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PSMA-PET-CT enables measuring molecular expression of prostate-specific membrane antigen (PSMA) , which is the target molecule of Lu-PSMA-617 (Lu-PSMA) therapy. However, the correlation of PSMA expression and overall survival (OS) in patients treated with Lu-PSMA therapy is currently unclear; especially with regard to coexistence of high and low PSMA expressing metastases. To this end, this retrospective single arm study elucidates the correlation of PSMA expression and overall survival in patients treated with Lu-PSMA therapy. Additionally, PET based criteria to define low PSMA expression were explored. Eighty-five patients referred to Lu-PSMA therapy were included in the analysis. Pretherapeutic Ga-PSMA-PET-CT scans were available for all patients. SUV of the highest PSMA expressing metastasis (PSMA ), SUV of the lowest PSMA expressing metastasis (PSMA ), and average SUV of all metastases (PSMA ) amongst other PET parameters were measured for each patient. A log-rank cutoff-finder was used to determine low (lowPSMA ) and high (highPSMA ) average PSMA expression as well as low (lowPSMA ) and high (highPSMA ) minimal PSMA expression. PSMA was a significant prognosticator of overall survival in contrast to PSMA (HR: 0.959; p = 0.047 vs. HR: 0.992; p = 0.231). Optimal log rank cut-offs were: PSMA = 14.3; PSMA = 10.2. Patients with low average PSMA expression (lowPSMA ) had significantly shorter survival compared to those with high average expression (highPSMA ) (5.3 vs. 15.1 months; p < 0.001; HR: 3.738, 95%CI = 1.953-7.154; p < 0.001). Patients with low PSMA expressing metastases (lowPSMA ) had shorter survival compared to those without a low PSMA expressing metastasis (highPSMA ) (p = 0.003; 7.9 months vs. 21.3; HR: 4.303, 95%CI = 1.521-12.178; p = 0.006). Patients that were classified as highPSMA but with lowPSMA had an intermediate overall survival (11.4 months; longer compared to lowPSMA , 5.3 months, p = 0.002; but shorter compared to highPSMA , 21.3 months, p = 0.02). Low average PSMA expression is a negative prognosticator of overall survival. Absence of low PSMA expressing metastases is associated with best overall survival and the maximum PSMA expression seems not suited to prognosticate overall survival. Low PSMA expression might therefore be a negative prognosticator for the outcome of patients treated with Lu-PSMA therapy. Future studies are warranted to elucidate the degree of low PSMA expression tolerable for Lu-PSMA therapy.

In the past two decades, extensive efforts have been made to develop agents targeting prostate-specific membrane antigen (PSMA) for prostate cancer imaging and therapy. To date, represented by two recent approvals of [68Ga]Ga-PSMA-11 and [18F]F-DCFPyL by the United States Food and Drug Administration (US-FDA) for positron emission tomography (PET) imaging to identify suspected metastases or recurrence in patients with prostate cancer, PSMA-targeting imaging and theranostic agents derived from small molecule PSMA inhibitors have advanced to clinical practice and trials of prostate cancer. The focus of current development of new PSMA-targeting agents has thus shifted to the improvement of in vivo pharmacokinetics and higher specific binding affinity with the aims to further increase the detection sensitivity and specificity and minimize the toxicity to non-target tissues, particularly the kidneys. The main strategies involve systematic chemical modifications of the linkage between the targeting moiety and imaging/therapy payloads. In addition to a summary of the development history of PSMA-targeting agents, this review provides an overview of current advances and future promise of PSMA-targeted imaging and theranostics with focuses on the structural determinants of the chemical modification towards the next generation of PSMA-targeting agents.

Glutamate carboxypeptidase II (GCPII) is a membrane-bound metallopeptidase predominantly expressed in neural and prostatic tissues, with significantly elevated levels in prostate carcinoma that increase with tumor grade. Despite its significance as a target for imaging and therapy in prostate cancer, its physiological function in this tissue remains poorly understood. To help fill this knowledge gap, we developed an integrated approach combining proximity labeling technologies for proteomic profiling (horseradish peroxidase, µMap, and riboflavin tetraacetate labeling) with our previously established iBody platform, which targets GCPII with a small-molecule specific inhibitor with proven efficacy as a chemical probe. Proximity labeling proteomic experiments on U251 MG–GCPII cells were followed by mass spectrometry and statistical analysis of protein abundances obtained by label-free quantification. Additionally, selected identified proteins were further validated through Western blot analyses and GCPII pulldown assays using cell lysates. This work identifies a network of GCPII-associated proteins that are potentially involved in cancer metabolism, migration, invasiveness, progression, and immune evasion. Our novel proximity proteomics labeling strategy provides a low-background framework, efficient biotinylation, and enhanced target binding via the avidity effect. Among the approaches tested, riboflavin tetraacetate-based iBody labeling exhibited the highest precision, underscoring its potential for membrane protein interactome mapping.

To facilitate prostate cancer imaging using targeted molecules, we constructed ultrasonic nanobubbles coupled with specific anti-PSMA (prostate specific membrane antigen) nanobodies, and evaluated their in vitro binding capacity and in vivo imaging efficacy. The \"targeted\" nanobubbles, which were constructed via a biotin-streptavidin system, had an average diameter of 487.60 ± 33.55 nm and carried the anti-PSMA nanobody as demonstrated by immunofluorescence. Microscopy revealed targeted binding of nanobubbles in vitro to PSMA-positive cells. Additionally, ultrasonography indicators of nanobubble imaging (including arrival time, peak time, peak intensity and enhanced duration) were evaluated for the ultrasound imaging in three kinds of animal xenografts (LNCaP, C4-2 and MKN45), and showed that these four indicators of targeted nanobubbles exhibited significant differences from blank nanobubbles. Therefore, this study not only presents a novel approach to target prostate cancer ultrasonography, but also provides the basis and methods for constructing small-sized and high-efficient targeted ultrasound nanobubbles.

Prostate-specific membrane antigen (PSMA) is a type II integral membrane protein expressed on the surface of prostate cancer (PCa) cells, particularly in androgen-independent, advanced, and metastatic disease. Previously, we demonstrated that N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-(18)F-fluorobenzyl-L-cysteine ((18)F-DCFBC) could image an experimental model of PSMA-positive PCa using PET. Here, we describe the initial clinical experience and radiation dosimetry of (18)F-DCFBC in men with metastatic PCa. Five patients with radiologic evidence of metastatic PCa were studied after the intravenous administration of 370 MBq (10 mCi) of (18)F-DCFBC. Serial PET was performed until 2 h after administration. Time-activity curves were generated for selected normal tissues and metastatic foci. Radiation dose estimates were calculated using OLINDA/EXM 1.1. Most vascular organs demonstrated a slow decrease in radioactivity concentration over time consistent with clearance from the blood pool, with primarily urinary radiotracer excretion. Thirty-two PET-positive suspected metastatic sites were identified, with 21 concordant on both PET and conventional imaging for abnormal findings compatible with metastatic disease. Of the 11 PET-positive sites not identified on conventional imaging, most were within the bone and could be considered suggestive for the detection of early bone metastases, although further validation is needed. The highest mean absorbed dose per unit administered radioactivity (μGy/MBq) was in the bladder wall (32.4), and the resultant effective dose was 19.9 ± 1.34 μSv/MBq (mean ± SD). Although further studies are needed for validation, our findings demonstrate the potential of (18)F-DCFBC as a new positron-emitting imaging agent for the detection of metastatic PCa. This study also provides dose estimates for (18)F-DCFBC that are comparable to those of other PET radiopharmaceuticals such as (18)F-FDG.

In tribute to our friend and colleague Michael Robinson, we review his involvement in the identification, characterization and localization of the metallopeptidase glutamate carboxypeptidase II (GCPII), originally called NAALADase. While Mike was characterizing NAALADase in the brain, the protein was independently identified by other laboratories in human prostate where it was termed prostate specific membrane antigen (PSMA) and in the intestines where it was named Folate Hydrolase 1 (FOLH1). It was almost a decade to establish that NAALADase, PSMA, and FOLH1 are encoded by the same gene. The enzyme has emerged as a therapeutic target outside of the brain, with the most notable progress made in the treatment of prostate cancer and inflammatory bowel disease (IBD). PSMA-PET imaging with high affinity ligands is proving useful for the clinical diagnosis and staging of prostate cancer. A molecular radiotherapy based on similar ligands is in trials for metastatic castration-resistant prostate cancer. New PSMA inhibitor prodrugs that preferentially block kidney and salivary gland versus prostate tumor enzyme may improve the clinical safety of this radiotherapy. The wide clinical use of PSMA-PET imaging in prostate cancer has coincidentally led to clinical documentation of GCPII upregulation in a wide variety of tumors and inflammatory diseases, likely associated with angiogenesis. In IBD, expression of the FOLH1 gene that codes for GCPII is strongly upregulated, as is the enzymatic activity in diseased patient biopsies. In animal models of IBD, GCPII inhibitors show substantial efficacy, suggesting potential theranostic use of GCPII ligands for IBD.

Tumor necrosis factor‑related apoptosis‑inducing ligand‑receptor 2 (TRAIL‑R2) can induce apoptosis in various tumors through the oligomerization of TRAIL. Several TRAIL‑R2 agonistic monoclonal antibodies have been tested in clinical trials but have failed owing to a lack of efficacy or severe hepatotoxicity. Although bispecific constructs have been developed to improve TRAIL‑R2 targeting and enhance efficacy against tumors while reducing adverse effects on hepatocytes, the risk of hepatotoxicity still persists. The present study used a TRAIL‑R2 antibody, E11, that does not trigger apoptosis in the absence of crosslinking and constructed a novel tetravalent bispecific IgG4‑based antibody, REGULGENT™, comprised of E11 and a clone that binds to prostate‑specific membrane antigen (PSMA), a specific marker for prostate tumors. PSMA/TRAIL‑R2 REGULGENT™ selectively induced death in PSMA/TRAIL‑R2 double‑positive cells but not in TRAIL‑R2 single‑positive cells and . By contrast, a bivalent bispecific antibody did not result in tumor cell death, indicating that tetravalent bispecific antibodies have an important role in inducing tumor cell apoptosis by binding to TRAIL‑R2 in a bivalent manner. Moreover, the present study demonstrated, for the first time to the best of the authors' knowledge, that PSMA/TRAIL‑R2 REGULGENT™ is not hepatotoxic (primary human hepatocytes) or (chimeric human hepatocyte‑transplanted PXB mouse model). This finding suggests that tetravalent bispecific therapeutics such as REGULGENT™ can be promising therapeutic agents for TRAIL‑R2‑positive tumors by exerting tumor‑specific activity while avoiding toxicity.

A series of novel α-sulfamidophosphonate derivatives (3a-3 g) were synthesized and evaluated for anticancer activity against different human cancer cell lines (PRI, K562, and JURKAT). The antitumor activity of all compounds using the MTT test remains moderate compared to the standard drug chlorambucil. Compounds 3c and 3 g were found to be more active anticancer agent against PRI and K562 cells with IC50 value 0.056–0.097 and 0.182–0.133 mM, respectively. Molecular docking study related to binding affinity and binding mode analysis showed that synthesized compounds had potential to inhibit glutamate carboxypeptidase II (GCPII). Furthermore, computational analysis was performed through Density Functional Theory (DFT) utilizing the B3LYP 6-31 G (d, p) basis set and the theoretical results were correlated with experimental data. The ADME/toxicity analyses carried out by Swiss ADME and OSIRIS software show that all synthesized molecules exhibited good pharmacokinetics, bioavailability, and had no toxicity profile.

Prostate cancer ranks as the fourth most common cancer among men, with approximately 1.47 million new cases reported annually. The emergence of prostate-specific membrane antigen (PSMA) as a critical biomarker has revolutionized the diagnosis and treatment of prostate cancer. Recent advancements in low-molecular-weight PSMA inhibitors, with their diverse chemical structures and binding properties, have opened new avenues for research and therapeutic applications in prostate cancer management. These novel agents exhibit enhanced tumor targeting and specificity due to their small size, facilitating rapid uptake and localization at the target site while minimizing the retention in non-target tissues. The primary aim of this study is to evaluate the potential of low-molecular-weight PSMA inhibitors labeled with radioisotopes as theranostic agents for prostate cancer. This includes assessing their efficacy in targeted imaging and therapy and understanding their pharmacokinetic properties and mechanisms of action. This study is a literature review focusing on in vitro and clinical research data. The in vitro studies utilize PSMA-targeted radioligands labeled with radioisotopes to assess their binding affinity, specificity, and internalization in prostate cancer cell lines. Additionally, the clinical studies evaluate the safety, effectiveness, and biodistribution of radiolabeled PSMA ligands in patients with advanced prostate cancer. The findings indicate promising outcomes regarding the safety and efficacy of PSMA-targeted radiopharmaceuticals in clinical settings. The specific accumulation of these agents in prostate tumor lesions suggests their potential for various applications, including imaging and therapy. This research underscores the promise of radiopharmaceuticals targeting PSMA in advancing the diagnosis and treatment of prostate cancer. These agents improve diagnostic accuracy and patients’ outcomes by enhancing imaging capabilities and enabling personalized treatment strategies.

Rationale Metabotropic glutamate 2 and 3 (mGluR2/3) receptors are implicated in drug addiction as they limit excessive glutamate release during relapse. N -acetylaspartylglutamate (NAAG) is an endogenous mGluR2/3 agonist that is inactivated by the glutamate carboxypeptidase II (GCPII) enzyme. GCPII inhibitors, and NAAG itself, attenuate cocaine-seeking behaviors. However, their effects on the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV) have not been examined. Objectives We determined whether withdrawal following repeated MDPV administration alters GCPII expression in corticolimbic regions. We also examined whether a GCPII inhibitor (2-(phosphonomethyl)-pentanedioic acid (2-PMPA)), and NAAG, reduce the rewarding and locomotor-stimulant effects of MDPV in rats. Methods GCPII was assessed following repeated MDPV exposure (7 days). The effects of 2-PMPA and NAAG on acute MDPV-induced hyperactivity were determined using a locomotor test. We also examined the inhibitory effects of 2-PMPA and NAAG on MDPV-induced place preference, and whether the mGluR2/3 antagonist LY341495 could prevent these effects. Results MDPV withdrawal reduced GCPII expression in the prefrontal cortex. Systemic injection of 2-PMPA (100 mg/kg) did not affect the hyperactivity produced by MDPV (0.5–3 mg/kg). However, nasal administration of NAAG did reduce MDPV-induced ambulation, but only at the highest dose (500 μg/10 μl). We also showed that 2-PMPA (10–30 mg/kg) and NAAG (10–500 μg/10 μl) dose-dependently attenuated MDPV place preference, and that the effect of NAAG was blocked by LY341495 (3 mg/kg). Conclusions These findings demonstrate that MDPV withdrawal produces dysregulation in the endogenous NAAG-GCPII signaling pathway in corticolimbic circuitry. Systemic administration of the GCPII inhibitor 2-PMPA, or NAAG, attenuates MDPV reward.