Xiaoping Xu

Ephrin type-A receptor 2 (EphA2) is a promising target in pancreatic ductal adenocarcinoma (PDAC). However, the clinical potential of targeting EphA2 requires further imaging evaluation. This study developed and preliminarily evaluated a novel ⁶⁸Ga-labeled radiotracer for PET imaging of EphA2 expression in PDAC patients. ⁶⁸Ga-FZEAR-1, ⁶⁸Ga-FZEAR-2, and ⁶⁸Ga-FZEAR-3 were synthesized, and their stability, affinity, pharmacokinetics were evaluated in vitro and in vivo. Further biological evaluation was performed in EphA2-positive and EphA2-negative tumor xenografts. A pilot first-in-human PET/CT study of the lead candidate, ⁶⁸Ga-FZEAR-2, was subsequently conducted in two PDAC patients. The three ⁶⁸Ga-radiotracers were synthesized with high radiochemical purity (> 99%) and demonstrated high stability and nanomolar affinity for EphA2. Cellular uptake was consistent with EphA2 expression and blocking assays confirmed specificity. In vivo, all tracers exhibited high tumor accumulation with low off-target uptake. ⁶⁸Ga-FZEAR-2 showed favorable tumor-targeting ability, pharmacokinetics, and safety profile. In the pilot clinical study (n = 2), ⁶⁸Ga-FZEAR-2 PET/CT visualized primary and metastatic lesions clearly without adverse effects. Immunohistochemical analysis confirmed EphA2 expression in lesions exhibiting high tracer uptake. A series of ⁶⁸Ga-labeled tracers for EphA2 imaging was successfully developed and evaluated. The lead candidate, ⁶⁸Ga-FZEAR-2, showed promising targeting specificity and favorable pharmacokinetics. A pilot study indicated that ⁶⁸Ga-FZEAR-2 provided preliminary evidence of noninvasive visualization of EphA2 expression in PDAC patients, thereby suggesting its potential as a tool for precision diagnosis in PDAC.

Nectin-4 is markedly overexpressed in urothelial carcinoma (UC) and represents a promising theranostic target for both radiotherapy and positron emission t

Background Prognostic stratification for microsatellite stable (MSS) gastric cancer (GC) remains challenging. This study evaluated the predictive and prognostic value of [⁶⁸Ga]Ga-NOTA-GSI PET/CT imaging in a large cohort of MSS GC patients receiving chemo-immunotherapy. Methods In this retrospective study, 145 patients with MSS GC underwent [⁶⁸Ga]Ga-NOTA-GSI PET/CT after two or three cycles of chemo-immunotherapy. Measurements included SUVmax, SUVmean, GSI tumor volume (GSI-TV), total lesion uptake (TLU), tumor-liver ratio (TLR), and tumor-blood ratio (TBR). The study analyzed associations between short-term treatment response (RECIST 1.1 or tumor regression grade score) and progression-free survival (PFS) using receiver operating characteristic (ROC) curves, logistic regression, and Cox proportional hazards models. Results Responders exhibited significantly higher uptake of [⁶⁸Ga]Ga-NOTA-GSI than non-responders, including SUVmax, sumSUVmax, and TBR (all P < 0.05) across all patients and various subgroups, while volumetric parameters (GSI-TV, TLU) showed no notable difference. SUVmax was a reliable predictor of response (AUC = 0.755 for all patients; AUC = 0.882 for the neoadjuvant subgroup). In survival analysis, an SUVmax ≥ 2.6 independently predicted significantly longer PFS (median PFS of 14.0 vs. 9.0 months; hazard ratio, 0.673; P = 0.016). Conclusion The study highlighted the significant value of [⁶⁸Ga]Ga-NOTA-GSI PET/CT in assessing the effectiveness of chemo-immunotherapy and predicting outcomes in MSS gastric cancer patients. Subgroup analysis confirmed its reliable predictive power across neoadjuvant, palliative, and adjuvant treatments, supporting the potential for its broad clinical application.

Purpose AG10 is a molecule that can bind to the thyroxine (T4) binding pocket of transthyretin (TTR). The reversible association between the hydrophilic peptides and TTR using AG10 could increase the circulation half-life (t_1/2). We hypothesized that modifying PSMA-617 with AG10 could extend the t_1/2 of PSMA-617 and mitigate the limitations caused by insufficient uptake. The aim of this study was to develop an optimal AG10-modified radiotherapeutic agent that could maximize both tumor uptake and absorbed dose, thereby enhancing therapeutic efficacy for the treatment of tumors, even with moderate PSMA expression. Methods Lysine was used as a linker for the conjugation of PSMA-617 and AG10 to synthesize AG10-PSMA-617 (AP-01). AP-01 was labeled with ⁶⁸Ga to image prostate carcinoma xenografts with moderate PSMA expression, serving as a reference for PSMA radio-ligand therapy (PRLT) based treatments. AP-01 was labeled with ¹⁷⁷Lu for the treatment of prostate carcinoma xenografts with moderate PSMA expression. The binding properties and biodistribution of ⁶⁸Ga-AP-01 and ¹⁷⁷Lu-AP-01 were studied both in vitro and in vivo. The cytotoxic effects of the ¹⁷⁷Lu-AP-01 were evaluated in prostate carcinoma xenografts. Results PSMA-617 was successfully conjugated with AG10 using lysine as the linker and labeled with ¹⁷⁷Lu to produce PRLT radiopharmaceuticals-¹⁷⁷Lu-AP-01. AP-01 was labeled with ⁶⁸Ga for imaging prostate carcinoma with moderate PSMA expression. AP-01 demonstrated a high binding affinity (IC₅₀ = 3.42 nM) for PSMA in vitro, comparable to that of PSMA-617 (IC₅₀ = 3.38 nM) (P = 0.324). PET/CT imaging of ⁶⁸Ga-AP-01 demonstrated significantly improved tumor uptake and retention as compared with ⁶⁸Ga-PSMA-617. The maximum uptake of ⁶⁸Ga-AP-01 and ⁶⁸Ga-PSMA-617 by 22Rv1 tumors was 18.07 ± 1.19%ID/g and 9.27 ± 1.20%ID/g at 4 h pi, respectively (P < 0.05). The in vivo targeting abilities of ¹⁷⁷Lu-AP-01 were evaluated through SPECT/CT imaging. The tumor (maximum)-to-muscle (maximum) (T/Mmax) ratio of ¹⁷⁷Lu-AP-01 was 49.28 ± 7.18 at 72 h pi. However, the T/Mmax ratio of ¹⁷⁷Lu-PSMA-617 was 8.39 ± 8.57 at 48 h pi. Biodistribution studies further confirmed the significantly higher tumor uptake of ¹⁷⁷Lu-AP-01 (4.87 ± 0.91%ID/g) compared to ¹⁷⁷Lu-PSMA-617 (1.12 ± 0.01%ID/g) at 96 h post-injection (P < 0.05). The inhibitory efficiency of ¹⁷⁷Lu-AP-01 on 22Rv1 tumor xenografts was 88.36%, which was superior to that of ¹⁷⁷Lu-PSMA-617 (73.36%) (P < 0.05). ¹⁷⁷Lu-AP-01 demonstrated no toxic effects on hepatorenal function, routine blood tests, or major organs in mice when compared to the control group. Conclusion In this study, AP-01 was successfully synthesized. ⁶⁸Ga-AP-01 and ¹⁷⁷Lu-AP-01 were obtained with high radiochemical purity and stability. High binding affinity and PSMA targeting specificity were identified in vitro and in vivo. With significantly enhanced tumor uptake and retention, ¹⁷⁷Lu-AP-01 has the potential to improve therapeutic efficacy for the treatment of prostate cancer with moderate PSMA expression.

A dual approach – targeting tumor cells with Tf and unleashing the immune system with mild PTT and PD-L1 blockade – created a favorable environment for long-lasting antitumor immunity.

Nectin cell adhesion molecule 4 (Nectin-4) is an emerging biomarker for cancer diagnosis and therapy. We developed a Nectin-4-targeted ⁶⁸Ga-DOTA-Sar10-Nectin-4 (⁶⁸Ga-FZ-NR-1) PET/CT radiotracer for detecting Nectin-4 expression in a tumor model and in triple-negative breast cancer (TNBC) patients. Methods: A series of Nectin-4-targeted radiotracers-⁶⁸Ga-FZ-NR-1, ⁶⁸Ga-DOTA-polyethylene glycol 5-Nectin-4 (⁶⁸Ga-FZ-NR-2), and ⁶⁸Ga-DOTA-polyethylene glycol 10-Nectin-4 (⁶⁸Ga-FZ-NR-3)-were synthesized, and their targeting ability and specificity were evaluated in vitro and in vivo. In vitro experiments were performed in the MDA-MB-468 (Nectin-4-positive) and MDA-MB-231 (Nectin-4-negative) cell lines. PET/CT imaging in tumor models was performed to assess the Nectin-4-targeting ability of the radiotracers. After preclinical experiments and screening, the ⁶⁸Ga-FZ-NR-1 radiotracer was selected for safety and efficacy evaluation in a first-in-human trial in TNBC patients. Positive lesions were biopsied and analyzed by immunohistochemistry to determine Nectin-4 expression levels. Results: The 3 ⁶⁸Ga-labeled radiotracers exhibited high radiochemical purity, stability, and strong affinity for Nectin-4. In vitro cell uptake studies showed that the radiotracers effectively targeted Nectin-4 in MDA-MB-468 cells, and ⁶⁸Ga-FZ-NR-1 showed the highest targeting efficacy. In the MDA-MB-468 tumor model, PET/CT imaging showed that ⁶⁸Ga-FZ-NR-1 was taken up at higher rates than ⁶⁸Ga-FZ-NR-2 and ⁶⁸Ga-FZ-NR-3, and it exhibited favorable pharmacokinetics and safety profiles. ⁶⁸Ga-FZ-NR-1 was thus selected for subsequent clinical trials. ⁶⁸Ga-FZ-NR-1 PET/CT effectively identified tumors in 9 patients with TNBC, which was confirmed by ¹⁸F-FDG PET/CT. Biopsy samples of the tumor lesions revealed that the positive lesions identified by ⁶⁸Ga-FZ-NR-1 PET/CT corresponded to areas of high Nectin-4 expression. Conclusion: A series of Nectin-4-targeted radiotracers (⁶⁸Ga-FZ-NR-1, ⁶⁸Ga-FZ-NR-2, and ⁶⁸Ga-FZ-NR-3) was developed and evaluated. Preclinical studies demonstrated that ⁶⁸Ga-FZ-NR-1 can identify tumors with high Nectin-4 expression. In a preliminary clinical study, ⁶⁸Ga-FZ-NR-1 was used to effectively identify and visualize Nectin-4-expressing tumor lesions in patients with TNBC, which was confirmed by immunohistochemistry. This radiotracer provides a noninvasive approach to the assessment of Nectin-4 and a potential basis for the development of Nectin-4-targeted treatments for TNBC.

Purpose: None of the antibody-drug conjugates (ADCs) targeting Claudin 18.2 (CLDN18.2) have received approval from regulatory authorities due to their limited clinical benefits. Leveraging the radiosensitizing ability of Deruxtecan (DXd) and the internal radiation therapy of ¹³¹I for tumors, we aimed to develop the first radio-antibody-drug conjugates (RADCs) for the treatment of gastric cancer. Methods: The CLDN18.2-specific antibody HLX58 was conjugated with the payload DXd through a cleavable maleimide glycynglycyn-phenylalanyn-glycyn (GGFG) peptide linker. HLX58-Der was labeled with ¹³¹I to produce RADC-¹³¹I-HLX58-Der. HLX58 was labeled with ¹²⁵I for imaging CLDN18.2-positive tumors, providing a reference for RADC treatment in solid tumors. The antigen-binding properties and biodistribution of the RADC were studied both in vitro and in vivo. The cytotoxic effects of the RADC were evaluated in CLDN18.2-positive tumor cell lines and xenografts. Results: HLX58 was successfully conjugated with DXd using the cleavable maleimide GGFG peptide linker and labeled with ¹³¹I to produce RADC-¹³¹I-HLX58-Der. HLX58 was labeled with ¹²⁵I for imaging CLDN18.2-positive tumors. Both ¹²⁵I-HLX58 and ¹³¹I-HLX58-Der exhibited significant binding affinity for the CLDN18.2-positive cancer cell line. The cytotoxic effect of ¹³¹I-HLX58-Der was observed in the CLDN18.2-positive cell line, with an IC₅₀ of 11.28 ng/mL. In terms of cytotoxicity, ¹³¹I-HLX58-Der exhibited greater activity compared to HLX58-Der. ¹²⁵I-HLX58 and ¹³¹I-HLX58-Der demonstrated similar biodistribution profiles in CLDN18.2-positive tumor models, achieving 5.72 ± 0.41%ID/g (48 h) and 5.83 ± 0.41%ID/g (72 h) in the tumor tissues postinjection, respectively. The average tumor size in groups treated with ¹³¹I-HLX58-Der and HLX58-Der was reduced by factors of 12.15 and 4.80, respectively, compared to the control group. ¹³¹I-HLX58-Der demonstrated no toxic effects on hepatorenal function, routine blood tests, or major organs in mice when compared to the control group. Conclusion: These findings validate the potential of RADCs targeting CLDN18.2 in treating CLDN18.2-expressing solid tumors.

The authors recently became aware that in Figure 7F, an incorrect image was shown for α-SMA staining of the KN046-treated sample. The correct image, provided from the original source data,