Lu-177 PSMA vs Comparator Treatments and Survival in Metastatic Castration-Resistant Prostate Cancer.

Importance: Observed treatment effects on overall survival (OS) differed substantially in the first 2 randomized clinical trials of lutetium Lu 177 vipivotide tetraxetan (Lu-177) prostate-specific membrane antigen (PSMA) in metastatic castration-resistant prostate cancer. Objective: To investigate factors associated with the observed difference in treatment effects on OS, including differences in the risk of crossover from randomized treatment after disease progression. Design, Setting, and Participants: This comparative effectiveness study used individual participant data from 2 randomized clinical trials, TheraP (A Randomised Phase 2 Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer [ANZUP Protocol 1603]) (n = 200), recruited from February 2018 to September 2019 in Australia, and published data from VISION (An International, Prospective, Open Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients With Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer) (n = 831), recruited from June 2018 to October 2019 in North America and Europe. Individual participant data for OS were reconstructed from VISION using the published survival curves. Data were analyzed February 6, 2018, to December 31, 2021, for TheraP and June 4, 2018, to January 27, 2021, for VISION. Interventions: TheraP randomized participants to receive treatment with Lu-177 PSMA or cabazitaxel. VISION randomized participants to receive treatment with or without Lu-177 PSMA in addition to physicians' choice of protocol-permitted treatments (PPT; approved hormonal treatments [such as abiraterone and enzalutamide], bisphosphonates, radiotherapy, denosumab, or glucocorticoids), excluding cabazitaxel. Main Outcomes and Measures: Patient characteristics, treatment protocols, and OS outcomes of the 2 trials were compared. Estimates of the effect on OS from TheraP were adjusted for crossover from randomly assigned treatment using a rank-preserving structural failure time model (RPSFTM) and inverse probability of censoring weights (IPCW) methods. Results: The 200 participants in TheraP and 831 participants in VISION were similar in age (median [range], 72 [49-86] vs 71 [40-94] years). Improved OS was observed in the comparator treatment group (cabazitaxel) in TheraP compared with VISION (PPT) (hazard ratio [HR], 0.53 [95% CI, 0.39-0.71]). The Lu-177 PSMA treatment groups in TheraP and VISION had similar OS (HR, 0.92 [95% CI, 0.70-1.19]). In TheraP, 20 of 101 participants in the cabazitaxel group crossed over to Lu-177 PSMA, while 32 of 99 participants in the Lu-177 PSMA arm crossed over to cabazitaxel. No statistically significant differences in OS between the Lu-177 PSMA and cabazitaxel groups of TheraP were observed after controlling for crossover to cabazitaxel: RPSFTM HR, 0.97 (95% CI, 0.60-1.58); IPCW HR, 0.92 (95% CI, 0.65-1.32); RPSFTM HR, 0.97 (95% CI, 0.60-1.58) and IPCW HR, 0.82 (95% CI, 0.54-1.24) for crossover to Lu-177 PSMA; RPSFTM HR, 0.96 (95% CI, 0.53-1.74) and IPCW HR, 0.82 (95% CI, 0.53-1.27) for crossover to either Lu-177 PSMA or cabazitaxel. Conclusions and Relevance: Findings of this secondary analysis of the TheraP and VISION randomized clinical trials suggest that the choice of comparator treatments (ie, cabazitaxel vs PPT) may explain the difference in the observed effect of Lu-177 PSMA on OS between the 2 trials. Causal inference methods such as RPSFTM and IPCW may help rule out crossover as a plausible explanation.

Adaptation of FDMT to include process-based models and consider regional aspects following radionuclide deposition events.

Experience from earlier nuclear accidents has clearly shown the need for maintaining and developing appropriate modelling capabilities. Dealing with complex issues such as human exposure following a nuclear accident necessitates the implementation of a set of interconnected models such as FDMT. FDMT is an integrated module within the two main European decision support systems for radiological emergency preparedness, ARGOS and JRODOS, to simulate the transfer of radionuclides along terrestrial food chains and to predict their activity concentrations in foodstuffs. In order to make the module more fit-for-purpose, FDMT has been implemented in a new modelling platform (ECOLEGO) which provides a high degree of flexibility with regard to conducting developmental work. This paper presents improvements in FDMT further through either the incorporation of new models or further elaboration of existing ones, as well as updates in default parameters. Models have also been made more fit-for-purpose through consideration of regional-specific parameters. Specific improvements include modelling developments related to dry deposition, radioactive particle weathering, radiocaesium transfer influenced by soil characteristics and, for a region-specific case, animal uptake. In addition, the paper presents new pathways and parameters (and updated values) to be considered for making FDMT more adapted for Norwegian conditions. Overall, the improvements made in the present work should significantly reduce the uncertainties associated with the outputs of the FDMT models.

Dose-rate coefficients for external exposure to radionuclides uniformly distributed in soil to an infinite depth.

Using a database on external exposures to environmental sources provided by the International Commission on Radiological Protection, monoenergetic and nuclide-specific dose-rate coefficients have been evaluated for volumetric sources with a uniform distribution to an effectively infinite depth in soil. Organ equivalent and effective dose rates for the public (newborns; 1-, 5-, 10-, and 15-year-old children; and adults), ambient dose equivalent rates, and air kerma free-in-air rates at 1 m above the ground were computed. This was performed using the weighted-integral method for monoenergetic photon and electron sources in an energy region of 10-2 to 8 MeV with 25 energy points to obtain the respective monoenergetic dose-rate coefficients. Then, based on these data, the dose-rate coefficients for 1252 radionuclides of 97 elements were evaluated. In those computations, the dose contribution from bremsstrahlung generated by electrons in the soil was also considered. In addition, dose-rate coefficients for the primordial radioactive decay chains of the thorium, uranium, and actinium series, as well as the decay of 137Cs with 137mBa in secular radioactive equilibrium, were obtained using the Bateman equation. For verification, the results of the effective dose rates for the 40K, 50V, thorium, and uranium series, as well as 137Cs/137mBa, were compared with those of previous studies and agreed within 10% for most cases. The results showed that the present dose-rate coefficients for radionuclides uniformly distributed to an infinite depth in soil were computed using appropriate procedures and can be used to assess external doses to the public, living on landfill soils containing naturally occurring radionuclides.

Lutetium-177-PSMA therapy for recurrent/metastatic salivary gland cancer: a prospective pilot study.

There is an urgent need for novel systemic therapies for recurrent/systemic salivary gland cancer, as current treatment options are scarce. [68Ga]Ga-PSMA-11 PET/CT revealed relevant uptake of prostate-specific membrane antigen (PSMA) in adenoid cystic carcinoma (AdCC) and salivary duct carcinoma (SDC). Therefore, we assessed the safety, feasibility, efficacy and radiation dosimetry of [177Lu]Lu-PSMA-I&T treatment in AdCC and SDC patients in a prospective pilot study. Methods: This single-center, single-arm study intended to include 10 recurrent/metastatic AdCC patients and five recurrent/metastatic SDC patients. AdCC patients could only participate in case of progressive and/or symptomatic disease. Patients required ≥ 1 lesion ≥ 1.5 cm with an SUVmax on [68Ga]Ga-PSMA-11 PET/CT above liver SUVmean. Patients were planned to receive four cycles ~ 7.4 GBq [177Lu]Lu-PSMA-I&T. In case of progressive disease per RECIST 1.1 at mid-treatment evaluation after two cycles, treatment was discontinued. Safety was the primary endpoint. Secondary endpoints included objective response rate (ORR), tumor- and organ-absorbed radiation doses and progression-free survival. Results: After screening, 10 out of 15 (67%) AdCC and two out of 10 (20%) SDC patients were eligible. Two patients (17%) demonstrated grade 3 treatment-related toxicity: lymphocytopenia (8%) and hyponatremia (8%). No dose-limiting toxicities occurred. In the AdCC cohort, six patients (60%) completed the four treatment cycles. Due to progressive disease, treatment was discontinued after two cycles in three patients (30%) and after one cycle in one patient (10%). No objective responses were observed (ORR: 0%). Three AdCC patients (30%) showed stable disease ≥ 6 months (7, 17 and 23 months). None of the two SDC patients completed the treatment: one patient deteriorated after the first cycle, while the other had progressive disease after two cycles. The high screen failure rate due to insufficient PSMA uptake resulted in premature closure of the SDC cohort. Dosimetry revealed low tumor-absorbed doses (median 0.07 Gy/GBq, range 0.001-0.63 Gy/GBq). Conclusions: [177Lu]Lu-PSMA-I&T in AdCC and SDC patients was safe and generally well-tolerated. However, efficacy was limited, likely due to low tumor-absorbed doses. For SDC, [177Lu]Lu-PSMA-I&T appears unfeasible due to insufficient PSMA uptake.

Advances in prostate cancer treatment: Radionuclide therapy for prostate cancer.

The optimal treatment of metastatic castration-resistant prostate cancer (mCRPC) continues to be challenging, given the multitude of life prolonging treatment options. Radionuclide therapy delivers concentrated doses of radiation via ionizing particles chelated to ligands or antibody-based molecules with specific tumor targets and is approved for patients with treatment resistant mCRPC. Variations of radionuclide therapies within the continuum of prostate cancer treatment are being investigated. Landmark phase III clinical trials of beta-emitting 177Lu-PSMA radionuclide therapy have demonstrated the utility of 177Lu-PSMA in the treatment of mCRPC. Further research into alpha-emitting radionuclide therapy and vectors may provide alternative treatments for patients with treatment resistant mCRPC. As radionuclide therapy treatment options evolve, assessing appropriate patient selection for radionuclide therapy is important and may be facilitated by advances in imaging and blood-based biomarkers. Exploration of other approved life prolonging therapies in combination with radionuclide therapy has shown increasing interest as a potential method of combatting radionuclide therapy resistance. In this chapter, we review various types of radionuclide therapies for mCRPC, patient selection for radionuclide therapy from outcome predictions, ongoing clinical trials of radiopharmaceuticals for treatment of prostate cancer, and the resistance mechanisms and challenges to radionuclide therapy.

Concentrations of radionuclides and trace elements in wetlands.

Environmental risks in wetlands are considered with radionuclides and trace elements to understand pollution accumulation. In this study, we aimed to determine the levels of radiation and heavy metals in water systems and assess pollution configurations. Radionuclides (222Rn, 210Pb and 210Po) and trace elements (Ag, As, Ba, Be, Cd, Co, Cr, Cu, Fe, Li, Mo, Ni, Pb, V and Zn) were measured to evaluate anthropogenic factors. Water pollution in wetlands was indicated by mean concentrations of 66.2 mBq/L for 222Rn, 3 mBq/L for 210Pb, 42 mBq/L for 210Po, 41 ppb for Zn, 37 ppb for Ba, 190 ppb for Fe and 481 ppb for Sr. These pollutants may be related to industrial facilities in Kirklareli city, Türkiye.

Early treatment response assessment with [177Lu]PSMA whole-body-scintigraphy compared to interim PSMA-PET.

BACKGROUND: Prostate-specific membrane antigen positron emission tomography (PSMA-PET) is an essential tool for patient selection before radioligand therapy (RLT). Interim-staging with PSMA-PET during RLT allows for therapy monitoring. However, its added value over post-treatment imaging is poorly elucidated. The aim of this study was to compare early treatment response assessed by post-therapeutic whole-body scans (WBS) with interim-staging by PSMA-PET after 2 cycles in order to prognosticate OS. METHODS: Men with metastasized castration-resistant PC (mCRPC) who had received at least two cycles of RLT, and interim PSMA-PET were evaluated retrospectively. PROMISE V2 framework was used to categorize PSMA expression and assess response to treatment. Response was defined as either disease control rate (DCR) for responders or progression for non-responders. RESULTS: A total of 188 men with mCRPC who underwent RLT between February 2015 and December 2021 were included. The comparison of different imaging modalities revealed a strong and significant correlation with Cramer V test: e.g. response on WBS during second cycle compared to interim PET after two cycles of RLT (cφ = 0.888, P < 0.001, n = 188). The median follow-up time was 14.7 months (range: 3-63 months; 125 deaths occurred). Median overall survival (OS) time was 14.5 months (95% CI: 11.9-15.9). In terms of OS analysis, early progression during therapy revealed a significantly higher likelihood of death: e.g. second cycle WBS (15 vs. 25 months, P < 0.001) with a HR of 2.81 (P < 0.001) or at PET timepoint after 2 cycles of RLT (11 vs. 24 months, P < 0.001) with a HR of 3.5 (P < 0.001). For early biochemical response, a PSA decline of at least 50% after two cycles of RLT indicates a significantly lower likelihood of death (26 vs. 17 months, P < 0.001) with a HR of 0.5 (P < 0.001). CONCLUSION: Response assessment of RLT by WBS and interim PET after two cycles of RLT have high congruence and can identify patients at risk of poor outcome. This indicates that interim PET might be omitted for response assessment, but future trials corroborating these findings are warranted.

Standard Safety Procedure Before Therapeutic Administration of 223Ra-Dichloride.

223Ra-dichloride is an α-emitter therapy approved for the treatment of castration-resistant prostate cancer with symptomatic bone metastases. 223Ra-dichloride is the first targeted α-therapy for this indication with evidence of benefit in overall survival. The administration is intravenous, and extravasation can cause severe injuries such as tissue necrosis. To prevent this side effect, some procedures can be performed according to the guideline of the European Association of Nuclear Medicine. Ionizing radiation is a well-established risk factor for the development of cutaneous squamous cell carcinoma, but surprisingly there are few reports of local adverse effects related to extravasation of radiotherapies at the injection sites. Recently, a possible case of cutaneous cancer was observed after 223Ra-dichloride extravasation. Methods: To complement the prevention of extravasation, we developed a standardized technique to be performed before the injection of 223Ra. Results: Our technique was successfully applied to the study population, and no apparent extravasation was seen. Conclusion: Our study suggests that use of this standardized technique before administration of 223Ra is helpful in preventing extravasation during this treatment.

Development and preclinical characterization of a novel radiotheranostic EphA2-targeting bicyclic peptide.

Erythropoietin-producing hepatocellular receptor A2 (EphA2), is a receptor tyrosine kinase involved in cell-cell interactions. It is known to be overexpressed in various tumors and is associated with poor prognosis. EphA2 has been proposed as a target for theranostic applications. Low molecular weight peptide-based scaffolds with low nanomolar affinities have been shown to be ideal in such applications. Bicyclic peptides have emerged as an alternative to traditional peptides for this purpose, offering affinities comparable to antibodies due to their constrained nature, along with high tissue penetration, and improved stability compared to linear counterparts. This study presents the development and comprehensive in vitro and in vivo preclinical evaluation of BCY18469, a novel EphA2-targeting bicyclic peptide-based radiotheranostic agent. Methods: The EphA2-targeting Bicycle® peptide BCY18469 was identified through phage-display and chemically optimized. BCY18469 was radiolabeled with 68Ga, 177Lu and 111In. The physicochemical properties, binding affinity and internalization as well as specificity of the peptide were evaluated in vitro. In vivo PET/MR and SPECT/CT imaging studies were performed using [68Ga]Ga-BCY18469 and [111In]In-BCY18469, respectively, along with biodistribution of [177Lu]Lu-BCY18469 up to 24 h post injection in HT1080- and PC-3-tumor bearing BALB/c nu/nu EphA2-overexpressing xenograft mouse models. Results: The EphA2-targeting bicyclic peptide BCY18469 showed high binding affinity toward human and mouse EphA2 (1.9 and 3.8 nM, respectively). BCY18469 specifically bound and internalized into EphA2-expressing HT1080 cells. Imaging studies showed high tumor enrichment at early time-points (SUV of 1.7 g/mL at 1 h p.i. and 1.2 g/mL at 2 h p.i. in PET/MRI, HT1080 xenograft) with tumor contrast as early as 5 min p.i. and kidney-mediated clearance. Biodistribution studies revealed high early tumor uptake (19.5 ± 3.5 %ID/g at 1 h p.i., HT1080 xenograft) with SPECT/CT imaging further confirming these findings (5.7 ± 1.5 %ID/g at 1 h p.i., PC-3 xenograft). Conclusion: BCY18469 demonstrated high affinity, specific targeting of EphA2, a favorable biodistribution profile, and clearance through renal pathways. These findings underscore the potentially important role of bicyclic peptides in advancing radiotheranostic approaches and encourage additional translational research.

Radiolabeled Probes from Derivatives of Natural Compounds Used in Nuclear Medicine.

Natural compounds are important precursors for the synthesis of new drugs. The development of novel molecules that are useful for various diseases is the main goal of researchers, especially for the diagnosis and treatment of many diseases. Some pathologies need to be treated with radiopharmaceuticals, and, for this reason, radiopharmaceuticals that use the radiolabeling of natural derivates molecules are arousing more and more interest. Radiopharmaceuticals can be used for both diagnostic and therapeutic purposes depending on the radionuclide. ß+- and gamma-emitting radionuclides are used for diagnostic use for PET or SPECT imaging techniques, while α- and ß--emitting radionuclides are used for in metabolic radiotherapy. Based on these assumptions, the purpose of this review is to highlight the studies carried out in the last ten years, to search for potentially useful radiopharmaceuticals for nuclear medicine that use molecules of natural origin as lead structures. In this context, the main radiolabeled compounds containing natural products as scaffolds are analyzed, in particular curcumin, stilbene, chalcone, and benzofuran. Studies on structural and chemical modifications are emphasized in order to obtain a collection of potential radiopharmaceuticals that exploit the biological properties of molecules of natural origin. The radionuclides used to label these compounds are 68Ga, 44Sc, 18F, 64Cu, 99mTc, and 125I for diagnostic imaging.

In-depth cross-validation of human and mouse CD4-specific minibodies for noninvasive PET imaging of CD4+ cells and response prediction to cancer immunotherapy.

Increasing evidence emphasizes the pivotal role of CD4+ T cells in orchestrating cancer immunity. Noninvasive in vivo imaging of the temporal dynamics of CD4+ T cells and their distribution patterns might provide novel insights into their effector and regulator cell functions during cancer immunotherapy (CIT). Methods: We conducted a comparative analysis of 89Zr-labeled anti-mouse (m) and anti-human (h) CD4-targeting minibodies (Mbs) for in vivo positron emission tomography (PET)/magnetic resonance imaging (MRI) of CD4+ T cells in human xenografts, syngeneic tumor-bearing wild-type (WT), and human CD4+ knock-in (hCD4-KI) mouse models. Results: Both 89Zr-CD4-Mbs yielded high radiolabeling efficiencies of >90%, immunoreactivities of >70%, and specific in vitro binding to their target antigens. The specificity of in vivo targeting of 89Zr-hCD4-Mb was confirmed by PET/MRI, revealing ~4-fold greater 89Zr-hCD4-Mb uptake in subcutaneous hCD4+ hematopoietic peripheral blood acute lymphoblastic leukemia tumors (HPB-ALL) than in solid hCD4- diffuse histiocytic lymphomas (DHL) and 89Zr-mCD4-Mb uptake in hCD4+ HPB-ALL tumors. In a comparative cross-validation study in anti-programmed death ligand (αPD-L1)/anti-4-1BB-treated orthotopic PyMT mammary carcinoma-bearing hCD4-KI and WT mice, we detected 2- to 3-fold enhanced species-specific 89Zr-hCD4-Mb or 89Zr-mCD4-Mb uptake within CD4+ cell-enriched secondary lymphatic organs (lymph nodes and spleens). The 89Zr-hCD4-Mb uptake in the PyMT tumors was more pronounced in hCD4-KI mice compared to the WT control littermates. Most importantly, MC38 adenocarcinoma-bearing mice treated with a combination of αPD-L1 and anti-lymphocyte-activation gene 3 (αLag-3) antibodies exhibited ~1.4-fold higher 89Zr-mCD4-Mb uptake than mice that were not responsive to therapy or sham-treated mice. Conclusion: CD4 PET/MRI enabled monitoring of the CD4+ cell distribution in secondary lymphatic organs and the tumor microenvironment, capable of predicting sensitivity to CIT. Our imaging approach will provide deeper insights into the underlying molecular mechanisms of CD4-directed cancer immunotherapies in preclinical mouse models and is applicable for clinical translation.

177Lu-labeling of nuclear localization sequence (NLS)-grafted HER2-receptor affine peptide.

Tagging of cell permeable nuclear localization sequence (NLS) with receptor targeting peptide vectors is an attractive strategy for selectively targeted translocation of therapeutic cargoes. The present study aimed at grafting nuclear localization sequence (NLS) onto breast cancer targeting rL-A9 peptide. Molecular docking analysis revealed higher binding affinity of the peptide, DOTA-NLS-rL-A9 (-26.1 kJ/mol) towards HER2 receptor in comparison to DOTA-rL-A9 peptide (-22.2 kJ/mol). Confocal microscopy data suggested significantly enhanced cellular internalization of NLS-tagged peptide. The engineered HER2-selective, DOTA-NLS-rL-A9 peptide scaffold was radiolabeled with Lu-177 for intracellular delivery of the theranostic radionuclide into tumor cells. [177Lu]Lu-DOTA-NLS-rL-A9 exhibited significantly enhanced binding affinity (4.58 ± 1.77 nM) towards human breast carcinoma SKBR3 cells and cellular internalization (85 % at 24 h) compared to its original analog, [177Lu]Lu-DOTA-rL-A9. In vivo biodistribution studies showed consistent retention of [177Lu]Lu-DOTA-NLS-rL-A9 in the tumor with negligible washout of radioactivity (∼4.1 % ID/g at 48 h). Prolonged tumor activity with rapid off-target tissue clearance resulted in significantly high tumor-to-background ratios. The radiopeptide, [177Lu]Lu-DOTA-NLS-rL-A9 thus, being precisely confined into HER2-expressing tumor cells and exhibiting favourable pharmacokinetic features is an efficient candidate for further screening.

Radionuclide Solid:liquid partitioning in an aged, reducing-grout wasteform recovered from a disposal facility.

The Saltstone Disposal Facility on the Savannah River Site in South Carolina disposes of Low-Level Waste in a reducing-grout waste form. Reducing grout is presently being evaluated as a subsurface disposal waste form at several other locations in the United States, as well as in Europe and Asia. The objective of this study was to collect core samples directly from the Saltstone Disposal Facility and measure desorption distribution coefficients (Kd; radionuclide concentration ratio of saltstone:liquid; (Bq/kg)/Bq/L)) and desorption apparent solubility values (ksp; radionuclide aqueous concentration (moles/L)). An important attribute of this study was that these tests were conducted with actual aged, grout waste form materials, not small-volume simulants prepared in a laboratory. The reducing grout is comprised of blast furnace slag, Class F fly ash, ordinary portland cement, and a radioactive salt waste solution generated during nuclear processing. The grout sample used in this study underwent hydrolyzation in the disposal facility for 30 months prior to measuring radionuclide leaching. Leaching experiments were conducted either in an inert (no oxygen) atmosphere to simulate conditions within the saltstone monolith prior to aging (becoming oxidized) or they were exposed to atmosphere conditions to simulate conditions of an aged saltstone. Importantly, these experiments were designed not to be diffusion limited, that is, the saltstone was ground finely and the suspensions were under constant agitation during the equilibration period. Under oxidized conditions, measured Tc Kd values were 10 mL/g, which was appreciably greater than the historical best-estimate value of 0.8 mL/g. This difference is likely the result of a fraction of the Tc remaining in the less soluble Tc(IV) form, even after extensive oxidation during the experiment. Under oxidized and reducing conditions, the measured Ba and Sr (both divalent alkaline earth metals) Kd value were more than an order of magnitude greater than historical best-estimate values of 100 mL/g. The unexpectedly high Ba and Sr Kd values were attributed to these radionuclides having sufficient time to age (form strong bonds) in the sulfur-rich saltstone sample. Apparent ksp values under reducing conditions were 10-9 mol/L Tc and 10-13 mol/L Pu, consistent with values measured with surrogate materials. Measured apparent Ba, Sr, and Th ksp values were significantly greater than historical best-estimates. The implications of the generally greater Kd values and lower ksp values in these measurements is that these cementitious waste forms have greater radionuclide retention than was previously estimated based on laboratory studies using surrogate materials. This work represents the first leaching study performed with an actual aged, reducing-grout sample and as such provides an important comparison to studies conducted with surrogate materials, and provides high pedigree data for other programs around the world evaluating reducing grouts as a wasteform for subsurface nuclear waste disposal.

Research on the influencing factors of radionuclide fractionation in surface nuclear explosions.

Fractionation plays an important role in the distribution of radioactive isotopes on particles formed in a nuclear explosion. This study examines the variables that affect radionuclide fractionation in surface nuclear explosions, including nuclear explosion yield, nuclear charge, solidification temperature, solidification time, and geological condition. The distribution of radionuclides is calculated using the improved Freiling radial-distribution model and the Bateman equation to describe radionuclide decay. Quantitative analysis is conducted to examine the impact of various influencing factors on the total ß radioactivity. Specifically, the mass chains 89 and 137, as well as mass chains 95 and 144, which represent the radioactive surface and volume distributions are investigated respectively. The results show that the total ß radioactivity increases as the explosion yield increases and as the solidification temperature decreases, and increases slightly as the solidification time increases. The radioactivity will concentrate more on the larger size particles under harder geological conditions. The influencing factors have greater impacts on the radioactive volume distributions than on the surface distributions, and the variations in distinct mass chains under the same influencing factors are inconsistent. Overall, the solidification temperature and the geological condition have significant impacts on the distribution of particle radioactivity, followed by the effects of explosion yield and nuclear charge. The distribution of particle radioactivity is not significantly affected by the solidification time.

Therapeutic response and safety of radioligand therapy with 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer patients.

Prostate cancer is one of the most common cancers and leading cause of death due to cancer across the globe. This persuaded researchers to devise innovative treatment modalities that may prove effective, safe, and demonstrate better outcomes in terms of patient morbidity and survival. The advancement in theranostics such as lutetium-177 (177Lu)-PSMA-617 radioligand therapies can target prostate cancer cells causing negligible or no damage to most of the normal tissues in patients. It has been proven to effectively improve the quality of life and progression-free survival. In this study, stage IV metastatic castration-resistant prostate cancer patients were treated with 177Lu-PSMA-617, and the therapeutic response and safety of 177Lu-PSMA-617 radioligand therapy were evaluated six months after the treatment. Additionally, molecular docking studies were also conducted to find the possible mechanism at the molecular level that causes the effectiveness of 177Lu-PSMA-617 in prostate cancer.

Analysis of the effect of citrate on radionuclide retention on portlandite.

We analysed how citrate (CIT), a chelating agent potentially present in radioactive waste disposals, affects the mobility of four radionuclides (RN): 63Ni, 233U, 152Eu, 238Pu in portlandite, an important hydrated phase of cement, a commonly used material for waste isolation. Portlandite was synthetized in the laboratory and showed high purity and grain size of few µm. This solid, buffers the pH to 12.5 and shows high adsorption capability for the studied RNs: 152Eu and 238Pu exhibited the highest adsorption (Kd ∼1·105 mL g-1) and 233U the lowest (Kd ∼8·102 mL g-1). CIT adsorption was also experimentally evaluated by batch sorption experiments and electrophoretic (ζ-potential) measurements: a non-lineal sorption behaviour was observed, with Kd values decreasing (from ∼1·103 mL g-1) as CIT concentration increased up to 1·10-2 M, according to portlandite sorption sites saturation. In the presence of CIT, a marginal decrease for 233U adsorption in portlandite was observed, one order of magnitude reduction for 63Ni, while 238Pu and 152Eu adsorption decreased significantly. The calculated sorption reduction factors (SRF) for the four RN in the presence of CIT at a concentration of 5·10-3 M were: 2.4, 9.7, 37 and 50.9 for 233U, 63Ni, 238Pu, and 152Eu, respectively. According to the available thermodynamic databases, low complexation between CIT and RN is predicted at pH = 12.5, thus the RN adsorption decrease in the presence of CIT must be attributed to the organic adsorption on portlandite. However, current thermodynamic are still incomplete for this ligand and this pH range and this limits a precise interpretation of the experimental data.

Assessment of the mobility of potentially toxic trace elements (PTEs) and radionuclides released in soils stabilized with mixtures of bentonite-lime-phosphogypsum.

Phosphogypsum (PG) is a solid by-product of the phosphate industry, rich in contaminants and produced in large quantities. Raw materials and stabilized specimens, consisting of bentonite-lime-PG mixtures, were characterized by mineralogical, microstructural, chemical, alpha-particle, and gamma-ray spectrometry analysis before hydration and after hardening. Compressive strength and leaching tests were performed on hardened specimens. The physicochemical parameters and chemical composition of leachates from raw materials and hardened specimens were determined. PG contains high concentrations of natural radionuclides, specially from U series. Uranium-238 activities are double in PG than the worldwide average for soil values. The mobility of PTEs from PG is Cd (2.43%), Zn (2.36%), Ni (2.07%), Cu (1.04%), Pb (0.25%), and As (0.21%). Cadmium is the cation most easily released by PG in water with a concentration 0.0316 mg kg-1. When PG is added to bentonite-lime mixture, cadmium is no longer released. The radionuclide 238,234U and 210Po predominates in the leachates of PG. However, the activity of 210Po becomes negligible in the leachates of bentonite-lime-PG mixtures. The addition of PG to bentonite-lime mixtures facilitates the trapping of trace elements (PTEs) and radionuclides, providing potential applications for PG as road embankments and fill coatings.

Efficient internalization of nano architectured 177Lu-hyaluronic acid@ zirconium-based metal-organic framework for the treatment of neuroblastoma: Unravelling toxicity, stability, radiolabelling and bio-distribution.

Zirconium-based metal-organic frameworks (UiO-66) have gained considerable attention owing to their versatile application. In the present research, UiO-66 was synthesized via a defect engineering approach, and its toxicity profile was explored. The synthesized nanomaterial was extensively characterized via spectroscopic methods such as FTIR and Raman spectroscopy, which confirmed the formation of the framework. X-ray diffraction (XRD) and transmission electron microscopy (TEM) were used to determine the crystallinity, shape and size of the nanoformulations. Thermal gravimetric analysis, 1H NMR spectroscopy and Brunauer-Emmett-Teller (BET) surface area analysis were used to identify the differences between pristine and defective UiO-66. Furthermore, the synthesized MOF was exposed to various pH conditions, serum protein and DMEM. Drug loading and release studies were evaluated using 5-fluorouracil as a model anticancer drug. The synthesized MOFs were modified with hyaluronic acid via mussel-inspired polymerization to increase their uptake and stability. More importantly, the toxicity of the nanoformulation was investigated via various toxicity studies, such as hemolysis assays and cell viability assays, and was further supported by in vivo acute and subacute toxicity data obtained from Wistar rats. Radiolabelling and bio-distribution studies were also performed using 177Lu to explore the bio-distribution profile of UiO-66.

Investigation of the Impact of the H310A FcRn Region Mutation on 89Zr-Immuno-PET Brain Imaging with a BBB-Shuttle Anti­Amyloid Beta Antibody.

PURPOSE: In the emerging field of antibody treatments for neurodegenerative diseases, reliable tools are needed to evaluate new therapeutics, diagnose and select patients, monitor disease progression, and assess therapy response. Immuno-PET combines the high affinity and exceptional specificity of monoclonal antibodies with the non-invasive imaging technique positron emission tomography (PET). Its application in neurodegenerative disease brain imaging has been limited due to the marginal uptake across the blood-brain barrier (BBB). The emergence of BBB-shuttle antibodies with enhanced uptake across the BBB extended immuno-PET to brain imaging. We recently reported about specific brain uptake of a bispecific aducanumab mTfR antibody in APP/PS1 TG mice using 89Zr-immuno-PET. However, a sufficient target-to-background ratio was reached at a relatively late scanning time point of 7 days post-injection. To investigate if a better target-to-background ratio could be achieved earlier, an aducanumab BBB-shuttle with a mutated Fc region for reduced FcRn affinity was evaluated. PROCEDURES: AduH310A-8D3 and Adu-8D3 were modified with DFO*-NCS and subsequently radiolabeled with 89Zr. The potential influence of the H310A mutation, modification with DFO*-NCS, and subsequent radiolabeling on the in vitro binding to amyloid-beta and mTfR1 was investigated via amyloid-beta peptide ELISA and FACS analysis using mTfR1 transfected CHO-S cells. Blood kinetics, brain uptake, in vivo PET imaging and target engagement of radiolabeled AduH310A-8D3 were evaluated and compared to non-mutated Adu-8D3 in APP/PS1 TG mice and wild-type animals as controls. RESULTS: Radiolabeling was performed with sufficient radiochemical yields and radiochemical purity. In vitro binding to amyloid-beta and mTfR1 showed no impairment. [89Zr]Zr-AduH310A-8D3 showed faster blood clearance and earlier differentiation of amyloid-beta-related brain uptake compared to [89Zr]Zr-Adu-8D3. However, only half of the brain uptake was observed for [89Zr]Zr-AduH310A-8D3. CONCLUSIONS: Although a faster blood clearance of AduH310A-8D3 was observed, it was concluded that no beneficial effects for 89Zr-immuno-PET imaging of brain uptake were obtained.

Zirconium- 89 Labeled Antibody K1-70 for PET Imaging of Thyroid-stimulating Hormone Receptor Expression in Thyroid Cancer.

PURPOSE: Thyroid-stimulating hormone receptor (TSHR) is a G-protein coupled receptor that is highly expressed on benign and malignant thyroid tissues. TSHR binding and activation has long been a component of thyroid cancer molecular imaging and radiotherapy, by promoting expression of the sodium-iodide symporter (NIS) and incorporation of I-131 into thyroid hormones. Here, we report the radiosynthesis and preclinical evaluation of a Zirconium-89 (89Zr) labeled TSHR antibody to serve as a positron emission tomography (PET) diagnostic correlate for therapeutic agents targeting TSHR without reliance on NIS. PROCEDURES: TSHR human monoclonal antibody K1-70 was conjugated to chelator desferrioxamine-p-benzyl-isothiocyanate, followed by labeling with Zr-89, yielding the radiotracer 89Zr-DFO-TSHR-Ab. The in vitro cellar uptake and binding affinity of 89Zr-DFO-TSHR-Ab were analyzed in three new TSHR stable overexpressing tumor cell lines and their corresponding wild types (WT) with low or no TSHR expression. 89Zr-DFO-TSHR-Ab PET/CT imaging of TSHR expression was evaluated in tumor mouse models bearing one TSHR-positive tumor and other negative control with or without the coinjection of antibody K1-70, and then verified by radiotracer biodistribution study and tumor immunohistochemistry (IHC). RESULTS: The conjugate DFO-TSHR-Ab was labeled with Zr-89 at 37 °C for 60 min and purified by PD-10 column in radiochemical yields of 68.8 ± 9.9%, radiochemical purities of 98.7 ± 0.8%, and specific activities of 19.1 ± 2.7 mCi/mg (n = 5). In vitro cell studies showed 89Zr-DFO-TSHR-Ab had significantly high uptake on TSHR expressing tumor cells with nanomolar affinity and high potency. Preclinical PET/CT imaging revealed that 89Zr-DFO-TSHR-Ab selectively detected TSHR expressing thyroid tumors and displayed improved in vivo performance with the coinjection of unlabeled TSHR antibody K1-70 leading to higher uptake in TSHR expressing tumors than parental WT tumors and physiologic tissues; this observation was confirmed by the biodistribution and immunostaining analyses. CONCLUSIONS: We synthesized 89Zr-labeled antibody K1-70 as a new radiopharmaceutical for PET imaging of TSHR. 89Zr-DFO-TSHR-Ab has high radioactive uptake and retention in TSHR expressing tumors and cleared quickly from most background tissues in mouse models. Our study demonstrated that 89Zr-DFO-TSHR-Ab has the potential for PET imaging of TSHR-positive thyroid cancer and monitoring TSHR-targeted therapy.