BACKGROUND Accurate clinical staging is fundamental to the precision management of gastric cancer (GC). Nonetheless, the clinical performance of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) in GC is limited by relatively low sensitivity, particularly for lymph node metastasis (LNM) and peritoneal metastasis (PM). AIM To compare 18F-fibroblast activation protein inhibitor (FAPI)-04 PET/CT with 18F-FDG PET/CT in patients with newly diagnosed GC and in those with suspected recurrence or metastasis after curative surgery. METHODS Twenty-one patients were prospectively enrolled, including 11 with newly diagnosed GC and 10 with suspected postoperative recurrence or metastasis. Each patient underwent both 18F-FAPI-04 and 18F-FDG PET/CT within 7 days. Lesions were verified by pathology and/or imaging follow-up. Diagnostic performance and quantitative parameters were compared, including maximum standardized uptake value (SUVmax), tumor-to-background ratio (TBR), FDG-derived metabolic tumor volume (MTV) and total lesion glycolysis (TLG), and FAPI-derived FAPI-avid tumor volume (FTV), and total lesion fibroblast activation protein expression (TLF). The peritoneal cancer index (PCI) was assessed for diffuse peritoneal disease. RESULTS Among the 21 patients (237 lesions in total), 11 (52.4%, 11/21) had newly diagnosed GC, and 10 (47.6%, 10/21) had suspected local recurrence or metastasis after surgery; only 1 patient (4.8%, 1/21) had suspected local recurrence. For primary tumors, 18F-FAPI-04 demonstrated higher uptake and contrast than 18F-FDG (SUVmax: 11.6 vs 6.5, P = 0.036; TBR: 11.5 vs 5.1, P = 0.009) and yielded higher tracer-specific total-lesion burden metrics (TLF vs TLG: 260.5 vs 57.9, P = 0.036). For LNMs, quantitative uptake and derived parameters were comparable between tracers (SUVmax: 6.6 vs 6.5, P = 0.703; TBR: 5.4 vs 6.4, P = 0.65; FTV vs MTV: 3.1 vs 1.9, P = 0.321; TLF vs TLG: 8.3 vs 6.3, P = 0.654). For PM, 18F-FAPI-04 showed substantially higher uptake and volumetric burden in nodular disease (SUVmax: 7.1 vs 3.2, P = 0.002; TBR: 7.4 vs 2.4, P = 0.002; FTV vs MTV: 13.2 vs 1.2, P = 0.003; TLF vs TLG: 39.3 vs 3.3, P = 0.004). In diffuse PM, 18F-FAPI-04 yielded a higher PCI score and higher SUVmax than 18F-FDG (PCI: 14 vs 2.5, P = 0.012; SUVmax: 8.0 vs 4.7, P = 0.001). For bone metastases, 18F-FAPI-04 also demonstrated higher uptake and contrast (SUVmax: 11.1 vs 5.5, P < 0.001; TBR: 10.4 vs 5.6, P < 0.001) and differed in tracer-specific total-lesion metrics (TLF vs TLG: 7.7 vs 9.5, P = 0.045). Among the 11 patients with primary GC, the sensitivity of 18F-FAPI-04 PET/CT for primary tumor detection was 100% compared with 90.9% for 18F-FDG PET/CT. For detection of LNM and PM, sensitivities were 100% and 100% with 18F-FAPI-04, vs 75% and 50% with 18F-FDG, respectively. CONCLUSION In this pilot study, we observed trends of higher tracer uptake and lesion-to-background contrast with 18F-FAPI-04 PET/CT compared to 18F-FDG PET/CT in primary GC, PMs, and bone metastases. Additionally, 18F-FAPI-04 PET/CT showed trends of a greater number of metastatic lesions overall, with higher detection yields particularly for PM, suggesting its potential value for initial staging and postoperative assessment in GC.

The programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in tumor immune regulation, with PD-L1 expression serving as a critical biomarker for patient stratification and response prediction. Accurate, noninvasive assessment of PD-L1 expression is, therefore, essential for guiding clinical decision-making. KN035 is an ∼79.6 kDa fusion protein comprising a humanized single-domain antibody linked to an Fc fragment, offering a smaller molecular size than conventional monoclonal antibodies. In this study, KN035 was conjugated with p-SCN-Bn-NOTA and radiolabeled with 64Cu to generate [64Cu]Cu-NOTA-KN035 for PET imaging of PD-L1. The tracer showed high radiochemical purity (>95%) and strong binding specificity in vitro. In vivo PET imaging and biodistribution studies were performed in H1975 (high PD-L1 expression) and A549 (low PD-L1 expression) nonsmall cell lung cancer (NSCLC) xenograft models. Clear tumor visualization was achieved at 4 h postinjection (5.62 ± 0.55%ID/g in H1975; 4.16 ± 0.18%ID/g in A549), with peak uptake at 48 h (12.32 ± 0.66 and 5.72 ± 0.21%ID/g, respectively). Tumor uptake decreased significantly after blocking with excess KN035, confirming the specificity. These results demonstrate the high PD-L1-targeting specificity of [64Cu]Cu-NOTA-KN035, suggesting its great potential as a noninvasive diagnostic tool for immunotherapy-based treatments in the future.

To improve senolytic efficacy and selectivity, we designed gemcitabine (Gem)-based galactoside prodrugs activated by senescence-associated β-galactosidase (SA-β-gal), bearing lysosome-targeting groups at the 3- and 5-positions of the self-immolative linker aromatic ring. This strategy avoids stereocenter formation and promotes faster, electron-donating-effect-driven drug release. Gal-dMor-Gem, with two morpholine groups, showed the strongest activity. Its senolytic index reached 16.1-56.7 across six senescent cell (SnC) models, a 2.8- to 3.7-fold improvement over the nontargeted SSK1. Gal-dMor-Gem released Gem faster and preferentially induced SnC apoptosis, as validated in a coculture model. Biodistribution studies confirmed its preferential accumulation and activation in senescent tissues. In senescent mice, Gal-dMor-Gem (0.5 mg/kg) surpassed SSK1 in restoring body weight, improving biochemical parameters, and reducing SA-β-gal, IL-6, and lamin B1 abnormalities in multiple organs. At 1.0 mg/kg, most markers returned to healthy levels. This work identifies Gal-dMor-Gem as a potent senolytic and highlights a generalizable strategy for developing targeted SA-β-gal-responsive prodrugs.

Purpose: Claudin 18.2 (CLDN18.2) is predominantly expressed in the gastric mucosa and becomes exposed and accessible during malignant transformation. Its highly restricted expression pattern and function in gastric cancer (GC) make CLDN18.2 a promising target for the treatment of GC. Accordingly, the accurate assessment of CLDN18.2 expression is imperative for CLDN18.2-targeted cancer therapeutics. In this study, we aimed to develop a CLDN18.2-targeting positron emission tomography (PET) probe for the in vivo assessment of CLDN18.2 expression. Methods and Materials: Anti-CLDN18.2 recombinant single-chain antibody fused with IgG1-fragment crystallizable (VHH-Fc) fusion protein NY005 was radiolabeled using p-isothiocyanatobenzyl-desferrioxamine B chelator and 89Zr to obtain the [89Zr]Zr-DFO-NY005 PET probe. The specific activity, radiochemical purity, and the stability of the probe were then assayed. We evaluated the CLDN18.2-targeting capability of [89Zr]Zr-DFO-NY005 in the A549hCLDN18.2 xenograft tumor model and investigated its biodistribution, pharmacokinetics, and biosafety in Institute of Cancer Research mice. Furthermore, we performed the PET/computed tomography imaging of [89Zr]Zr-DFO-NY005 in patients with GC to assess the clinical application potential. Results: The successfully synthesized [89Zr]Zr-DFO-NY005 exhibited promising specific activity, radiochemical purity, and stability and demonstrated excellent targeting capability against CLDN18.2 in the A549hCLDN18.2 xenograft tumor model. After administration, [89Zr]Zr-DFO-NY005 was mainly distributed in the liver, spleen, and kidneys of Institute of Cancer Research mice. In vivo assessment showed that [89Zr]Zr-DFO-NY005 had a T1/2a of 2.6 hour and a T1/2b of 98.84 hour, with no apparent toxicity detected. PET/computed tomography imaging performed in patients with GC demonstrated the capability of [89Zr] Zr-DFO-NY005 for the noninvasive assessment of CLDN18.2 expression. Conclusions: We successfully developed a CLDN18.2-targeting PET probe, [89Zr]Zr-DFO-NY005, and demonstrated promising capability for the evaluation of CLDN18.2 expression in GC. (c) 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Abstract Background: The clinical efficacy of PSMA targeted RLT for metastatic PCa has been well established by Pluvicto®. However, the suboptimal characteristics of existing agents, such as short tumor retention and rapid clearance, may limit the efficiency of radiation energy from 177Lu decay. The small molecular compound, 3D1015, is a newly designed PSMA-targeted ligand with high affinity. Its radiolabeled product, 177Lu-PSMA-3D1015 (hereafter “3D1015”), has been developed to prolong its retention in the tumor tissue, and has shown excellent tumor inhibition effect at low dose, along with great safety profile. Method: The binding affinity of ligand to PSMA was evaluated using LNCaP cells via FACS-based competition assay, with PSMA-617 as a reference. In vivo biodistribution and efficacy were assessed in LNCaP xenograft B-NDG mice by calculating uptake (%ID/g) and measuring TGI (%) across dose groups. A single-dose toxicity study in SD rats was conducted to determine the dose tolerance and identify target toxic organs. An exploratory study further investigated the dosimetry and safety of 3D1015 in patients with PSMA-positive mCRPC who had failed SOCs. Eligible patients received a single administration of 3D1015 (10 mCi, i.v.) then underwent qSPECT/CT at different timepoints. Results: IC values were 1.47 nM for 3D1015 ligand and 4.11 nM for PSMA-617. Radiolabeling with 177Lu under mild conditions achieved >97% RCP. Biodistribution studies revealed rapid and sustained tumor uptake of 3D1015, reaching 36.50 %ID/g at 120 h, with renal excretion indicated by high kidney exposure (max: 59.47 %ID/g at 72 h). Efficacy studies demonstrated dose-dependent efficacy (TGI: 80.0%, 98.3%, and 99.8% at 0.1, 0.5, and 1.0 mCi/mouse, respectively). A dose of 0.5 mCi 3D1015 achieved superior TGI versus 1.0 mCi 177Lu-PSMA-617 (TGI: 94.0%). Toxicity study identified the spleen as the primary target organ, with a MTD of 15 mCi/kg; transient toxicities in body weight, food intake, and hematology were fully reversible. Two patients received a single dose of 10 mCi of 3D1015. SPECT/CT imaging indicated that the drug was primarily excreted via the hepatobiliary/intestinal route rather than the renal excretion pathway as shown in the previous animal toxicity research. Uptake of 3D1015 was observed in all pre-identified lesions till 216 h. Mean absorbed dose in kidneys, submandibular and parotid glands, liver, spleen, and bone marrow was 0.80, 1.35, 0.44, 1.12, and 0.12 mGy/MBq, respectively. No > G2 TRAEs occurred. A 14% decline of PSA was observed in 1pts after one dose of 10mCi infusion. Conclusion: 177Lu-PSMA-3D1015 exhibits high PSMA affinity and prolonged retention in tumor, potentially driving potent efficacy at lower doses. Its distinct hepatobiliary excretion profile differentiates it from existing therapies. These findings address key limitations of current RLTs, and further clinical trials are ongoing. Citation Format: Lu Hou, Quanpeng Wang, Haitian Fu, Chuang Xi, Wanggui Yang, Fangqiang Tang, Qing Gao, Lan Qin, Wenhua Huang, Henry Ho, Chunjing Yu, John Gong. Development and evaluation of a novel high affinity PSMA-targeted radioligand177Lu-PSMA-3D1015 for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7182.

A novel theranostic radiopharmaceutical targeting prostate-specific membrane antigen (PSMA), [68Ga]Ga/[177Lu]Lu–NYM032, was developed and its diagnostic and therapeutic potential in the treatment of prostate cancer (PCa) was preliminarily evaluated. The diagnostic efficacy of the PET tracer [68Ga]Ga–NYM032 was first evaluated in PSMA-positive xenograft-bearing models (LNCaP models), followed by evaluation in 10 PCa patients using [68Ga]Ga–PSMA617 a comparator. Finally, the therapeutic potential of [177Lu]Lu–NYM032 was evaluated in LNCaP models. [68Ga]Ga/[177Lu]Lu–NYM032 was well-tolerated, and no adverse events were observed in the preclinical and clinical studies. [68Ga]Ga–NYM032 demonstrated PSMA specificity and high radioactive uptake in LNCaP tumors. [68Ga]Ga–NYM032 uptake (SUVmax) did not differ from [68Ga]Ga–PSMA617 uptake in the same in situ lesions at the same p.i. time point (median 9.40 vs. 6.85, P = 0.123, n = 8). Compared with [68Ga]Ga–PSMA617 uptake, [68Ga]Ga–NYM032 uptake was significantly higher in osseous metastases (median 5.10 vs. 3.88, P < 0.001, n = 48), and higher in lymph node metastases (median 7.81 vs. 5.46, n = 2). [177Lu]Lu–NYM032 showed high aggregation in the lesions of LNCaP models and long retention times. [177Lu]Lu–NYM032 could inhibit tumor progression in LNCaP models, and its therapeutic efficiency strengthened with increasing radio-dosage (18.5–74 MBq/mouse). The tumor volume in the high radio-dosage treatment group (74 MBq/mouse) was significantly smaller than that in the blank control group at 21 days p.i. (107.14 ± 13.68 mm3 vs. 1351.86 ± 249.98 mm3, P < 0.001, n = 7). [68Ga]Ga/[177Lu]Lu-NYM032 has considerable potential as a novel and powerful theranostic radiopharmaceutical for PCa. The clinical evaluation of this study was registered at Clinicaltrial.gov (NCT06389695) on 29 Apr, 2024.

PURPOSE:Claudin 18.2 (CLDN18.2) is predominantly expressed in the gastric mucosa and becomes exposed and accessible during malignant transformation. Its highly restricted expression pattern and function in gastric cancer (GC) make CLDN18.2 a promising target for the treatment of GC. Accordingly, the accurate assessment of CLDN18.2 expression is imperative for CLDN18.2-targeted cancer therapeutics. In this study, we aimed to develop a CLDN18.2-targeting positron emission tomography (PET) probe for the in vivo assessment of CLDN18.2 expression. METHODS AND MATERIALS:Anti-CLDN18.2 recombinant single-chain antibody fused with IgG1-fragment crystallizable (VHH-Fc) fusion protein NY005 was radiolabeled using p-isothiocyanatobenzyl-desferrioxamine B chelator and 89Zr to obtain the [89Zr]Zr-DFO-NY005 PET probe. The specific activity, radiochemical purity, and the stability of the probe were then assayed. We evaluated the CLDN18.2-targeting capability of [89Zr]Zr-DFO-NY005 in the A549hCLDN18.2 xenograft tumor model and investigated its biodistribution, pharmacokinetics, and biosafety in Institute of Cancer Research mice. Furthermore, we performed the PET/computed tomography imaging of [89Zr]Zr-DFO-NY005 in patients with GC to assess the clinical application potential. RESULTS:The successfully synthesized [89Zr]Zr-DFO-NY005 exhibited promising specific activity, radiochemical purity, and stability and demonstrated excellent targeting capability against CLDN18.2 in the A549hCLDN18.2 xenograft tumor model. After administration, [89Zr]Zr-DFO-NY005 was mainly distributed in the liver, spleen, and kidneys of Institute of Cancer Research mice. In vivo assessment showed that [89Zr]Zr-DFO-NY005 had a T1/2α of 2.6 hour and a T1/2β of 98.84 hour, with no apparent toxicity detected. PET/computed tomography imaging performed in patients with GC demonstrated the capability of [89Zr]Zr-DFO-NY005 for the noninvasive assessment of CLDN18.2 expression. CONCLUSIONS:We successfully developed a CLDN18.2-targeting PET probe, [89Zr]Zr-DFO-NY005, and demonstrated promising capability for the evaluation of CLDN18.2 expression in GC.

Objectives: Prostate-specific membrane antigen (PSMA)-targeted radioligands are promising diagnostic tools for the targeted positron emission tomography (PET) imaging of prostate cancer (PCa). In present work, we aimed to develop a novel PSMA tracer to provide an additional option for prostate cancer diagnosis. Methods: Our team designed a new structure of the PSMA tracer and evaluated it with cellular experiments in vitro to preliminarily verify the targeting and specificity of 68Ga-NOTA-GC-PSMA. PET/CT imaging of PSMA-positive xenograft-bearing models in vivo to further validate the in vivo specificity and targeting of the radiotracer. Pathological tissue sections from prostate cancer patients were compared with pathological immunohistochemistry and pathological tissue staining results by radioautography experiments to assess the targeting-PSMA of 68Ga-NOTA-GC-PSMA on human prostate cancer pathological tissues. Results: The novel tracer showed high hydrophilicity and rapid clearance rate. Specific cell binding and micro-PET imaging experiments showed that 68Ga-NOTA-GC-PSMA displayed a high specific LNCaP tumor cell uptake (1.70% ± 0.13% at 120 min) and tumor-to-muscle (T/M) and tumor-to-kidney (T/K) ratio (13.87 ± 11.20 and 0.20 ± 0.08 at 60 min, respectively). Conclusions: The novel tracer 68Ga-NOTA-GC-PSMA is promising radionuclide imaging of PCa.

e17039 Background: 68 Ga-NYM032 is a radiolabeled small-molecule targeting prostate-specific membrane antigen (PSMA), designed as an imaging agent for detecting PSMA-expressing tumors. The specific aim of this first-in-human study (NCT 06389695) aims to assess logistical feasibility, estimate radiochemical safety, and calculate radiation absorbed doses per unit of radioactivity administered. Methods: This single-center, open-label, single-dose escalation study followed a standard 3+3 design, enrolling nine healthy volunteers across three cohort. Participants received a single dose of 74, 148 or 259 MBq of 68 Ga-NYM032.Post-injection, each volunteer underwent PET/CT imaging at 0.5h, 1h, 2h and 3h p.i. Blood and urine samples were collected at predefined intervals. Vital signs and 12-lead electrocardiogram were performed within 1h post-imaging. Adverse events were monitored over 2 to 5 days following injection. Results: All volunteers tolerated the procedures well. There were no subjective complaints and no observable adverse events on serial vital sign measurements, clinical laboratory tests, and electrocardiograms. Image quality was uniformly high, making the identification of individual organs boundaries feasible. After the administration of 68 Ga-NYM032, OLINDA dosimetry calculations revealed the highest absorbed doses in the kidneys (0.25 mGy/MBq) and urinary bladder wall (0.13 mGy/MBq), with a mean effective dose of 0.02 mSv/MBq, corresponding to 1.5–5.2 mSv for injected doses of 74–259 MBq. Lower absorbed doses were observed in the liver and red marrow. Pharmacokinetic analysis indicated a rapid decline in blood drug concentration, with systemic exposure (C max and AUC (0-t) ) increasing with dose escalation. Conclusions: This Phase Ia study confirms that 68 Ga-NYM032 is well tolerated in healthy volunteers, with no significant safety concerns observed. The dosimetry results indicate that the absorbed doses in normal organs remain within safe limits. Pharmacokinetic data show rapid clearance from the bloodstream, and the quality of the PET/CT scan images seems very high. Clinical trial information: NCT06389695 .

e17040 Background: Targeting Prostate-specific membrane antigen (PSMA) offers a promising therapeutic strategy for mCRPC. 177 Lu-NYM032 is a novel radionuclide drug conjugate that targets PSMA-expressing tumor cells. It was designed to deliver higher doses of radiation to neoplastic cells and lower doses of radiation to all other tissues than existing agents. The specific aims of this Phase I/II study (NCT06383052) include assessing the logistical feasibility, evaluating the safety, estimating the tolerability, and exploring the efficacy of 177 Lu-NYM032 in patients with PSMA-positive mCRPC. Methods: This single-center, single-arm, Phase I/II trial aims to recruit 40 men diagnosed with progressive mCRPC. The phase I dose-escalation was designed with a modified 3+3 model to determine the maximum tolerated dose (MTD) of 177 Lu-NYM032. Doses of 1.9, 3.7, 5.5, and 7.4 GBq were administered once every 6 weeks for up to 6 cycles. The MTD was defined as the highest dose level at which a dose-limiting toxicity (DLT) occurs in in fewer than 1/3 of participants, or no more than 2 of 6 participants. The phase II dose-expansion cohort will enroll an additional 30 participants to further evaluate the safety and anti-tumor efficacy of 177 Lu-NYM032 at the recommended Phase II dose (RP2D). Key eligibility criteria include confirmed PSMA-positive disease on 68 Ga-NYM032 PET/CT, no discordant lesions on 18 F-FDG PET/CT, prior progression following at least one potent androgen receptor (AR)-targeted therapy and docetaxel, or refusal/unfitness for chemotherapy. Selection criteria required subjects to have adequate organ function, an ECOG performance status 0-2, and no prior treatment with another radioisotope. Results: As of 1 January 2025, 11 Chinese participants with PSMA-positive mCRPC have been enrolled in the Phase I dose-escalation cohort. Patients were treated with 177 Lu-NYM032 at dose levels of 1.98 GBq (n = 1), 3.7 GBq (n = 4), 5.5 GBq (n = 3) and 7.4 GBq (n = 3). The treatments were well-tolerated, with all treatment-emergent adverse events (TEAEs) limited to Grade 1-2 except for one case of Grade 3 anemia. No DLTs had been reported. Among the 9 patients who completed 2 cycles of treatment, 7 (78%) experienced a reduction in PSA levels, with 6 (67%) demonstrating a greater than 50% decrease in PSA. Conclusions: Preliminary results from this ongoing Phase I/II trial indicate that 177 Lu-NYM032 is associated with manageable safety profile and demonstrates encouraging efficacy in patients with PSMA-positive mCRPC. These findings support the continued evaluation of 177 Lu-NYM032, with further studies needed to define the optimal dose and confirm its clinical benefit. The trial is ongoing, and additional data will be critical in determining the therapeutic potential of this novel radiolabeled drug. Research Sponsor: Norroy Bioscience Co., Ltd. Clinical trial information: NCT06383052 .

A suitable theranostic molecule targeting the fibroblast activation protein (FAP) might provide individualized and precise diagnostic and therapeutic solutions for patients with FAP-positive tumors. In this study, a FAP-targeted molecule, FAPI-JNU, was developed with picomolar affinity for FAP. [68Ga]Ga/[177Lu]Lu-FAPI-JNU was synthesized and verified by HPLC, demonstrating high radiochemical purity (>95%) and yield (>90%). Favorable biodistribution and tumor-targeting specificity of [68Ga]Ga-FAPI-JNU were determined in tumor-bearing mice expressing FAP (n = 4), with higher tumor uptake observed compared to [68Ga]Ga-FAPI-46. Clinical PET/CT imaging with [68Ga]Ga-FAPI-JNU showed superior detection of lymph node metastases, bone metastases, and recurrent lesions compared to [18F]F-FDG (n = 9). [177Lu]Lu-FAPI-JNU demonstrated effective tumor targeting and inhibition of tumor development in tumor-bearing mice, with the high radio-dosage group (46 MBq/mouse, n = 6) showing significant antitumor efficacy compared to the blank control group. The developed radiopharmaceuticals, [68Ga]Ga/[177Lu]Lu-FAPI-JNU, show potential for clinical use in diagnostic imaging and tumor therapy through FAP targeting.

The discovery of biomarkers for malignant tumors is driving the development of new radiopharmaceuticals in nuclear medicine. The development and optimization of novel radiopharmaceuticals to occupy an increasingly important role in tumor diagnosis and treatment. In recent years, fibroblast activation protein (FAP) has gained attention as a promising tumor target due to its widespread expression across various tumors. FAP inhibitor (FAPI) radiopharmaceuticals are considered to be the most promising to be developed for targeting FAP due to their rapid and specific tumor targeting. This review briefly outlines the developmental history of FAP-targeted small-molecule enzyme activity inhibitors, highlighting the effective role of targeting molecules, linkers, and certain functional groups in the delivery of radioisotopes to cancerous tissues. These development strategies will serve as a reference for the further development and application of relevant radiopharmaceuticals. This review also delineates the progress on clinical FAPI as a radioisotope delivery vehicle for the targeted radioligand therapy of tumors and introduces the latest combination therapy involving FAPI radiopharmaceutical for tumor treatment. The findings provide novel therapeutic insights into the targeted radioligand therapy of tumors.

Preclinical studies have shown that the long-acting PSMA-targeting radiopharmaceutical [177Lu]Lu-LNC1011 based on dansylated amino acid modification had high tumor uptake and prolonged retention. This study aimed to explore its safety and efficacy in patients with metastatic castration-resistant prostate cancer (mCRPC). Eight mCRPC patients who met the inclusion criteria received intravenous treatment with [177Lu]Lu-LNC1011. Treatment was repeated every 6 weeks for up to a maximum of 6 cycles. Molecular imaging and hematology markers were the main evaluation indicators. The primary endpoints were biochemical (PSA) response and molecular imaging response. Toxicity grading was assessed using the Common Terminology Criteria for Adverse Events version 5.0. Hematological toxicity was the primary side effect. In all patients, adverse events (AEs) after [177Lu]Lu-LNC1011 treatment were primarily characterized by decreased levels of hemoglobin, white blood cells and platelets. Grade 3 anemia was recorded in 1 patient, and grade 2 leukopenia and thrombocytopenia were recorded in 4 patients. The average systemic effective dose was 0.18 mSv/MBq, and the kidney was the organ with the highest absorbed dose (3.11 ± 0.26 mSv/MBq). Long half-life (71.30 ± 8.23 h) and high absorbed dose [5.77, (range 5.5–14 Gy/GBq)] were calculated in the lesions. All patients had a more than 50 https://clinicaltrials.gov/study/NCT06809426?term=NCT06809 . NCT06809426, registration date: 2025-01-23.

Integrin-α6 is an attractive diagnostic and therapeutic biomarker in cancer, because it is highly expressed in several types of malignancies. Based on our previous findings, we designed a cyclic peptide, NOTA-A6P, to enhancing affinity, tumor uptake and serum stability, and then developed a cyclic radiotracer, [18F]AlF-NOTA-A6P, for the specific detection of early colorectal cancer by PET/CT imaging. [18F] AlF-NOTA-A6P was automatically labeled for colorectal cancer imaging in a novel synthesis module. The affinity, stability, radiochemical yield (RCY), radiochemical purity (RCP), molar activity (Am), and octanol-water partition coefficient of [18F]AlF-NOTA-A6P were investigated. Results demonstrated that the tracer exhibited high serum stability, high RCY (58.1 ± 4.1 %) (undecay-corrected, n = 5) and hydrophilicity. In vivo microPET/CT imaging of LS174T and HT29 xenograft tumor models with high integrin-α6 expression indicated that [18F]AlF-NOTA-A6P exhibited higher tumor uptake and tumor-to-muscle ratio than SW620, which has low integrin-α6 expression. Moreover, the specificity of [18F]AlF-NOTA-A6P for integrin-α6 was confirmed by additional methods, including autoradiography, hematoxylin and eosin staining, and immunohistochemical staining. In conclusion, a cyclic peptide NOTA-A6P targeting integrin-α6 was designed and a promising PET tracer [18F]AlF-NOTA-A6P was synthesized in a novel cassette-type synthesis module. The tracer demonstrated a favorable binding affinity with integrin-α6, stability in human serum and specificity for colorectal cancer xenograft mice. These properties render it a promising non-invasive PET radiotracer for the detection of integrin-α6-overexpressing cancers, including colorectal cancer.

Purpose: The asialoglycoprotein receptor (ASGPR), expressed exclusively on mammalian hepatocyte membranes, recognizes ligands terminated with beta-D-galactose (Gal) and N-acetylglucosamine (GalNAc). This study aims to develop a Ga-68-labeled monovalent GalNAc derivative that particularly interacts with ASGPR. It also aims to assess the potential utility of this derivative in visualizing ASGPR-related liver dysfunction using positron emission tomography (PET)/ computed tomography (CT) imaging. Methods: The PET imaging probe Ga-68-NOTA-GalNAc was developed and characterized with regard to radiochemical purity, biocompatibility, biodistribution patterns, and specific ASGPR-targeting ability. Groups of normal mice, mice with acute liver injury (ALI) induced by CCl4, mice with early-stage liver fibrosis induced by CCl4, mice with nonalcoholic fatty liver disease (NAFLD), and orthotopic HepG2 hepatoma-bearing mice were imaged with Ga-68-NOTA-GalNAc PET to evaluate the potential of this technique in monitoring ASGPR-related liver dysfunction. Results: Ga-68-NOTA-GalNAc, a hydrophilic compound with high radiochemical purity (>99 %) and good liver targeting ability, particularly binds ASGPR on the surface of hepatocytes with moderate affinity (KD = 6.82 mu M). Compared with control, ASGPR-related liver dysfunction groups, even the group of mice with ALI (P <0.0001), revealed sensitive distinctions in the liver uptake value of Ga-68-NOTA-GalNAc. The Ga-68-NOTA-GalNAc absorbed in the livers of mice with early-stage liver fibrosis and NAFLD group is significantly less than that absorbed in the livers of mice in the normal group (P <0.0001). Hepatoma can be visualized in orthotopic HepG2 hepatoma-bearing mice because of different radioactivity accumulated in the nontumor region and lesion region, corresponding to the ASGPR expression confirmed with immunohistochemical staining. Conclusion: Ga-68-NOTA-GalNAc has the potential to be a specific, noninvasive, and sensitive PET imaging agent for ASGPR-related liver dysfunction.

This study aimed to investigate the diagnostic efficacy of [68Ga]Ga-NYM046 PET/CT in animal models and patients with clear cell renal cell carcinoma (ccRCC) and to compare its performance with that of 18F-FDG PET/CT. Methods: The in vivo biodistribution of [68Ga]Ga-NYM046 was evaluated in mice bearing OS-RC-2 xenografts. Twelve patients with ccRCC were included in the study; all completed paired [68Ga]Ga-NYM046 PET/CT and 18F-FDG PET/CT. The diagnostic efficacies of these 2 PET tracers were compared. Moreover, the positive rate of carbonic anhydrase IX in the pathologic tissue sections was compared with the SUVmax obtained by PET/CT. Results: The tumor accumulation of [68Ga]Ga-NYM046 at 1 h after injection in OS-RC-2 xenograft tumor models was 7.21 ± 2.39 injected dose per gram of tissue. Apart from tumors, the kidney and stomach showed high-uptake distributions. In total, 9 primary tumors, 96 involved lymph nodes, and 147 distant metastases in 12 patients were evaluated using [68Ga]Ga-NYM046 and 18F-FDG PET/CT. Compared with 18F-FDG PET/CT, [68Ga]Ga-NYM046 PET/CT detected more primary tumors (9 vs. 1), involved lymph nodes (95 vs. 92), and distant metastases (137 vs. 127). In quantitative analysis, the primary tumors' SUVmax (median, 13.5 vs. 2.4; z = -2.668, P = 0.008) was significantly higher in [68Ga]Ga-NYM046 PET/CT. Conversely, the involved lymph nodes' SUVmax (median, 5.9 vs. 7.6; z = -3.236, P = 0.001) was higher in 18F-FDG PET/CT. No significant differences were found for distant metastases (median SUVmax, 5.0 vs. 5.0; z = -0.381, P = 0.703). Higher [68Ga]Ga-NYM046 uptake in primary tumors corresponded to higher expression of carbonic anhydrase IX, with an R 2 value of 0.8274. Conclusion: [68Ga]Ga-NYM046 PET/CT offers a viable strategy for detecting primary tumors, involved lymph nodes, and distant metastases in patients with ccRCC.

Positron emission tomography/magnetic resonance (PET/MR) imaging combines the advantages of MR imaging with PET, provides more diagnostic information than single imaging modality. Asialoglycoprotein receptor (ASGPR) is abundantly expressed in the liver and has already been applied as a target for the hepatic imaging. Here we developed a Fe3O4 nanoparticle (NP)-based dual-modality probe targeting ASGPR for tumor PET/MR imaging. The dual-modality imaging probe was constructed by branched polyethyleneimine (PEI)-coated Fe3O4 NPs attached with N-acetylgalactosamine (GalNAc) derivatives and NOTA chelator, followed by radiolabeling with 68Ga. PET imaging results demonstrated that 68Ga-FPGN displayed high levels of uptake in the normal liver tissue and no or low uptake in tumors in situ. 68Ga-FPGN exhibited T2-weighted MRI, which reduced the T2 signal of normal liver tissue and enhance the visualization of tumor area. Our study proved the viability of 68Ga-FPGN as a novel PET/MR dual-modal probe for liver tumors imaging.

Rationale: Although programmed death-ligand 1 (PD-L1) inhibitors have achieved efficacy in cancer therapy, their response rate is low.Differences in the prognosis of patients with cancer under anti-PD-L1 treatment are related to the PD-L1 level in tumors.Accurate PD-L1 detection can optimize the accuracy of tumor immunotherapy and avoid ineffective clinical diagnosis and treatments.Methods: We investigated the imaging efficiency and therapy monitoring capacity of [ 89 Zr]Zr-DFO-KN035 immunoPET for tumors.We labeled the monodomain anti-PD-L1 antibody KN035 with the radionuclide zirconium-89 and used this tracer for PET imaging.[ 89 Zr]Zr-DFO-KN035 uptakes in patients with PD-L1-positive tumors, including primary and metastatic tumors, as well as in normal tissues, were comparatively assessed by using positron emission tomography/computed tomography imaging.Results: In PD-L1-positive patients, [ 89 Zr]Zr-DFO-KN035 was sensitive in tumor-targeting imaging and could detect multiple metastatic foci, including multiple bone metastases (tumor-to-muscle ratios of 7.102 and 6.118 at 55 and 120 h, respectively) and lymph-node metastases (tumor-to-muscle ratios of 11.346 and 6.542 at 55 and 120 h, respectively).The needed radioactive dose of [ 89 Zr]Zr-DFO-KN035 (55.5-92.5 MBq) used in this study was considerably lower than that of [ 18 F]FDG (370-555 MBq).[ 89 Zr]Zr-DFO-KN035 monitored and predicted the site of adverse reactions in antitumor immunotherapy.Moreover, after antitumor treatment, [ 89 Zr]Zr-DFO-KN035 enabled observational imaging for therapeutic efficacy evaluation, which can help predict patient prognosis.Conclusion: [ 89 Zr]Zr-DFO-KN035 can be used for the diagnosis and therapy monitoring of PD-L1-positive tumors and provide noninvasive and comprehensive observations for tumor diagnostic imaging, prognosis prediction, and efficacy evaluation.

Background:In the past 5 years, ferroptosis-associated cancer immunity has been attracted significant research interest.Objective:This study was performed to identify and analyze the global output trend for ferroptosis in cancer immunity.Methods:Relevant studies were retrieved from the Web of Science Core Collection on Feb 10th, 2023. The VOSviewer and Histcite softwares were utilized to perform the visual bibliometric and deep mining analyses.Results:A total of 694 studies (530 articles (76.4%) and 164 (23.6%) review articles) were retrieved from the Web of Science Core Collection for visualization analyses. The top 3 key keywords were ferroptosis, prognosis and immunotherapy. The top 30 local citation score (LCS) authors were all collaborators of Zou Weiping. Deep mining of 51 nanoparticle-related articles showed that BIOMATERIALS was the most popular journal. The primary goal of gene signatures related to ferroptosis and cancer immunity was to establish prognostic predictions.Conclusion:There has been a significant increase in ferroptosis-associated immune publications in the recent 3 years. The key research hotspots include mechanisms, prediction and therapeutic outcomes. The most influential article was from the Zou Weiping's group, which proposed that system xc-mediated ferroptosis is induced by CD8(+) T cell-secreted IFNγ after PD-L1 blockage for immunotherapy. The frontier of research in the field of ferroptosis-associated immune is the study on nanoparticle and gene signature The limitation of this bibliometric study is that publications on this topic are few.

Prostate-specific membrane antigen (PSMA) is a promising diagnostic biomarker for prostate cancer (PCa). NYM016, a novel small-molecule PSMA-targeted fluorescence probe for the surgical navigation of PCa, was designed in this work. Furthermore, the potential of the PET agent [68Ga]Ga–NYM016 for the radionuclide imaging of PCa was evaluated. NYM016 was designed with the near-infrared fluorescent group Cyanine 7 (Cy7) and the chelating group NOTA. The radioactive probe [68Ga]Ga–NYM016 was designed and synthesized on the basis of NYM016. The abovementioned probes were assessed in PSMA-positive xenograft-bearing models and patients diagnosed with PCa. NYM016 obviously aggregated in the tumor site of the mouse model, and its fluorescence intensity was stable within 24 h. NYM016 was well-tolerated, and no adverse events were found in the clinical study. Moreover, it was also observed in the excised lesions from the patient with PCa, and its fluorescence aggregated at the same site where PSMA was highly expressed. In addition, the PSMA xenograft demonstrated intense [68Ga]Ga–NYM016 uptake at 2.5 min after injection. At 3 h after injection, [68Ga]Ga–NYM016 uptake by the PSMA xenograft gradually increased to 6.40 ± 0.19