Gastrin-releasing Peptide Research Articles

A fluorescence-based lateral flow immunoassay using AIEgen-encapsulated nanoparticles to rapidly and sensitively detect pro-gastrin-releasing peptide.

Afluorescence lateral flow immunoassay (F-LFIA) is presentedusing nanoparticles with encapsulated molecules whose emission is caused by aggregation as the fluorescent label to quantitatively detect gastrin-releasing peptide precursor(proGRP) in serum. The detection system was optimized to achieve a broad linear detection range of 10 ~ 5000 pg/mL and a detection limit of 6 pg/mL for F-LFIA. The proposed method exhibited good sensitivity, specificity, and reproducibility. The performance and applicability of the F-LFIA were evaluated in the analysisof 183 human serum samples, and the results were strongly correlated with those of the electrochemiluminescence immunoassay. The proposed F-LFIA can serve as a precise and rapid detection method to detect proGRP and has potential for the early diagnosis of small-cell lung cancer (SCLC).

Serum biomarkers in neuroendocrine cell hyperplasia of infancy.

Neuroendocrine cell hyperplasia of infancy (NEHI) is a form of childhood interstitial lung disease of unknown origin associated with hyperplasia of pulmonary neuroendocrine cells (PNECs). Diagnosis is based on the characteristic clinical picture and typical radiological imaging, and, in some cases, on lung biopsies. To date, no biochemical indicators of the disease have been identified. We aimed to determine biomarkers that could be useful in the management of children diagnosed with NEHI. Patients with NEHI and healthy children were enrolled. Concentrations of serum biomarkers secreted by PNECs (calcitonin gene-related peptide and gastrin-releasing peptide) and biomarkers of the destruction of alveolar capillary membrane (surfactant proteins A and D [SP-A and SP-D]; glycoprotein Krebs von den Lungen-6 [KL-6]; metalloproteinases 7 and 9 [MMP-7 and MMP-9]; tissue inhibitor of metalloprotease 1) were measured. Fifty-two children with NEHI and 23 healthy children were included in the study. The median age of children with NEHI was 3.9 years. There were no differences in serum levels of biomarkers secreted by PNECs between groups. KL-6 levels were significantly higher in children with NEHI than in healthy ones (median 119.6 vs. 92.1 U/mL, p = 0.003); however, concentrations of KL-6 were low in both groups. No significant differences existed between groups for the remaining biomarkers associated with the destruction of the alveolar-capillary membrane. Measurement of serum biomarkers released by PNECs and those associated with the destruction of the alveolar-capillary membrane does not appear to be useful in the management of children with NEHI.

Synthesis and Evaluation of 68Ga- and 177Lu-Labeled [Pro14]bombesin(8-14) Derivatives for Detection and Radioligand Therapy of Gastrin-Releasing Peptide Receptor-Expressing Cancer.

The gastrin-releasing peptide receptor (GRPR) is overexpressed in a variety of cancers and represents a promising target for diagnosis and therapy. However, the extremely high accumulation in the pancreas observed for most of the clinically evaluated GRPR-targeted radiopharmaceuticals could limit their applications. In this study, we synthesized one GRPR antagonist (ProBOMB5) and two GRPR agonists (LW02056 and LW02057) by replacing the 4-thiazolidinecarboxylic acid (Thz14) residue in our previously reported GRPR-targeted tracers with Pro14. The 68Ga and 177Lu labeling were conducted in HEPES (2 M, pH 5.0) buffer and acetate (0.1 M, pH 4.5) buffer, respectively, and the radiolabeled products were obtained in a 24-57% decay-corrected radiochemical yield and >92% radiochemical purity. The binding affinities (Ki) of Ga-ProBOMB5, Ga-LW02056, Ga-LW02057, and Lu-ProBOMB5 were measured via in vitro competition binding assays and were 12.2 ± 1.89, 14.7 ± 4.81, 13.8 ± 2.24, and 13.6 ± 0.25 nM, respectively. The PET imaging and ex vivo biodistribution studies were conducted in PC-3 tumor-bearing mice at 1 h post injection. [68Ga]Ga-ProBOMB5, [68Ga]Ga-LW02056, and [68Ga]Ga-LW02057 enabled clear tumor visualization in PET images. The tumor uptake values of [68Ga]Ga-ProBOMB5, [68Ga]Ga-LW02056, and [68Ga]Ga-LW02057 were 12.4 ± 1.35, 8.93 ± 1.96, and 7.64 ± 0.55%ID/g, respectively, and their average pancreas uptake values were minimal (0.60-1.37%ID/g). Longitudinal SPECT imaging and ex vivo biodistribution studies were also conducted for [177Lu]Lu-ProBOMB5 and clinically validated [177Lu]Lu-RM2. Despite comparable tumor uptake at 1 h post injection ([177Lu]Lu-ProBOMB5:8.09 ± 1.70%ID/g; [177Lu]Lu-RM2:7.73 ± 0.96%ID/g), a faster clearance from PC-3 tumor xenografts was observed for [177Lu]Lu-ProBOMB5, leading to a lower radiation-absorbed dose delivered to tumors. Our data demonstrate that [68Ga]Ga-ProBOMB5 is a promising tracer for clinical translation for detecting GRPR-expressing tumor lesions. However, further optimizations are needed for [177Lu]Lu-ProBOMB5 to prolong tumor retention for therapeutic applications.

Head-to-Head Comparison of [68Ga]Ga-NOTA-RM26 and [18F]FDG PET/CT in Patients with Gastrointestinal Stromal Tumors: A Prospective Study.

Gastrointestinal stromal tumors (GISTs) are the most common stromal tumors in the gastrointestinal tract. This study was designed to evaluate a gastrin-releasing peptide receptor antagonist PET tracer, [68Ga]Ga-NOTA-RM26, and compare it with [18F]FDG PET/CT in the assessment of patients with GISTs. Methods: With institutional review board approval and informed consent, 30 patients with suspected or proven GISTs based on abdominal CT or gastroscopy were recruited. All patients underwent [68Ga]Ga-NOTA-RM26 and [18F]FDG PET/CT scans. Pathology and other patient information were collected. Results: No radiopharmaceutical-related adverse events were observed in the patients. In total, 18 lesions in 16 patients were diagnosed as GIST, 3 patients were diagnosed with schwannoma, and 4 patients were diagnosed with leiomyoma. In 18 GISTs, the mean SUVmax of [68Ga]Ga-NOTA-RM26 PET was significantly higher than that of [18F]FDG PET (17.07 ± 19.57 vs. 2.28 ± 1.65; P < 0.01), and [68Ga]Ga-NOTA-RM26 PET/CT had a higher tumor detection rate than did [18F]FDG PET/CT (88.9% vs. 50%; P < 0.01). The uptake of [68Ga]Ga-NOTA-RM26 in GISTs was significantly higher than that in 2 other benign tumors (leiomyoma or schwannoma) (17.07 ± 19.57 vs. 4.23 ± 1.77; P = 0.014). With the SUVmax cutoff value of 6.0, the sensitivity of 68Ga-NOTA-RM26 PET/CT in diagnosing GISTs is 72% and the specificity is 85.7%. Conclusion: Compared with [18F]FDG PET/CT, [68Ga]Ga-NOTA-RM26 PET/CT is a promising and effective imaging modality for the detection of GISTs.

Combining serum CDK1 with tumor markers for the diagnosis of small cell lung cancer.

An investigation of the diagnostic and clinical value of cell cycle-dependent kinase 1 (CDK1) in small cell lung cancer (SCLC). A large tertiary hospital in Jiangxi Province enrolled 80 SCLC cases, 105 cases of non-small cell lung cancer (NSCLC), 114 cases of pulmonary nodule (PN) and 60 control cases from December 2022 to December 2023. ELISA was used to measure CDK1 levels in serum. The expression levers of neuron-specific enolase (NSE), Pro gastrin-releasing peptide (ProGRP), squamous cell carcinoma antigen (SCCA), carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199) and cytokeratin 19 fragment (YFRA21-1) were detected by electrochemiluminescence immunoassay. ①CDK1, ProGRP, NSE, and CA199 expressions were significantly higher in the SCLC group compared to the NSCLC, PN and Control groups (P < 0.01). ②Spearman correlation analysis showed that serum levels of CDK1, NSE, and ProGRP were associated with clinical staging and lymph node metastasis in SCLC patients (P < 0.05). ③The serum levels of CDK1, NSE, and ProGRP in patients with extensive-disease (ED) SCLC were higher than those in patients with limited-disease (LD) SCLC (P < 0.05), and the serum levels of CDK1, NSE, and ProGRP in SCLC patients with lymph node metastasis were higher than those without lymph node metastasis (P < 0.05). ④Compared with the NSCLC group, the AUC of subjects diagnosed with SCLC by CDK1 was the largest and the sensitivity was the highest, 0.831 and 72.50%, the specificity of ProGRP in diagnosing SCLC is the highest, at 95.20% (P < 0.01). Compared with the PN group, CDK1 had the highest AUC, sensitivity, and specificity in diagnosing SCLC, with values of 0.93%, 88.80%, and 94.70%, respectively (P < 0.01). ⑤The combination of CDK1, ProGRP and NSE had the highest AUC and sensitivity of 0.903 and 86.30% for the diagnosis of SCLC (P < 0.01). CDK1 not only plays an important role in assisting the diagnosis of SCLC but also in the differential diagnosis between SCLC and NSCLC. The combination of CDK1 and NSE and ProGRP can significantly improve the diagnostic performance and provide new ideas for the clinical diagnosis of SCLC.

Kappa opioids inhibit spinal output neurons to suppress itch.

Itch is a protective sensation that drives scratching. Although specific cell types have been proposed to underlie itch, the neural basis for itch remains unclear. Here, we used two-photon Ca2+ imaging of the dorsal horn to visualize neuronal populations that are activated by itch-inducing agents. We identify a convergent population of spinal interneurons recruited by diverse itch-causing stimuli that represents a subset of neurons that express the gastrin-releasing peptide receptor (GRPR). Moreover, we find that itch is conveyed to the brain via GRPR-expressing spinal output neurons that target the lateral parabrachial nuclei. We then show that the kappa opioid receptor agonist nalfurafine relieves itch by selectively inhibiting GRPR spinoparabrachial neurons. These experiments provide a population-level view of the spinal neurons that respond to pruritic stimuli, pinpoint the output neurons that convey itch to the brain, and identify the cellular target of kappa opioid receptor agonists for the inhibition of itch.

Preclinical Investigation of [212Pb]Pb-DOTAM-GRPR1 for Peptide Receptor Radionuclide Therapy in a Prostate Tumor Model.

The role of gastrin-releasing peptide receptor (GRPR) in various diseases, including cancer, has been extensively studied and has emerged as a promising therapeutic target. In this study, we successfully achieved the use of [212Pb]Pb-DOTAM-GRPR1, comprising the α-particle generator, 212Pb, combined with a GRPR-targeting peptide, GRPR1, in a prostate cancer model. Methods: Pharmacokinetics, toxicity, radiation dosimetry, and efficacy were assessed in GRPR-positive prostate tumor-bearing mice after intravenous administration of [212Pb]Pb-DOTAM-GRPR1 (where DOTAM is 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane). Results: Preclinical studies have shown tumor targeting of up to 5 percent injected dose per gram over 24 h, and optimization of the drug formulation and quantity has led to minimized oxidation and off-target binding, respectively. Particularly, an increase in peptide amount from 28 to 280 ng was shown to reduce off-target uptake, especially at the level of the pancreas, by about 30%. Furthermore, dosimetry studies confirmed the kidney as the dose-limiting organ, and toxicity studies revealed that a nontoxic dose of up to 1,665 kBq could be injected into mice. Efficacy studies indicated a median survival time of 9 wk in the control group, which received only a buffer solution, compared with 19 wk in the group that received 4 injections of 370 kBq at 3-wk intervals. Conclusion: Taken together, these combined data demonstrate the safety, tolerability, and efficacy of [212Pb]Pb-DOTAM-GRPR1, thus warranting further exploration in clinical trials.

Gastrin-releasing peptide receptor as theranostic target in estrogen-receptor positive breast cancer: A preclinical study of the theranostic pair [55Co]Co- and [177Lu]Lu-DOTA-RM26

BackgroundPatients with advanced metastatic estrogen receptor-positive breast cancer often develop resistance to standard treatments, leading to uncontrolled progression. Thus, innovative therapies are urgently needed. The gastrin-releasing peptide receptor (GRPR) is overexpressed in various cancers, including breast cancer, making it an interesting theranostic target. RM26, a GRPR-targeting antagonist, has demonstrated promising in vivo kinetics in prostate cancer models. This study evaluated the theranostic capabilities of [55Co]Co−/[177Lu]Lu-DOTA-RM26 in vitro in estrogen receptor-positive breast cancer cells and assessed the diagnostic potential of [55Co]Co-DOTA-RM26 in vivo in a breast cancer mouse model. MethodsWe analyzed the binding specificity of [57Co]Co-/[177Lu]Lu-DOTA-RM26 in T47D breast cancer cells, using [57Co]Co-DOTA-RM26 as a surrogate for [55Co]Co-DOTA-RM26. The therapeutic efficacy of increasing [177Lu]Lu-DOTA-RM26 concentrations was determined via viability assay in vitro. Ex vivo biodistribution of [57Co]Co-DOTA-RM26 (17.2 ± 2.7 kBq, 33 ± 5.2 pmol/mouse) was investigated in 12 mice (n= 4/group) with orthotopic breast cancer tumors. The mice were sacrificed at 4 and 24 h post-injection (pi), including a blocking group (20 nmol of unlabeled [Tyr4]-Bombesin) at 4 h pi. For imaging, two tumor-bearing mice underwent [55Co]Co-DOTA-RM26 PET/CT, 4 and 24 h pi (2.8 ± 0.2 MBq, 167.5 ± 0.5 pmol/mouse), with or without GRPR blocking. ResultsIn vitro studies revealed high, specific binding of [57Co]Co-DOTA-RM26 (43 ± 1 % of total added activity per 106 cells (%IA/106)) and [177Lu]Lu-DOTA-RM26 (37 ± 4 %IA/106). The activity was predominantly localized at the cell surface: 71 ± 3 % and 80 ± 6 % for [57Co]Co-DOTA-RM26 and [177Lu]Lu-DOTA-RM26, respectively. [177Lu]Lu-DOTA-RM26 significantly reduced cell viability at all activity concentrations >0.625 MBq/mL (p < 0.0001), with cell viability below 1 % at concentrations ≥5 MBq/mL. Biodistribution data (n = 12) indicated a high, specific tumor uptake of [57Co]Co-DOTA-RM26, surpassing all other tissues significantly at both time points, 3.7 ± 0.6 % of the injected activity per gram (%IA/g) 4 h pi and 0.98 ± 0.05 %IA/g 24 h pi. The kidneys showed the second-highest uptake (2.0 ± 0.1 %IA/g 4 h pi), followed by the pancreas (1.4 ± 0.4 %IA/g 4 h pi). PET/CT imaging with [55Co]Co-DOTA-RM26 supported the biodistribution data and, distinctly visualized the tumor 24 h pi and showed an improved tumor-to-background compared to the earlier time points. Effective GRPR blocking significantly reduced tumor uptake in the PET images 24 h pi. ConclusionThese findings suggest that the theranostic pair [55Co]Co−/[177Lu]Lu-DOTA-RM26 holds significant promise as a theranostic agent for estrogen receptor-positive breast cancer.

Detection rate of gastrin-releasing peptide receptor (GRPr) targeted tracers for positron emission tomography (PET) imaging in primary prostate cancer: a systematic review and meta-analysis.

The gastrin-releasing peptide receptor (GRPr) has gained recognition as a promising target for both diagnostic and therapeutic applications in a variety of human cancers. This study aims to explore the primary tumor detection capabilities of [68Ga] Ga-GRPr PET imaging, specifically in newly diagnosed intra-prostatic prostate cancer lesions (PCa). Following PRISMA-DTA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy Studies) guidelines, a systematic literature search was conducted using the Medline, Embase, Scopus, and Web of Science databases. Data regarding patient characteristics and imaging procedure details-including the type of radiotracer used, administered activity, image acquisition time, scanner modality, criteria, and detection rate of index test-were extracted from the included studies. The pooled patient-and lesion-based detection rates, along with their corresponding 95% confidence intervals (CI), were calculated using a random effects model. The final analysis included 9 studies involving 291 patients and 350 intra-prostatic lesions with [68Ga] Ga-GRPr PET imaging in primary PCa. In per-patient-based analysis of [68Ga] Ga-GRPr PET imaging, the pooled detection rates of overall and patients with Gleason score ≥ 7 were 87.09% (95% CI 74.98-93.82) and 89.01% (95% CI 68.17-96.84), respectively. In per-lesion-based analysis, the pooled detection rate [68Ga] Ga-GRPr PET imaging was 78.54% (95% CI 69.8-85.29). The pooled detection rate mpMRI (multiparametric magnetic resonance imaging) in patient-based analysis was 91.85% (95% CI 80.12-96.92). The difference between the detection rates of the mpMRI and [68Ga] Ga-GRPr PET imaging was not statistically significant (OR 0.90, 95% CI 0.23-3.51). Our findings suggest that [68Ga] Ga-GRPr PET imaging has the potential as a diagnostic target for primary PCa. Future research is needed to determine the effectiveness of [68Ga] Ga-GRPr PET in delivering additional imaging data and guiding therapeutic decisions.

Linking GERD and the Peptide Bombesin: A New Therapeutic Strategy to Modulate Inflammatory, Oxidative Stress and Clinical Biochemistry Parameters.

Gastroesophageal reflux disease (GERD) represents one of the most prevalent foregut illnesses, affecting a large portion of individuals worldwide. Recent research has shown that inflammatory mediators such as cytokines, chemokines, and enzymes are crucial for causing esophageal mucosa alterations in GERD patients. It seems likely that the expression of various cytokines in the esophageal mucosa also induces oxidative stress by increasing the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). As humoral agents and peptidergic neurotransmitters that may support the enterogastric axis, bombesin and its related bombesin-like peptide, GRP (gastrin releasing peptide), have not been fully investigated. Therefore, considering all these assumptions, this study aimed to evaluate the influence of bombesin in reestablishing biochemical markers linked with inflammation and oxidative/nitrosative stress in GERD pathological settings. C57BL/6 mice were alternatively overfed and fasted for 56 days to induce GERD and then treated with bombesin (0.1, 0.5, and 1 mg/kg intraperitoneally) once daily for 7 days, and omeprazole was used as the positive control. After 7 days of treatment, gastric pain and inflammatory markers were evaluated. Abdominal pain was significantly reduced following bombesin administration, which was also successful in diminishing inflammatory and oxidative/nitrosative stress markers in a manner overlapping with omeprazole. Moreover, bombesin was also able to appreciably modulate gastric pH as a result of the restoration of gastric homeostasis. Overall, these observations indicated that the upregulation of bombesin and interconnected peptides is a promising alternative approach to treat GERD patients.

Evaluation of ABD-Linked RM26 Conjugates for GRPR-Targeted Drug Delivery.

Targeting the gastrin-releasing peptide receptor (GRPR) with the bombesin analogue RM26, a 9 aa peptide, has been a promising strategy for cancer theranostics, with recent success in radionuclide imaging of prostate cancer. However, therapeutic application of the short peptide RM26 would require a longer half-life to prevent fast clearance from the circulation. Conjugation to an albumin-binding domain (ABD) is a viable strategy to extend the in vivo half-life of peptides and proteins. We previously reported an ABD-fused RM26 peptide targeting GRPR (ABD-RM26 Gen 1) that showed prolonged and stable tumor uptake over 144 h; however, the observed high kidney uptake indicated that the conjugate's binding to albumin was reduced and that this could be an obstacle for its use as a delivery system for targeted therapy, especially for radiotherapy. Here, we have designed, produced, and preclinically evaluated a series of novel ABD-RM26 conjugates with the aim of improving the conjugate's binding to albumin and decreasing the kidney uptake. We developed three second-generation constructs with varying formats, differing in the relative positions of the targeting moieties and the radionuclide chelator. The produced conjugates were radiolabeled with indium-111 and evaluated in vitro and in vivo. All constructs displayed improved biophysical characteristics, biodistribution, and lower kidney uptake compared to previously reported first-generation molecules. The ABD-RM26 Gen 2A conjugate showed the best biodistribution profile with a nearly 6-fold reduction in kidney uptake. However, the ABD-RM26 Gen 2A conjugate's binding to GRPR was compromised. This conjugate's assembly of albumin- and GRPR-binding moieties might be used for further development of drug conjugates for targeted therapy/radiotherapy of GRPR-expressing cancers.

Targeted radionuclide therapy for gliomas: emerging clinical trial landscape.

According to the new WHO classification of 2021, gliomas are a heterogeneous group of tumors with very different histology, molecular genetics and prognoses. In addition to glioblastomas, the most common gliomas, there are also numerous less common gliomas, some of which have a very favorable prognosis. Targeted radionuclide therapy is a therapeutic option that can be attractive if a tumor can be targeted based on its molecular characteristics. It is particularly useful when tumors cannot be completely resected or when conventional imaging does not fully capture the extent of the tumor. Numerous approaches to radionuclide therapy for gliomas are in early development. The most advanced approaches for patients with gliomas in the clinic employ L-type amino acid transporter 1 as an uptake mechanism for radiolabeled amino acids or target somatostatin receptor 2 or gastrin-releasing peptide receptor. Here, we discuss the various target structures of radionuclide therapy in gliomas and provide an outlook for which glioma entities radionuclide therapy could most likely provide a therapeutic alternative.

Radiopharmaceuticals Targeting Gastrin-Releasing Peptide Receptor for Diagnosis and Therapy of Prostate Cancer.

The high incidence and heavy disease burden of prostate cancer (PC) require accurate and comprehensive assessment for appropriate disease management. Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) cannot detect PSMA-negative lesions, despite its key role in PC disease management. The overexpression of gastrin-releasing peptide receptor (GRPR) in PC lesions reportedly performs as a complementary target for the diagnosis and therapy of PC. Radiopharmaceuticals derived from the natural ligands of GRPR have been developed. These radiopharmaceuticals enable the visualization and quantification of GRPR within the body, which can be used for disease assessment and therapeutic guidance. Recently developed radiopharmaceuticals exhibit improved pharmacokinetic parameters without deterioration in affinity. Several heterodimers targeting GRPR have been constructed as alternatives because of their potential to detect tumor lesions with a low diagnostic efficiency of single target detection. Moreover, some GRPR-targeted radiopharmaceuticals have entered clinical trials for the initial staging or biochemical recurrence detection of PC to guide disease stratification and therapy, indicating considerable potential in PC disease management. Herein, we comprehensively summarize the progress of radiopharmaceuticals targeting GRPR. In particular, we discuss the impact of ligands, chelators, and linkers on the distribution of radiopharmaceuticals. Furthermore, we summarize a potential design scheme to facilitate the advancement of radiopharmaceuticals and, thus, prompt clinical translation.

Adrenergic Agonists Activate Transcriptional Activity in Immortalized Neuronal Cells From the Mouse Suprachiasmatic Nucleus.

The suprachiasmatic nucleus of the hypothalamus (SCN) houses the central circadian oscillator of mammals. The main neurotransmitters produced in the SCN are γ-amino-butyric acid, arginine-vasopressin (AVP), vasoactive intestinal peptide (VIP), pituitary-derived adenylate cyclase-activating peptide (PACAP), prokineticin 2, neuromedin S, and gastrin-releasing peptide (GRP). Apart from these, catecholamines and their receptors were detected in the SCN as well. In this study, we confirmed the presence of β-adrenergic receptors in SCN and a mouse SCN-derived immortalized cell line by immunohistochemical, immuno-cytochemical, and pharmacological techniques. We then characterized the effects of β-adrenergic agonists and antagonists on cAMP-regulated element (CRE) signaling. Moreover, we investigated the interaction of β-adrenergic signaling with substances influencing parallel signaling pathways. Our findings have potential implications on the role of stress (elevated adrenaline) on the biological clock and may explain some of the side effects of β-blockers applied as anti-hypertensive drugs.

Utility of 64Cu-Sarcophagine-Bombesin PET/CT in Men with Biochemically Recurrent Prostate Cancer and Negative or Equivocal Findings on 68Ga-PSMA-11 PET/CT.

Despite a high detection rate of 68Ga-prostate-specific membrane antigen (PSMA) PET/CT in biochemical recurrence (BCR) of prostate cancer, a significant proportion of men have negative 68Ga-PSMA-11 PET/CT results. Gastrin-releasing peptide receptor, targeted by the copper-chelated bombesin analog 64Cu-sarcophagine-bombesin (SAR-BBN) PET/CT, is also overexpressed in prostate cancer. In this prospective imaging study, we investigate the detection rate of 64Cu-SAR-BBN PET/CT in patients with BCR and negative or equivocal 68Ga-PSMA-11 PET/CT results. Methods: Men with confirmed adenocarcinoma of the prostate, prior definitive therapy, and BCR (defined as a prostate-specific antigen [PSA] level > 0.2 ng/mL) with negative or equivocal 68Ga-PSMA-11 PET/CT results within 3 mo were eligible for enrollment. 64Cu-SAR-BBN PET/CT scans were acquired at 1 and 3 h after administration of 200 MBq of 64Cu-SAR-BBN, with further delayed imaging undertaken optionally at 24 h. PSA (ng/mL) was determined at baseline. All PET (PSMA and bombesin) scans were assessed visually. Images were read with masking of the clinical results by 2 experienced nuclear medicine specialists, with a third reader in cases of discordance. Accuracy was defined using a standard of truth that included biopsy confirmation, confirmatory imaging, or response to targeted treatment. Results: Twenty-five patients were enrolled. Prior definitive therapy was radical prostatectomy (n = 24, 96%) or radiotherapy (n = 1, 4%). The median time since definitive therapy was 7 y (interquartile range [IQR], 4-11 y), and the Gleason score was 7 or less (n = 15, 60%), 8 (n = 3, 12%), or 9 (n = 7, 28%). The median PSA was 0.69 ng/mL (IQR, 0.28-2.45 ng/mL). Baseline PSMA PET scans were negative in 19 patients (76%) and equivocal in 6 (24%). 64Cu-SAR-BBN PET-avid disease was identified in 44% (11/25): 12% (3/25) with local recurrence, 20% (5/25) with pelvic node metastases, and 12% (3/25) with distant metastases. The κ-score between readers was 0.49 (95% CI, 0.16-0.82). Patients were followed up for a median of 10 mo (IQR, 9-12 mo). Bombesin PET/CT results were true-positive in 5 of 25 patients (20%), false-positive in 2 of 25 (8%), false-negative in 7 of 25 (28%), and unverified in 11 of 25 (44%). Conclusion: 64Cu-SAR-BBN PET/CT demonstrated sites of disease recurrence in 44% of BCR cases with negative or equivocal 68Ga-PSMA-11 PET/CT results. Further evaluation to confirm diagnostic benefit is warranted.

Bimodal MRI/Fluorescence Nanoparticle Imaging Contrast Agent Targeting Prostate Cancer.

We developed a novel site-specific bimodal MRI/fluorescence nanoparticle contrast agent targeting gastrin-releasing peptide receptors (GRPrs), which are overexpressed in aggressive prostate cancers. Biocompatible ultra-small superparamagnetic iron oxide (USPIO) nanoparticles were synthesized using glucose and casein coatings, followed by conjugation with a Cy7.5-K-8AOC-BBN [7-14] peptide conjugate. The resulting USPIO(Cy7.5)-BBN nanoparticles were purified by 100 kDa membrane dialysis and fully characterized using transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier transform infrared (FTIR) spectroscopy, and magnetic resonance imaging (MRI) relaxivity, as well as evaluated for in vitro and in vivo binding specificity and imaging efficacy in PC-3 prostate cancer cells and xenografted tumor-bearing mice. The USPIO(Cy7.5)-BBN nanoparticles had a core diameter of 4.93 ± 0.31 nm and a hydrodynamic diameter of 35.56 ± 0.58 nm. The r2 relaxivity was measured to be 70.2 ± 2.5 s-1 mM-1 at 7T MRI. The Cy7.5-K-8AOC-BBN [7-14] peptide-to-nanoparticle ratio was determined to be 21:1. The in vitro GRPr inhibitory binding (IC50) value was 2.5 ± 0.7 nM, indicating a very high binding affinity of USPIO(Cy7.5)-BBN to the GRPr on PC-3 cells. In vivo MRI showed significant tumor-to-muscle contrast enhancement in the uptake group at 4 h (31.1 ± 3.4%) and 24 h (25.7 ± 2.1%) post-injection compared to the blocking group (4 h: 15.3 ± 2.0% and 24 h: -2.8 ± 6.8%; p < 0.005). In vivo and ex vivo near-infrared fluorescence (NIRF) imaging revealed significantly increased fluorescence in tumors in the uptake group compared to the blocking group. These findings demonstrate the high specificity of bimodal USPIO(Cy7.5)-BBN nanoparticles towards GRPr-expressing PC-3 cells, suggesting their potential for targeted imaging in aggressive prostate cancer.

Synthesis and Evaluation of the First 68Ga-Labeled C-Terminal Hydroxamate-Derived Gastrin-Releasing Peptide Receptor-Targeted Tracers for Cancer Imaging with Positron Emission Tomography.

Gastrin-releasing peptide receptor (GRPR), overexpressed in many solid tumors, is a promising imaging marker and therapeutic target. Most reported GRPR-targeted radioligands contain a C-terminal amide. Based on the reported potent antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH, we synthesized C-terminal hydroxamate-derived [68Ga]Ga-LW02075 ([68Ga]Ga-DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH) and [68Ga]Ga-LW02050 ([68Ga]Ga-DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH), and compared them with the closely related and clinically validated [68Ga]Ga-SB3 ([68Ga]Ga-DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt). Binding affinities (Ki) of Ga-SB3, Ga-LW02075, and Ga-LW02050 were 1.20 ± 0.31, 1.39 ± 0.54, and 8.53 ± 1.52 nM, respectively. Both Ga-LW02075 and Ga-LW02050 were confirmed to be GRPR antagonists by calcium release assay. Imaging studies showed that PC-3 prostate cancer tumor xenografts were clearly visualized at 1 h post injection by [68Ga]Ga-SB3 and [68Ga]Ga-LW02050 in PET images, but not by [68Ga]Ga-LW02075. Ex vivo biodistribution studies conducted at 1 h post injection showed that the tumor uptake of [68Ga]Ga-LW02050 was comparable to that of [68Ga]Ga-SB3 (5.38 ± 1.00 vs. 6.98 ± 1.36 %ID/g), followed by [68Ga]Ga-LW02075 (3.97 ± 1.71 %ID/g). [68Ga]Ga-SB3 had the highest pancreas uptake (37.3 ± 6.90 %ID/g) followed by [68Ga]Ga-LW02075 (17.8 ± 5.24 %ID/g), while the pancreas uptake of [68Ga]Ga-LW02050 was only 0.53 ± 0.11 %ID/g. Our data suggest that [68Ga]Ga-LW02050 is a promising PET tracer for detecting GRPR-expressing cancer lesions.

Effectiveness Analysis of the Combined Detection of CEA, SCC, CYFRA21-1, NSE and ProGRP for Early Diagnosis of Lung Cancer

Objective To explore the diagnostic value and application effect of the combined detection of CEA (carcinoembryonic antigen), SCC (squamous cell carcinoma antigen), CYFRA21-1 (soluble fragment of cytokeratin 19), NSE (neuron specific enolase) and proGRP (gastrin releasing peptide precursor) in early lung cancer. Method 66 patients who admitted to the hospital from April 2019 to February 2024 were selected as the early stage lung cancer group and the other 159 patients were selected as the benign lung group, in which all subjects were tested for NSE, CEA, ProGRP, CYFRA21-1, and SCC levels and were confirmed by histopathological analysis. In ROC analysis, the cut-off point, AUC, accuracy, sensitivity and specificity between single and combined detection indicators are analyzed. Result The size of cut-off point, AUC, accuracy, sensitivity, specificity, positive and negative detection rate and accuracy rate is 0.3072, 0.790, 89.33%, 0.894, 0.893, 89.40% (59/66), 89.31% (142/159) and 89.33% ((142+59)/225) respectively and it is obviously superior to those of single detection method. Meanwhile, indicator of SCC showed the worst performance by single detection. Conclusion The combined detection indicators have high diagnostic value in early diagnosis of lung cancer, and the sensitivity, positive detection rate, AUC value and accuracy have been significantly improved.

Evaluation of gastrin-releasing peptide receptor, prostate-specific membrane antigen, and neurotensin receptor 1 as potential biomarkers for accurate prostate cancer stratified diagnosis

BackgroundStudies on single-target PET imaging of gastrin-releasing peptide receptor (GRPR), prostate-specific membrane antigen (PSMA), or neurotensin receptor 1(NTR1) have been reported. However, the performance of these three targets in the progression of PCa remains unclear. Our study aims to compare the expression of GRPR, PSMA, and NTR1 in patients with prostatic intraepithelial neoplasia (PIN), prostate cancer (PCa), and lymph node metastasis. We synthesized molecular probes targeting the markers to achieve a non-invasive precise detection of PCa patients with PET/CT imaging.MethodsIn this study, the expression of GRPR, PSMA, and NTR1 was evaluated by immunohistochemistry in 34 PIN, 171 PCa, and 22 lymph node metastasis tissues of patients. The correlation between their expression and the clinicopathological parameters of PCa patients was assessed. Sixteen PCa patients with different Gleason scores (GS) underwent dual-tracer (68Ga-NOTA-RM26 and 68Ga-NOTA-PSMA617) PET/CT.ResultsIn the PIN stage, the expression of GRPR was significantly higher than that of PSMA and NTR1 (P < 0.001), while NTR1 expression was significantly higher than PSMA and GRPR expression in primary PCa (P = 0.001). High PSMA expression in PCa patients was associated with shorter progression-free survival (P = 0.037) and overall survival (P = 0.035). PCa patients with high GS had higher tumor uptake of 68Ga-NOTA-PSMA617 than those with low GS (P = 0.001), while PCa patients with low GS had higher tumor uptake of 68Ga-NOTA-RM26 than those with high GS (P = 0.001).ConclusionsThis study presents three novel biomarkers (PSMA, GRPR, and NTR1) as imaging agents for PET/CT, and may offer a promising approach for non-invasive precise detection and Gleason grade prediction of PCa patients.

Sigh generation in preBötzinger Complex.

We explored neural mechanisms underlying sighing. Photostimulation of parafacial (pF) neuromedin B (NMB) or gastrin releasing peptide (GRP), or preBötzinger Complex (preBötC) NMBR or GRPR neurons elicited ectopic sighs with latency inversely related to time from preceding endogenous sigh. Of particular note, ectopic sighs could be produced without involvement of these peptides or their receptors in preBötC. Moreover, chemogenetic or optogenetic activation of preBötC SST neurons induced sighing, even in the presence of NMBR and/or GRPR antagonists. We propose that an increase in the excitability of preBötC NMBR or GRPR neurons not requiring activation of their peptide receptors activates partially overlapping pathways to generate sighs, and that preBötC SST neurons are a downstream element in the sigh generation circuit that converts normal breaths into sighs.