomography (PET). In Europe (Austria, Germany, France), [68Ga]Ga-DOTA-TOC was already approved back in 2016. This radiopharmaceutical combines the radionuclide 68Ga with the somatostatin analogue DOTA-TOC for specific imaging of tumor cells expressing SSTRs. Such a targeting approach can also be used for therapy planning in the case of both localized as well as disseminated disease and potentially for the evaluation of treatment response.

Atomic in vivo nanogenerators such as actinium-225, thorium-227, and radium-223 are of increasing interest and importance in the treatment of patients with metastatic cancer diseases. This is due to their peculiar physical, chemical, and biological characteristics, leading to astonishing responses in otherwise resistant patients. Nevertheless, there are still a few obstacles and hurdles to be overcome that hamper the broader utilization in the clinical setting. Next to the limited supply and relatively high costs, the in vivo complex stability and the fate of the recoiling daughter radionuclides are substantial problems that need to be solved. In radiobiology, the mechanisms underlying treatment efficiency, possible resistance mechanisms, and late side effect occurrence are still far from being understood and need to be unraveled. In this review, the current knowledge on the scientific and clinical background of targeted alpha therapies is summarized. Furthermore, open issues and novel approaches with a focus on the future perspective are discussed. Once these are unraveled, targeted alpha therapies with atomic in vivo nanogenerators can be tailored to suit the needs of each patient when applying careful risk stratification and combination therapies. They have the potential to become one of the major treatment pillars in modern cancer management.

IntroductionPSMA-targeted radionuclide therapy with lutetium-177 has emerged as an effective treatment option for metastatic, castration-resistant prostate cancer (mCRPC). Recently, the concept of modifying PSMA radioligands with an albumin-binding entity was demonstrated as a promising measure to increase the tumor uptake in preclinical experiments. The aim of this study was to translate the concept to a clinical setting and evaluate the safety and dosimetry of [177Lu]Lu-PSMA-ALB-56, a novel PSMA radioligand with albumin-binding properties.MethodsTen patients (71.8 ± 8.2 years) with mCRPC received an activity of 3360 ± 393 MBq (120–160 μg) [177Lu]Lu-PSMA-ALB-56 followed by whole-body SPECT/CT imaging over 7 days. Volumes of interest were defined on the SPECT/CT images for dosimetric evaluation for healthy tissue and tumor lesions. General safety and therapeutic efficacy were assessed by measuring blood biomarkers.Results[177Lu]Lu-PSMA-ALB-56 was well tolerated, and no severe adverse events were observed. SPECT images revealed longer circulation of [177Lu]Lu-PSMA-ALB-56 in the blood with the highest uptake in tumor lesions at 48 h post injection. Compared with published data for other therapeutic PSMA radioligands (e.g. PSMA-617 and PSMA I&T), normalized absorbed doses of [177Lu]Lu-PSMA-ALB-56 were up to 2.3-fold higher in tumor lesions (6.64 ± 6.92 Gy/GBq) and similar in salivary glands (0.87 ± 0.43 Gy/GBq). Doses to the kidneys and red marrow (2.54 ± 0.94 Gy/GBq and 0.29 ± 0.07 Gy/GBq, respectively) were increased.ConclusionOur data demonstrated that the concept of albumin-binding PSMA-radioligands is feasible and leads to increased tumor doses. After further optimization of the ligand design, the therapeutic outcomes may be improved for patients with prostate cancer.

The use of radionuclides for targeted endoradiotherapy is a rapidly growing field in oncology. In particular, the focus on the biological effects of different radiation qualities is an important factor in understanding and implementing new therapies. Together with the combined approach of imaging and therapy, therapeutic nuclear medicine has recently made great progress. A particular area of research is the use of alpha-emitting radionuclides, which have unique physical properties associated with outstanding advantages, e.g., for single tumor cell targeting. Here, recent results and open questions regarding the production of alpha-emitting isotopes as well as their chemical combination with carrier molecules and clinical experience from compassionate use reports and clinical trials are discussed.

Prostate-specific membrane antigen (PSMA)-targeted radioligands have been used for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Recently, albumin-binding PSMA radioligands with enhanced blood circulation were developed to increase the tumor accumulation of activity. The present study aimed at the design, synthesis and preclinical evaluation of a novel class of PSMA-targeting radioligands equipped with ibuprofen as a weak albumin-binding entity in order to improve the pharmacokinetic properties. : Four novel glutamate-urea-based PSMA ligands were synthesized with ibuprofen, conjugated via variable amino acid-based linker entities. The albumin-binding properties of the Lu-labeled PSMA ligands were tested using mouse and human plasma. Affinity of the radioligands to PSMA and cellular uptake and internalization was investigated using PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu tumor cells. The tissue distribution profile of the radioligands was assessed in biodistribution and imaging studies using PC-3 PIP/flu tumor-bearing nude mice. : The PSMA ligands were obtained in moderate yields at high purity (>99%). Lu-labeling of the ligands was achieved at up to 100 MBq/nmol with >96% radiochemical purity. assays confirmed high binding of all radioligands to mouse and human plasma proteins and specific uptake and internalization into PSMA-positive PC-3 PIP tumor cells. Biodistribution studies and SPECT/CT scans revealed high accumulation in PC-3 PIP tumors but negligible uptake in PC-3 flu tumor xenografts as well as rapid clearance of activity from background organs and tissues. Lu-Ibu-DAB-PSMA, in which ibuprofen was conjugated via a positively-charged diaminobutyric acid (DAB) entity, showed distinguished tumor uptake and the most favorable tumor-to-blood and tumor-to-kidney ratios. : The high accumulation of activity in the tumor and fast clearance from background organs was a common favorable characteristic of PSMA radioligands modified with ibuprofen as albumin-binding entity. Lu-Ibu-DAB-PSMA emerged as the most promising candidate; hence, more detailed preclinical investigations with this radioligand are warranted in view of a clinical translation.

PurposeThe folate receptor (FR) is frequently overexpressed in a variety of tumor types and, hence, an interesting target for radionuclide therapy. The aim of this study was to evaluate a new class of albumin-binding radioconjugates comprising 5-methyltetrahydrofolate (5-MTHF) as a targeting agent and to compare their properties with those of the previously established folic acid-based [177Lu]Lu-OxFol-1.Methods[177Lu]Lu-6R-RedFol-1 and [177Lu]Lu-6S-RedFol-1 were investigated in vitro using FR-positive KB tumor cells. Biodistribution studies were performed in KB tumor-bearing mice, and the areas under the curve (AUC0 → 120h) were determined for the uptake in tumors and kidneys. [177Lu]Lu-6R-RedFol-1 was compared with [177Lu]Lu-OxFol-1 in a therapy study over 8 weeks using KB tumor-bearing mice.ResultsBoth radioconjugates demonstrated similar in vitro properties as [177Lu]Lu-OxFol-1; however, the tumor uptake of [177Lu]Lu-6R-RedFol-1 and [177Lu]Lu-6S-RedFol-1 was significantly increased in comparison with [177Lu]Lu-OxFol-1. In the case of [177Lu]Lu-6S-RedFol-1, also the kidney uptake was increased; however, renal retention of [177Lu]Lu-6R-RedFol-1 was similar to that of [177Lu]Lu-OxFol-1. This led to an almost 4-fold increased tumor-to-kidney AUC0 → 120h ratio of [177Lu]Lu-6R-RedFol-1 as compared with [177Lu]Lu-6S-RedFol-1 and [177Lu]Lu-OxFol-1. At equal activity, the therapeutic effect of [177Lu]Lu-6R-RedFol-1 was better than that of [177Lu]Lu-OxFol-1, reflected by a slower tumor growth and, consequently, an increased median survival time (49 days vs. 34 days).ConclusionThis study demonstrated the promising potential of 5-MTHF-based radioconjugates for FR-targeting. Application of [177Lu]Lu-6R-RedFol-1 resulted in unprecedentedly high tumor-to-kidney ratios and, as a consequence, a superior therapeutic effect as compared with [177Lu]Lu-OxFol-1. These findings, together with the absence of early side effects, make [177Lu]Lu-6R-RedFol-1 attractive in view of a future clinical translation.

The objective of the article is twofold: first, to employ the knowledge of the recurrence of low-frequency words in authorial texts; and second, to prevent the misuse of this knowledge. Contrary to the prevailing authorship attribution theory and practice (Evert et al. 2017, Juola 2008), our research has revealed that the personal linguistic profile is not primarily composed of frequent words with grammatical functions. Instead, we have identified that a distinct set of full-meaning words defines an individual’s linguistic profile (Faltýnek 2020, Faltýnek – Matlach 2021). An examination of these meanings reveals an individual’s unconscious language habits and, consequently, their personality settings. Such personal profiling is referred to as “deep content” and “deep sentiment analysis”. The innovation in question has the potential to facilitate a novel form of linguistic personalization in digital communication, one that has not been previously observed or utilized. The main aim of this article is to describe the algorithm to conduct single-person linguistic deep content and deep sentiment profiling and personalization. We will describe technical steps to provide such a form of digital communication processing and to facilitate the adjustment of a text targeted at an individual, described as a System and method for adapting text based data structures to text samples (Patent No.: US11797753B2, Faltýnek et al. 2023). This algorithm can be used to (a) produce a personal linguistic profile (analogically to psychometrics instruments such as NEO-FFI Big Five, Minnesota Multiphasic Personality Inventory (MMPI)), (b) target digital communication to an individual by “translating” a text to their language (i.e. linguistic habits) and stimulate desired feelings to a predetermined content. The algorithm is, however, also designed (c) to be used to avoid procedures (a) and (b) using any kind of digital communication platform by an individual. This algorithm is implemented in the software Cloakspeech (Faltýnek – Benešová – Kučera 2025), which provides personalization of AI-generated texts: AI speaks like a particular person.

Background The targeting of the prostate-specific membrane antigen (PSMA) is of particular interest for radiotheragnostic purposes of prostate cancer. Radiolabeled PSMA-617, a 1,4,7,10-tetraazacyclododecane- N , N′ , N′′ , N′′′ -tetraacetic acid (DOTA)-functionalized PSMA ligand, revealed favorable kinetics with high tumor uptake, enabling its successful application for PET imaging ( 68 Ga) and radionuclide therapy ( 177 Lu) in the clinics. In this study, PSMA-617 was labeled with cyclotron-produced 44 Sc ( T 1/2  = 4.04 h) and investigated preclinically for its use as a diagnostic match to 177 Lu-PSMA-617. Results 44 Sc was produced at the research cyclotron at PSI by irradiation of enriched 44 Ca targets, followed by chromatographic separation. 44 Sc-PSMA-617 was prepared under standard labeling conditions at elevated temperature resulting in a radiochemical purity of >97% at a specific activity of up to 10 MBq/nmol. 44 Sc-PSMA-617 was evaluated in vitro and compared to the 177 Lu- and 68 Ga-labeled match, as well as 68 Ga-PSMA-11 using PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu prostate cancer cells. In these experiments it revealed similar in vitro properties to that of 177 Lu- and 68 Ga-labeled PSMA-617. Moreover, 44 Sc-PSMA-617 bound specifically to PSMA-expressing PC-3 PIP tumor cells, while unspecific binding to PC-3 flu cells was not observed. The radioligands were investigated with regard to their in vivo properties in PC-3 PIP/flu tumor-bearing mice. 44 Sc-PSMA-617 showed high tumor uptake and a fast renal excretion. The overall tissue distribution of 44 Sc-PSMA-617 resembled that of 177 Lu-PSMA-617 most closely, while the 68 Ga-labeled ligands, in particular 68 Ga-PSMA-11, showed different distribution kinetics. 44 Sc-PSMA-617 enabled distinct visualization of PC-3 PIP tumor xenografts shortly after injection, with increasing tumor-to-background contrast over time while unspecific uptake in the PC-3 flu tumors was not observed. Conclusions The in vitro characteristics and in vivo kinetics of 44 Sc-PSMA-617 were more similar to 177 Lu-PSMA-617 than to 68 Ga-PSMA-617 and 68Ga-PSMA-11. Due to the almost four-fold longer half-life of 44 Sc as compared to 68 Ga, a centralized production of 44 Sc-PSMA-617 and transport to satellite PET centers would be feasible. These features make 44 Sc-PSMA-617 particularly appealing for clinical application.

Cancer is one of the most complex and challenging human diseases, with rising incidences and cancer-related deaths despite improved diagnosis and personalized treatment options. Targeted alpha therapy (TαT) offers an exciting strategy emerging for cancer treatment which has proven effective even in patients with advanced metastatic disease that has become resistant to other treatments. Yet, in many cases, more sophisticated strategies are needed to stall disease progression and overcome resistance to TαT. The combination of two or more therapies which have historically been used as stand-alone treatments is an approach that has been pursued in recent years. This review aims to provide an overview on TαT and the four main pillars of therapeutic strategies in cancer management, namely external beam radiation therapy (EBRT), immunotherapy with checkpoint inhibitors (ICI), cytostatic chemotherapy (CCT), and brachytherapy (BT), and to discuss their potential use in combination with TαT. A brief description of each therapy is followed by a review of known biological aspects and state-of-the-art treatment practices. The emphasis, however, is given to the motivation for combination with TαT as well as the pre-clinical and clinical studies conducted to date.

Background Prostate-specific membrane antigen (PSMA) is an established target for the imaging and treatment of prostate cancer. This study focused on the preclinical evaluation of three novel PSMA inhibitors—P15, P16, and P19—which were structurally modified compared to the clinically used PSMA-617. Two main strategies were pursued: a chemical approach following the so-called reversed synthetic strategy, and the replacement of the naphthyl-based linker moiety with an analogous diphenyl-based moiety. The aim was to assess the impact of these modifications on physicochemical properties, in vitro behaviour, and in vivo pharmacokinetics following radiolabelling with ⁶⁸Ga. Results Radiolabelling of all three novel compounds with ⁶⁸Ga resulted in high radiochemical purity above 98% under physiological pH conditions and above 97% during stability testing in human plasma. All compounds exhibited hydrophilic characteristics based on partition coefficient measurements. Notable differences were observed in plasma protein binding, with P15 and P16 showing significantly lower binding compared to PSMA-617 and P19. In vitro assays using LNCaP prostate cancer cells demonstrated similar cellular uptake and internalization across all tested compounds. In vivo evaluation using Positron Emission Tomography/Computed Tomography (PET/CT) imaging in LNCaP tumour-bearing mice confirmed the tumour-targeting ability of all three inhibitors. These findings were further supported by biodistribution studies, which highlighted efficient and specific accumulation in tumour tissue. Among the tested compounds, P19 demonstrated the most promising overall profile in terms of stability, binding characteristics, and tumour uptake. Conclusions The stereochemical modifications in the linker region significantly influenced the in vitro and in vivo behaviour of the PSMA inhibitors. Despite similar cellular uptake, differences in plasma protein binding and pharmacokinetics were evident. Among the three novel compounds, P19 emerged as a particularly promising candidate for further investigation, also indicating that the diphenyl moiety might serve as a favourable linker building block in analogy to the naphthyl moiety. Our observations suggest potential not only for diagnostic imaging with ⁶⁸Ga, but also for therapeutic applications using 177 Lu, which offers a longer half-life suitable for delayed imaging and treatment intervals in prostate cancer management.