6,320 results on '"Bombesin"'
Search Results
2. Reconstructing the cell-cell interaction network among mouse immune cells.
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Azadian, Somayeh, Doustmohammadi, Alireza, Naseri, Mohadeseh, Khodarahmi, Masoud, Arab, Seyed, Yazdanifar, Mahboubeh, Zahiri, Javad, and Lewis, Nathan
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cell-cell interaction ,immune system ,immunological genome project ,intercellular interaction ,network reconstruction ,Signal Transduction ,Neurokinin B ,Receptors ,Bombesin ,Stromal Cells ,Immunotherapy ,Ligands ,Lymph Nodes ,Blood Cells ,Immune System - Abstract
Intercellular interactions and cell-cell communication are critical to regulating cell functions, especially in normal immune cells and immunotherapies. Ligand-receptor pairs mediating these cell-cell interactions can be identified using diverse experimental and computational approaches. Here, we reconstructed the intercellular interaction network between Mus musculus immune cells using publicly available receptor-ligand interaction databases and gene expression data from the immunological genome project. This reconstructed network accounts for 50,317 unique interactions between 16 cell types between 731 receptor-ligand pairs. Analysis of this network shows that cells of hematopoietic lineages use fewer communication pathways for interacting with each other, while nonhematopoietic stromal cells use the most network communications. We further observe that the WNT, BMP, and LAMININ pathways are the most significant contributors to the overall number of cell-cell interactions among the various pathways in the reconstructed communication network. This resource will enable the systematic analysis of normal and pathologic immune cell interactions, along with the study of emerging immunotherapies.
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- 2023
3. 68-Ga PSMA 11 PET/MRI and 68-Ga RM2 PET/MRI for Evaluation of Prostate Cancer Response to HIFU Therapy
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General Electric and Andrei Iagaru, Professor of Radiology (Nuclear Medicine)
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- 2024
4. 68Ga PSMA 11 PET/MRI and 68Ga RM2 PET/MRI for Biopsy Guidance in Patients With Suspected Prostate Cancer
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General Electric and Andrei Iagaru, Professor of Radiology (Nuclear Medicine)
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- 2024
5. 68-Ga-RM2 PET/MRI in Imaging Patients With Estrogen Receptor-Positive Breast Cancer
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General Electric and Andrei Iagaru, Professor of Radiology (Nuclear Medicine) at the Stanford University Medical Center
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- 2023
6. 68Ga-RM2 PET/CT in Detecting Regional Nodal and Distant Metastases in Patients With Intermediate or High-Risk Prostate Cancer
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Andrei Iagaru, Associate Professor of Radiology
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- 2023
7. Bimodal MRI/Fluorescence Nanoparticle Imaging Contrast Agent Targeting Prostate Cancer.
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Xu, Hang, Yu, Ping, Bandari, Rajendra P., Smith, Charles J., Aro, Michael R., Singh, Amolak, and Ma, Lixin
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PEPTIDE receptors , *MAGNETIC resonance imaging , *CONTRAST media , *TRANSMISSION electron microscopy , *PEPTIDES - Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2024
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8. Radiolabeled iron oxide nanoparticles functionalized with PSMA/BN ligands for dual-targeting of prostate cancer.
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Bajwa, Danae Efremia, Salvanou, Evangelia-Alexandra, Theodosiou, Maria, Koutsikou, Theodora S., Efthimiadou, Eleni K., Bouziotis, Penelope, and Liolios, Christos
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IN vitro studies ,WOUND healing ,LIGANDS (Chemistry) ,SINGLE-photon emission computed tomography ,RESEARCH funding ,PROSTATE tumors ,RADIOISOTOPES ,TECHNETIUM ,PEPTIDE hormones ,DESCRIPTIVE statistics ,IRON compounds ,PROSTATE-specific membrane antigen ,MOLECULAR structure ,ANALYSIS of variance ,HEMOLYSIS & hemolysins ,BIOLOGICAL assay ,COMPARATIVE studies ,NANOPARTICLES ,CELL receptors - Abstract
Introduction: Prostate cancer (PCa) is the second most frequent cancer diagnosis in men and the fifth leading cause of death worldwide. Prostate Specific Membrane Antigen (PSMA) and Gastrin Releasing Peptide (GRP) receptors are overexpressed in PCa. In this study, we have developed iron oxide nanoparticles (IONs) functionalized with the Prostate Specific Membrane Antigen (PSMA) and Gastrin Releasing Peptide (GRP) ligands for dual targeting of Prostate cancer. Methods: IONs were developed with a thin silica layer on their surface with MPTES (carrying -SH groups, IONs-SH), and they were coupled either with a pharmacophore targeting PSMA (IONs-PSMA) or with bombesin peptide (IONs-BN), targeting GRP receptors, or with both (IONs-PSMA/BN). The functionalized IONs were characterized for their size, zeta potential, and efficiency of functionalization using dynamic light scattering (DLS) and Fourier-Transform Infrared Spectroscopy (FT-IR). All the aforementioned types of IONs were radiolabeled directly with Technetium-99m (
99m Tc) and evaluated for their radiolabeling efficiency, stability, and binding ability on two different PCa cell lines (PC3 and LNCaP). Results and Discussion: The MTT assay demonstrated low toxicity of the IONs against PC3 and LNCaP cells, while the performed wound-healing assay further proved that these nanostructures did not affect cellular growth mechanisms. The observed hemolysis ratio after co-incubation with red blood cells was extremely low. Furthermore, the99m Tc-radiolabeled IONs showed good stability in human serum, DTPA, and histidine, and high specific binding rates in cancer cells, supporting their future utilization as potential diagnostic tools for PCa with Single Photon Emission Computed Tomography (SPECT) imaging. [ABSTRACT FROM AUTHOR]- Published
- 2024
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9. Structural insights into ligand recognition, selectivity, and activation of bombesin receptor subtype-3
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Changyao Li, Youwei Xu, Wenxin Su, Xinheng He, Jingru Li, Xinzhu Li, H. Eric Xu, and Wanchao Yin
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structural biology ,BRS3 ,GPCR ,bombesin ,Biology (General) ,QH301-705.5 - Abstract
Summary: Bombesin receptor subtype-3 (BRS3) is an important orphan G protein-coupled receptor that regulates energy homeostasis and insulin secretion. As a member of the bombesin receptor (BnR) family, the lack of known endogenous ligands and high-resolution structure has hindered the understanding of BRS3 signaling and function. We present two cryogenic electron microscopy (cryo-EM) structures of BRS3 in complex with the heterotrimeric Gq protein in its active states: one bound to the pan-BnR agonist BA1 and the other bound to the synthetic BRS3-specific agonist MK-5046. These structures reveal the architecture of the orthosteric ligand pocket underpinning molecular recognition and provide insights into the structural basis for BRS3’s selectivity and low affinity for bombesin peptides. Examination of conserved micro-switches suggests a shared activation mechanism among BnRs. Our findings shed light on BRS3’s ligand selectivity and signaling mechanisms, paving the way for exploring its therapeutic potential for diabetes, obesity, and related metabolic disorders.
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- 2024
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10. Copper-64 SAR Bombesin in PSMA Negative Prostate Cancer (BOP) (BOP)
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Clarity Pharmaceuticals Ltd and Louise Emmett, Professor
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- 2023
11. Biodistribution and radiation dosimetry of [99mTc]Tc-N4-BTG in patients with biochemical recurrence of prostate cancer
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Andreas Rinscheid, Alexander Gäble, Georgine Wienand, Alexander Dierks, Malte Kircher, Thomas Günther, Marianne Patt, Ralph A. Bundschuh, Constantin Lapa, and Christian H. Pfob
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Prostate cancer ,Theranostics ,Bombesin ,PET ,GRPR ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 - Abstract
Abstract Background In patients with prostate cancer (PCa), imaging with gastrin-releasing peptide receptor (GRPR) ligands is an alternative to PSMA-targeted tracers, particularly if PSMA expression is low or absent. [99mTc]Tc-N4-BTG is a newly developed GRPR-directed probe for conventional scintigraphy and single photon emission computed tomography (SPECT) imaging. The current study aims to investigate the safety, biodistribution and dosimetry of [99mTc]Tc-N4-BTG in patients with biochemical recurrence (BCR) of PCa. Results No adverse pharmacologic effects were observed. Injection of [99mTc]Tc-N4-BTG resulted in an effective dose of 0.0027 ± 0.0002 mSv/MBq. The urinary bladder was the critical organ with the highest mean absorbed dose of 0.028 ± 0.001 mGy/MBq, followed by the pancreas with 0.0043 ± 0.0015 mGy/MBq, osteogenic cells with 0.0039 ± 0.0005 mGy/MBq, the kidneys with 0.0034 ± 0.0003 mGy/MBq, and the liver with 0.0019 ± 0.0004 mGy/MBq, respectively. No focal tracer uptake suggestive of PCa recurrence could be revealed for any of the patients. Conclusion [99mTc]Tc-N4-BTG appears to be a safe diagnostic agent. Compared to GRPR-targeted PET tracers, this 99mTc-labelled SPECT agent could contribute to a broader application and better availability of this novel approach. Further research to assess its clinical value is warranted.
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- 2024
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12. Characterization of the expression of gastrin‐releasing peptide and its receptor in the trigeminal and spinal somatosensory systems of Japanese macaque monkeys: Insight into humans
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Takanami, Keiko, Oti, Takumi, Kobayashi, Yasuhisa, Hasegawa, Koki, Ito, Takashi, Tsutsui, Naoaki, Ueda, Yasumasa, Carstens, Earl, Sakamoto, Tatsuya, and Sakamoto, Hirotaka
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Biotechnology ,Neurodegenerative ,Underpinning research ,1.1 Normal biological development and functioning ,Animals ,DNA ,Complementary ,Gastrin-Releasing Peptide ,Humans ,Ligands ,Macaca fuscata ,Pruritus ,Receptors ,Bombesin ,Sense Organs ,gastrin-releasing peptide ,gastrin-releasing peptide receptor ,itch ,ligand derivative stain ,macaque monkey ,primates ,trigeminal sensory system ,Zoology ,Medical Physiology ,Neurology & Neurosurgery - Abstract
Gastrin-releasing peptide (GRP) and its receptor (GRPR) have been identified as itch mediators in the spinal and trigeminal somatosensory systems in rodents. In primates, there are few reports of GRP/GRPR expression or function in the spinal sensory system and virtually nothing is known in the trigeminal system. The aim of the present study was to characterize GRP and GRPR in the trigeminal and spinal somatosensory system of Japanese macaque monkeys (Macaca fuscata). cDNA encoding GRP was isolated from the macaque dorsal root ganglion (DRG) and exhibited an amino acid sequence that was highly conserved among mammals and especially in primates. Immunohistochemical analysis demonstrated that GRP was expressed mainly in the small-sized trigeminal ganglion and DRG in adult macaque monkeys. Densely stained GRP-immunoreactive (ir) fibers were observed in superficial layers of the spinal trigeminal nucleus caudalis (Sp5C) and the spinal cord. In contrast, GRP-ir fibers were rarely observed in the principal sensory trigeminal nucleus and oral and interpolar divisions of the spinal trigeminal nucleus. cDNA cloning, in situ hybridization, and Western blot revealed substantial expression of GRPR mRNA and GRPR protein in the macaque spinal dorsal horn and Sp5C. Our Western ligand blot and ligand derivative stain for GRPR revealed that GRP directly bound in the macaque Sp5C and spinal dorsal horn as reported in rodents. Finally, GRP-ir fibers were also detected in the human spinal dorsal horn. The spinal and trigeminal itch neural circuits labeled with GRP and GRPR appear to function also in primates.
- Published
- 2022
13. Biodistribution and radiation dosimetry of [99mTc]Tc-N4-BTG in patients with biochemical recurrence of prostate cancer.
- Author
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Rinscheid, Andreas, Gäble, Alexander, Wienand, Georgine, Dierks, Alexander, Kircher, Malte, Günther, Thomas, Patt, Marianne, Bundschuh, Ralph A., Lapa, Constantin, and Pfob, Christian H.
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SINGLE-photon emission computed tomography , *RADIATION dosimetry , *CANCER relapse , *PROSTATE cancer , *DISEASE relapse , *PROSTATE , *HOLMIUM , *PANCREAS - Abstract
Background: In patients with prostate cancer (PCa), imaging with gastrin-releasing peptide receptor (GRPR) ligands is an alternative to PSMA-targeted tracers, particularly if PSMA expression is low or absent. [99mTc]Tc-N4-BTG is a newly developed GRPR-directed probe for conventional scintigraphy and single photon emission computed tomography (SPECT) imaging. The current study aims to investigate the safety, biodistribution and dosimetry of [99mTc]Tc-N4-BTG in patients with biochemical recurrence (BCR) of PCa. Results: No adverse pharmacologic effects were observed. Injection of [99mTc]Tc-N4-BTG resulted in an effective dose of 0.0027 ± 0.0002 mSv/MBq. The urinary bladder was the critical organ with the highest mean absorbed dose of 0.028 ± 0.001 mGy/MBq, followed by the pancreas with 0.0043 ± 0.0015 mGy/MBq, osteogenic cells with 0.0039 ± 0.0005 mGy/MBq, the kidneys with 0.0034 ± 0.0003 mGy/MBq, and the liver with 0.0019 ± 0.0004 mGy/MBq, respectively. No focal tracer uptake suggestive of PCa recurrence could be revealed for any of the patients. Conclusion: [99mTc]Tc-N4-BTG appears to be a safe diagnostic agent. Compared to GRPR-targeted PET tracers, this 99mTc-labelled SPECT agent could contribute to a broader application and better availability of this novel approach. Further research to assess its clinical value is warranted. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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14. 68Ga-RM2 PET/MRI in Biochemically Recurrent Prostate Cancer
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Andrei Iagaru, Principal Investigator
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- 2023
15. Preparation of 64Cu-NODAGA-RGD-BBN labeled compound and its absorbed dose estimation in humans based on mouse data
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N. Amraee, B. Alirezapour, M. Hosntalab, A. Haddadi, and H. Yousefnia
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rgd ,bombesin ,heterodimer peptide ,copper-64 ,absorbed dose ,Nuclear and particle physics. Atomic energy. Radioactivity ,QC770-798 - Abstract
Calculating the absorbed dose in the human body is one of the first steps in radiopharmaceutical development. This study estimates the dose absorbed by humans from the novel identified compound of 64Cu-NODAGA-RGD-BBN. For this purpose, 64Cu-NODAGA-RGD-BBN labeled compound was first prepared by changing the labeling decisions in optimal conditions. The stability of labeled heterodimer peptide was evaluated in phosphate-buffered saline (PBS) and human blood serum for 12 hours. After that, the complex's bio-distribution was investigated in tumor-bearing mice for 12 hours after injection. Finally, the dose absorbed by humans after injection of the 64Cu-NODAGA-RGD-BBN labeled compound was calculated based on mouse data using RADAR and mass extrapolation methods. The results showed that the obtained labeled compound could be produced with a high radiochemical purity of more than 99% and is highly stable (higher than 96%). 64Cu-NODAGA-RGD-BBN showed high uptake in gastrin-releasing peptide receptor-expressing tumors compared to other non-target organs. Furthermore, the dose assessment for this compound indicated that the body and other organs did not absorb a significant dose after injection.
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- 2023
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16. Linking GERD and the Peptide Bombesin: A New Therapeutic Strategy to Modulate Inflammatory, Oxidative Stress and Clinical Biochemistry Parameters
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Alessio Ardizzone, Sarah Adriana Scuderi, Lelio Crupi, Michela Campolo, Irene Paterniti, Anna Paola Capra, and Emanuela Esposito
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gastroesophageal reflux diseases (GERD) ,bombesin ,inflammation ,oxidative stress ,vitamins ,Therapeutics. Pharmacology ,RM1-950 - Abstract
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.
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- 2024
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17. Research Study Findings from BC Cancer Research Institute Update Understanding of Cancer Imaging [Synthesis and Evaluation of Novel [superscript]68Ga-Labeled [D-Phe[superscript]6,Leu[superscript]13psThz[superscript]14]bombesin(6-14) Analogs for Cancer Imaging wi
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Oncology, Experimental ,Bombesin ,Cancer -- Research ,Physical fitness ,Health - Abstract
2024 JUN 15 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Investigators publish new report on cancer imaging. According to news originating from [...]
- Published
- 2024
18. Towards Cancer Nanoradiopharmaceuticals—Radioisotope Nanocarrier System for Prostate Cancer Theranostics Based on Radiation-Synthesized Polymer Nanogels.
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Rurarz, Beata Paulina, Urbanek, Kinga Anna, Karczmarczyk, Urszula, Raczkowska, Joanna, Habrowska-Górczyńska, Dominika Ewa, Kozieł, Marta Justyna, Kowalska, Karolina, Kadłubowski, Sławomir, Sawicka, Agnieszka, Maurin, Michał, Piastowska-Ciesielska, Agnieszka Wanda, and Ulański, Piotr
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PROSTATE tumors treatment , *RADIOISOTOPES , *SYNTHETIC drugs , *NANOTECHNOLOGY , *RESEARCH funding , *DESCRIPTIVE statistics , *NANOMEDICINE , *MOLECULAR structure , *PROSTATE tumors , *NANOPARTICLES - Abstract
Simple Summary: This research article reports the complete process of the fabrication and characterization of a targeted radioisotope nanocarrier platform designed for the theranostic management of prostate cancer. The state-of-the-art radiation synthesis of poly(acrylic acid) nanogels is followed by functionalization and radiolabeling, as well as both in vitro and in vivo assessment of the nanoplatform's performance. Despite the need for further optimization of the system, our research is an outstanding example of radionanomedicine applications in the field of theranostic cancer management. Despite the tremendous development of oncology, prostate cancer remains a debilitating malignancy. One of the most promising approaches to addressing this issue is to exploit the advancements of nanomedicine in combination with well-established nuclear medicine and radiotherapy. Following this idea, we have developed a radioisotope nanocarrier platform of electron-beam-synthesized nanogels based on poly(acrylic acid). We have developed a functionalization protocol, showing the very high (>97%) efficiency of the conjugation in targeting a ligand–bombesin derivative. This engineered peptide can bind gastrin-releasing peptide receptors overexpressed in prostate cancer cells; moreover, it bears a radioisotope-chelating moiety. Our nanoplatform exhibits very promising performance in vitro; the radiolabeled nanocarriers maintained high radiochemical purity of >90% in both the labeling buffer and human serum for up to 14 days. The application of the targeted nanocarrier allowed also effective and specific uptake in PC-3 prostate cancer cells, up to almost 30% after 4 h, which is a statistically significant improvement in comparison to carrier-free radiolabeled peptides. Although our system requires further studies for more promising results in vivo, our study represents a vital advancement in radionanomedicine—one of many steps that will lead to effective therapy for castration-resistant prostate cancer. [ABSTRACT FROM AUTHOR]
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- 2023
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19. Bombesins: A New Frontier in Hybrid Compound Development.
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Serafin, Pawel and Kleczkowska, Patrycja
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DRUG interactions , *ANTINEOPLASTIC agents , *DRUG efficacy , *GASTROINTESTINAL diseases , *RHEUMATOID arthritis - Abstract
Recently, bombesin (BN) and its analogs have attracted much attention as excellent anticancer agents because they interact with specific receptors widely distributed on the surface of various cancer cells. However, their biological properties proceed far beyond this, given a broad spectrum of activity. Bombesin receptor ligands are effective drugs for the treatment of rheumatoid arthritis or gastrointestinal diseases. However, most diseases are complex, and the use of polytherapy may lead to pharmacokinetic and pharmacodynamic drug–drug interactions, resulting in side effects. Therefore, there is a need to develop effective compounds that also contain BN or its analogs, which are combined with other structural entities, thus generating a so-called hybrid drug. Hybrid drugs that contain bombesin pharmacophore(s) may be proposed as a solution to the problem of polytherapy or the lack of an effective cure. Such structures have now demonstrated the desired efficacy, though information on these aforementioned compounds is relatively scarce. Therefore, our paper aims to encourage researchers to focus on bombesins. Herein, we indicate that the hybrid approach should also be firmly applied to bombesins and the BN receptor family. This paper's structure is divided into two main sections demonstrating bombesins and their properties, as well as recent data on bombesin-based hybrid compounds and their potential usefulness in medicine. Overall, it refers to the discovery and synthesis of modified bombesin-based hybrid compounds. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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20. Bimodal MRI/Fluorescence Nanoparticle Imaging Contrast Agent Targeting Prostate Cancer
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Hang Xu, Ping Yu, Rajendra P. Bandari, Charles J. Smith, Michael R. Aro, Amolak Singh, and Lixin Ma
- Subjects
prostate cancer ,bombesin ,gastrin-releasing peptide receptor ,near-infrared fluorescence imaging ,MRI ,Chemistry ,QD1-999 - Abstract
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.
- Published
- 2024
- Full Text
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21. Bombesin-like peptide recruits disinhibitory cortical circuits and enhances fear memories
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Melzer, Sarah, Newmark, Elena R, Mizuno, Grace Or, Hyun, Minsuk, Philson, Adrienne C, Quiroli, Eleonora, Righetti, Beatrice, Gregory, Malika R, Huang, Kee Wui, Levasseur, James, Tian, Lin, and Sabatini, Bernardo L
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Neurosciences ,Mental Health ,Behavioral and Social Science ,Brain Disorders ,Basic Behavioral and Social Science ,Underpinning research ,1.1 Normal biological development and functioning ,Neurological ,Amino Acid Sequence ,Animals ,Auditory Cortex ,Bombesin ,Calcium ,Calcium Signaling ,Conditioning ,Classical ,Fear ,Gastrin-Releasing Peptide ,Gene Expression Regulation ,Genes ,Immediate-Early ,HEK293 Cells ,Humans ,Intracellular Space ,Male ,Memory ,Mice ,Inbred C57BL ,Nerve Net ,Receptors ,Bombesin ,Sound ,Vasoactive Intestinal Peptide ,CRISPR-Cas9 ,VIP cells ,cortex ,disinhibition ,fear memory ,gastrin-releasing peptide ,neuropeptide ,Gastrin-releasing peptide ,CRISPR/Cas9 ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Disinhibitory neurons throughout the mammalian cortex are powerful enhancers of circuit excitability and plasticity. The differential expression of neuropeptide receptors in disinhibitory, inhibitory, and excitatory neurons suggests that each circuit motif may be controlled by distinct neuropeptidergic systems. Here, we reveal that a bombesin-like neuropeptide, gastrin-releasing peptide (GRP), recruits disinhibitory cortical microcircuits through selective targeting and activation of vasoactive intestinal peptide (VIP)-expressing cells. Using a genetically encoded GRP sensor, optogenetic anterograde stimulation, and trans-synaptic tracing, we reveal that GRP regulates VIP cells most likely via extrasynaptic diffusion from several local and long-range sources. In vivo photometry and CRISPR-Cas9-mediated knockout of the GRP receptor (GRPR) in auditory cortex indicate that VIP cells are strongly recruited by novel sounds and aversive shocks, and GRP-GRPR signaling enhances auditory fear memories. Our data establish peptidergic recruitment of selective disinhibitory cortical microcircuits as a mechanism to regulate fear memories.
- Published
- 2021
22. The effects of novel macrocyclic chelates on the targeting properties of the 68Ga-labeled Gastrin releasing peptide receptor antagonist RM2
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Yinwen Wang, Hongmei Yuan, Sufan Tang, Yang Liu, Ping Cai, Nan Liu, Yue Chen, and Zhijun Zhou
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GRPr ,Bombesin ,RM2 ,Chelators ,AAZTA5 ,DATA5m ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 - Abstract
Abstract Background The gastrin-releasing peptide receptor (GRPr) is a molecular target for the visualization of prostate cancer. Bombesin (BN) analogs are short peptides with a high affinity for GRPr. RM2 is a bombesin-based antagonist. It has been demonstrated that RM2 have superior in vivo biodistribution and targeting properties than high-affinity receptor agonists. This study developed new RM2-like antagonists by introducing the novel bifunctional chelators AAZTA5 and DATA5m to RM2. Results The effects of different macrocyclic chelating groups on drug targeting properties and the possibility of preparing 68Ga-radiopharmaceuticals in a kit-based protocol were investigated using 68Ga-labeled entities. Both new RM2 variants were labelled with 68Ga3+ resulting in high yields, stability, and low molarity of the ligand. DATA5m-RM2 and AAZTA5-RM2 incorporated 68Ga3+ nearly quantitatively at room temperature within 3–5 min, and the labelling yield for 68Ga-DOTA-RM2 was approximately 10% under the same conditions. 68Ga-AAZTA5-RM2 showed stronger hydrophilicity according to partition coefficient. Although the maximal cellular uptake values of the three compounds were similar, 68Ga-AAZTA5-RM2 and 68Ga-DATA5m-RM2 peaked more rapidly. Biodistribution studies showed high and specific tumor uptake, with a maximum of 9.12 ± 0.81 percentage injected activity per gram of tissue (%ID/g) for 68Ga-DATA5m-RM2 and 7.82 ± 0.61%ID/g for 68Ga-AAZTA5-RM2 at 30 min after injection. Conclusions The conditions for complexation of DATA5m-RM2 and AAZTA5-RM2 with gallium-68 are milder, faster and require less amount of precursors than DOTA-RM2. Chelators had an evident influence on the pharmacokinetics and targeting properties of 68Ga-X-RM2 derivatives. Positively charged 68Ga-DATA5m-RM2 provided a high tumor uptake, high image contrast and good capability of targeting GRPr.
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- 2023
- Full Text
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23. Biodistribution and radiation dosimetry of [99mTc]Tc-N4-BTG in patients with biochemical recurrence of prostate cancer
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Rinscheid, Andreas, Gäble, Alexander, Wienand, Georgine, Dierks, Alexander, Kircher, Malte, Günther, Thomas, Patt, Marianne, Bundschuh, Ralph A., Lapa, Constantin, and Pfob, Christian H.
- Published
- 2024
- Full Text
- View/download PDF
24. GRPR-targeting radiotheranostics for breast cancer management
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Alice D’Onofrio, Swantje Engelbrecht, Tilman Läppchen, Axel Rominger, and Eleni Gourni
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gastrin-releasing peptide receptor (GRPR) ,Bombesin ,breast cancer ,molecular imaging ,peptide receptor radionuclide therapy (PRRT) ,Medicine (General) ,R5-920 - Abstract
Breast Cancer (BC) is the most common cancer worldwide and, despite the advancements made toward early diagnosis and novel treatments, there is an urgent need to reduce its mortality. The Gastrin-Releasing Peptide Receptor (GRPR) is a promising target for the development of theranostic radioligands for luminal BC with positive estrogen receptor (ER) expression, because GRPR is expressed not only in primary lesions but also in lymph nodes and distant metastasis. In the last decades, several GRPR-targeting molecules have been evaluated both at preclinical and clinical level, however, most of the studies have been focused on prostate cancer (PC). Nonetheless, given the relevance of non-invasive diagnosis and potential treatment of BC through Peptide Receptor Radioligand Therapy (PRRT), this review aims at collecting the available preclinical and clinical data on GRPR-targeting radiopeptides for the imaging and therapy of BC, to better understand the current state-of-the-art and identify future perspectives and possible limitations to their clinical translation. In fact, since luminal-like tumors account for approximately 80% of all BC, many BC patients are likely to benefit from the development of GRPR-radiotheranostics.
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- 2023
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25. Reports from University of Virginia Describe Recent Advances in Life Science (Neuromedin B-expressing Neurons In the Retrotrapezoid Nucleus Regulate Respiratory Homeostasis and Promote Stable Breathing In Adult Mice)
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United States. National Institutes of Health ,Neurons ,Homeostasis ,Bombesin ,Physical fitness ,Health ,University of Virginia - Abstract
2024 FEB 3 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Current study results on Life Science have been published. According to news [...]
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- 2024
26. Radiolabeled iron oxide nanoparticles functionalized with PSMA/BN ligands for dual-targeting of prostate cancer
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Danae Efremia Bajwa, Evangelia-Alexandra Salvanou, Maria Theodosiou, Theodora S. Koutsikou, Eleni K. Efthimiadou, Penelope Bouziotis, and Christos Liolios
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prostate cancer ,PSMA ,bombesin ,bispecific heterodimers ,iron oxide nanoparticles ,99mTc ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 - Abstract
IntroductionProstate cancer (PCa) is the second most frequent cancer diagnosis in men and the fifth leading cause of death worldwide. Prostate Specific Membrane Antigen (PSMA) and Gastrin Releasing Peptide (GRP) receptors are overexpressed in PCa. In this study, we have developed iron oxide nanoparticles (IONs) functionalized with the Prostate Specific Membrane Antigen (PSMA) and Gastrin Releasing Peptide (GRP) ligands for dual targeting of Prostate cancer.MethodsIONs were developed with a thin silica layer on their surface with MPTES (carrying -SH groups, IONs-SH), and they were coupled either with a pharmacophore targeting PSMA (IONs-PSMA) or with bombesin peptide (IONs-BN), targeting GRP receptors, or with both (IONs-PSMA/BN). The functionalized IONs were characterized for their size, zeta potential, and efficiency of functionalization using dynamic light scattering (DLS) and Fourier-Transform Infrared Spectroscopy (FT-IR). All the aforementioned types of IONs were radiolabeled directly with Technetium-99m (99mTc) and evaluated for their radiolabeling efficiency, stability, and binding ability on two different PCa cell lines (PC3 and LNCaP).Results and DiscussionThe MTT assay demonstrated low toxicity of the IONs against PC3 and LNCaP cells, while the performed wound-healing assay further proved that these nanostructures did not affect cellular growth mechanisms. The observed hemolysis ratio after co-incubation with red blood cells was extremely low. Furthermore, the 99mTc-radiolabeled IONs showed good stability in human serum, DTPA, and histidine, and high specific binding rates in cancer cells, supporting their future utilization as potential diagnostic tools for PCa with Single Photon Emission Computed Tomography (SPECT) imaging.
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- 2023
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27. The effects of novel macrocyclic chelates on the targeting properties of the 68Ga-labeled Gastrin releasing peptide receptor antagonist RM2.
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Wang, Yinwen, Yuan, Hongmei, Tang, Sufan, Liu, Yang, Cai, Ping, Liu, Nan, Chen, Yue, and Zhou, Zhijun
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PEPTIDE receptors , *CHELATES , *GASTRIN , *TARGETED drug delivery , *MOLARITY , *CHELATING agents , *MACROCYCLIC compounds - Abstract
Background: The gastrin-releasing peptide receptor (GRPr) is a molecular target for the visualization of prostate cancer. Bombesin (BN) analogs are short peptides with a high affinity for GRPr. RM2 is a bombesin-based antagonist. It has been demonstrated that RM2 have superior in vivo biodistribution and targeting properties than high-affinity receptor agonists. This study developed new RM2-like antagonists by introducing the novel bifunctional chelators AAZTA5 and DATA5m to RM2. Results: The effects of different macrocyclic chelating groups on drug targeting properties and the possibility of preparing 68Ga-radiopharmaceuticals in a kit-based protocol were investigated using 68Ga-labeled entities. Both new RM2 variants were labelled with 68Ga3+ resulting in high yields, stability, and low molarity of the ligand. DATA5m-RM2 and AAZTA5-RM2 incorporated 68Ga3+ nearly quantitatively at room temperature within 3–5 min, and the labelling yield for 68Ga-DOTA-RM2 was approximately 10% under the same conditions. 68Ga-AAZTA5-RM2 showed stronger hydrophilicity according to partition coefficient. Although the maximal cellular uptake values of the three compounds were similar, 68Ga-AAZTA5-RM2 and 68Ga-DATA5m-RM2 peaked more rapidly. Biodistribution studies showed high and specific tumor uptake, with a maximum of 9.12 ± 0.81 percentage injected activity per gram of tissue (%ID/g) for 68Ga-DATA5m-RM2 and 7.82 ± 0.61%ID/g for 68Ga-AAZTA5-RM2 at 30 min after injection. Conclusions: The conditions for complexation of DATA5m-RM2 and AAZTA5-RM2 with gallium-68 are milder, faster and require less amount of precursors than DOTA-RM2. Chelators had an evident influence on the pharmacokinetics and targeting properties of 68Ga-X-RM2 derivatives. Positively charged 68Ga-DATA5m-RM2 provided a high tumor uptake, high image contrast and good capability of targeting GRPr. [ABSTRACT FROM AUTHOR]
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- 2023
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28. Novel Positron-Emitting Radiopharmaceuticals
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Keinänen, Outi, Nash, Aaron G., Sarrett, Samantha M., Sarparanta, Mirkka, Lewis, Jason S., Zeglis, Brian M., Volterrani, Duccio, editor, Erba, Paola A., editor, Strauss, H. William, editor, Mariani, Giuliano, editor, and Larson, Steven M., editor
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- 2022
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29. Nanostrategies for Therapeutic and Diagnostic Targeting of Gastrin-Releasing Peptide Receptor.
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Rurarz, Beata Paulina, Bukowczyk, Małgorzata, Gibka, Natalia, Piastowska-Ciesielska, Agnieszka Wanda, Karczmarczyk, Urszula, and Ulański, Piotr
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PEPTIDE receptors , *LIGAND field theory , *G protein coupled receptors , *DRUG target , *INDIVIDUALIZED medicine , *GASTROINTESTINAL cancer - Abstract
Advances in nanomedicine bring the attention of researchers to the molecular targets that can play a major role in the development of novel therapeutic and diagnostic modalities for cancer management. The choice of a proper molecular target can decide the efficacy of the treatment and endorse the personalized medicine approach. Gastrin-releasing peptide receptor (GRPR) is a G-protein-coupled membrane receptor, well known to be overexpressed in numerous malignancies including pancreatic, prostate, breast, lung, colon, cervical, and gastrointestinal cancers. Therefore, many research groups express a deep interest in targeting GRPR with their nanoformulations. A broad spectrum of the GRPR ligands has been described in the literature, which allows tuning of the properties of the final formulation, particularly in the field of the ligand affinity to the receptor and internalization possibilities. Hereby, the recent advances in the field of applications of various nanoplatforms that are able to reach the GRPR-expressing cells are reviewed. [ABSTRACT FROM AUTHOR]
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- 2023
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30. Targeting the Gastrin-Releasing Peptide Receptor (GRP-R) in Cancer Therapy: Development of Bombesin-Based Peptide–Drug Conjugates.
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Gomena, Jacopo, Vári, Balázs, Oláh-Szabó, Rita, Biri-Kovács, Beáta, Bősze, Szilvia, Borbély, Adina, Soós, Ádám, Ranđelović, Ivan, Tóvári, József, and Mező, Gábor
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PEPTIDE receptors , *CANCER treatment , *CARCINOGENESIS , *BREAST , *DRUG delivery systems , *PEPTIDES , *CANCER cells - Abstract
Targeted tumour therapy has proved to be an efficient alternative to overcome the limitations of conventional chemotherapy. Among several receptors upregulated in cancer cells, the gastrin-releasing peptide receptor (GRP-R) has recently emerged as a promising target for cancer imaging, diagnosing and treatment due to its overexpression on cancerous tissues such as breast, prostate, pancreatic and small-cell lung cancer. Herein, we report on the in vitro and in vivo selective delivery of the cytotoxic drug daunorubicin to prostate and breast cancer, by targeting GRP-R. Exploiting many bombesin analogues as homing peptides, including a newly developed peptide, we produced eleven daunorubicin-containing peptide–drug conjugates (PDCs), acting as drug delivery systems to safely reach the tumour environment. Two of our bioconjugates revealed remarkable anti-proliferative activity, an efficient uptake by all three tested human breast and prostate cancer cell lines, high stability in plasma and a prompt release of the drug-containing metabolite by lysosomal enzymes. Moreover, they revealed a safe profile and a consistent reduction of the tumour volume in vivo. In conclusion, we highlight the importance of GRP-R binding PDCs in targeted cancer therapy, with the possibility of further tailoring and optimisation. [ABSTRACT FROM AUTHOR]
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- 2023
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31. Towards Cancer Nanoradiopharmaceuticals—Radioisotope Nanocarrier System for Prostate Cancer Theranostics Based on Radiation-Synthesized Polymer Nanogels
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Beata Paulina Rurarz, Kinga Anna Urbanek, Urszula Karczmarczyk, Joanna Raczkowska, Dominika Ewa Habrowska-Górczyńska, Marta Justyna Kozieł, Karolina Kowalska, Sławomir Kadłubowski, Agnieszka Sawicka, Michał Maurin, Agnieszka Wanda Piastowska-Ciesielska, and Piotr Ulański
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prostate cancer ,nanogels ,nanocarriers ,nanoradiopharmaceuticals ,bombesin ,gastrin-releasing peptide receptor ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Despite the tremendous development of oncology, prostate cancer remains a debilitating malignancy. One of the most promising approaches to addressing this issue is to exploit the advancements of nanomedicine in combination with well-established nuclear medicine and radiotherapy. Following this idea, we have developed a radioisotope nanocarrier platform of electron-beam-synthesized nanogels based on poly(acrylic acid). We have developed a functionalization protocol, showing the very high (>97%) efficiency of the conjugation in targeting a ligand–bombesin derivative. This engineered peptide can bind gastrin-releasing peptide receptors overexpressed in prostate cancer cells; moreover, it bears a radioisotope-chelating moiety. Our nanoplatform exhibits very promising performance in vitro; the radiolabeled nanocarriers maintained high radiochemical purity of >90% in both the labeling buffer and human serum for up to 14 days. The application of the targeted nanocarrier allowed also effective and specific uptake in PC-3 prostate cancer cells, up to almost 30% after 4 h, which is a statistically significant improvement in comparison to carrier-free radiolabeled peptides. Although our system requires further studies for more promising results in vivo, our study represents a vital advancement in radionanomedicine—one of many steps that will lead to effective therapy for castration-resistant prostate cancer.
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- 2023
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32. Bombesins: A New Frontier in Hybrid Compound Development
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Pawel Serafin and Patrycja Kleczkowska
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bombesin ,bombesin receptors ,hybrid development ,efficacy ,biological properties ,Pharmacy and materia medica ,RS1-441 - Abstract
Recently, bombesin (BN) and its analogs have attracted much attention as excellent anticancer agents because they interact with specific receptors widely distributed on the surface of various cancer cells. However, their biological properties proceed far beyond this, given a broad spectrum of activity. Bombesin receptor ligands are effective drugs for the treatment of rheumatoid arthritis or gastrointestinal diseases. However, most diseases are complex, and the use of polytherapy may lead to pharmacokinetic and pharmacodynamic drug–drug interactions, resulting in side effects. Therefore, there is a need to develop effective compounds that also contain BN or its analogs, which are combined with other structural entities, thus generating a so-called hybrid drug. Hybrid drugs that contain bombesin pharmacophore(s) may be proposed as a solution to the problem of polytherapy or the lack of an effective cure. Such structures have now demonstrated the desired efficacy, though information on these aforementioned compounds is relatively scarce. Therefore, our paper aims to encourage researchers to focus on bombesins. Herein, we indicate that the hybrid approach should also be firmly applied to bombesins and the BN receptor family. This paper’s structure is divided into two main sections demonstrating bombesins and their properties, as well as recent data on bombesin-based hybrid compounds and their potential usefulness in medicine. Overall, it refers to the discovery and synthesis of modified bombesin-based hybrid compounds.
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- 2023
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33. Understanding the Loss of Maternal Care in Avian Brood Parasites Using Preoptic Area Transcriptome Comparisons in Brood Parasitic and Non-parasitic Blackbirds.
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Lynch, Kathleen, OConnell, Lauren, Louder, Matthew, Balakrishnan, Christopher, and Fischer, Eva
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brood parasitism ,maternal behavior ,neoteny ,preoptic area ,transcriptome ,Acetylcholinesterase ,Animals ,Behavior ,Animal ,Early Growth Response Protein 1 ,Female ,Gene Expression Profiling ,Maternal Behavior ,Neuropeptides ,Passeriformes ,Preoptic Area ,Receptors ,Bombesin ,Receptors ,Nerve Growth Factor ,Receptors ,Prolactin ,Somatostatin - Abstract
Parental care is critical for offspring survival in many species. However, parental behaviors have been lost in roughly 1% of avian species known as the obligate brood parasites. To shed light on molecular and neurobiological mechanisms mediating brood parasitic behavior, we compared brain gene expression patterns between two brood parasitic species and one closely related non-parasitic Icterid (blackbird) species. Our analyses focused on gene expression changes specifically in the preoptic area (POA), a brain region known to play a critical role in parental behavior across vertebrates. Using comparative transcriptomic approaches, we identified gene expression patterns associated with brood parasitism. We evaluated three non-mutually exclusive alternatives for the evolution of brood parasitism: (1) retention of juvenile-like (neotenic) gene expression, (2) reduced expression of maternal care-related genes in the POA, and/or (3) increased expression of genes inhibiting maternal care. We find evidence for neotenic expression patterns in both species of parasitic cowbirds as compared to maternal, non-parasites. In addition, we observed differential expression in a number of genes with previously established roles in mediating maternal care. Together, these results provide the first insight into transcriptomic and genetic mechanisms underlying the loss of maternal behavior in avian brood parasites.
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- 2019
34. Bombesin protects myocardium against ischemia/reperfusion injury via activation of the Keap1-Nrf2-HO-1 signaling pathway.
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Zhang, Jinyi, Du, Yanhuan, Xiong, Zhenyu, Cheng, Hang, Du, Yi, Xiong, Yulian, Lv, Jianfeng, Huang, Wenquan, Qiu, Kuncheng, and Zhang, Shizhong
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NUCLEAR factor E2 related factor , *VAGUS nerve stimulation , *MYOCARDIAL infarction , *PEPTIDES , *REPERFUSION injury , *HEART - Abstract
It has been reported that some peptides released by the gastro-intestinal tract play important roles in the prevention of myocardial ischemia/reperfusion injury (MIRI). Bombesin (BN) is a biologically active peptide released by non-adrenergic non-cholinergic nerves on the gastric antrum mucosa controlled by the vagus nerve. However, there is a lack of reports on the impact of BN on MIRI. This study aimed to explore the influence of BN on MIRI and its underlying mechanism. MIRI was induced by either 30 min of global ischemia in Langendorff perfused rat hearts, or by ligation of the descending coronary artery for 30 min in anesthetized Spraque-Dawley rats, and both were followed by 120 min reperfusion. Infarct size and left ventricular function were assessed, and lactate dehydrogenase (LDH), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) levels were measured spectrophotometrically, while cardiomyocyte apoptosis was detected by TUNEL assay. The content of BN in plasma was measured with enzyme-linked immunosorbent assays (ELISA). The expression of caspase 3, Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) were quantified. BN and vagus nerve stimulation improved cardiac contractile function and reduced myocardial infarct size, attenuated oxidative stress damage and myocardial cell apoptosis, increased the expression of Keap1, Nrf2, and HO-1. and these effects were blocked by using a BN receptor antagonist. BN provides protection against MIRI, and its underlying mechanism is through activation of the Keap1/Nrf2/HO-1 pathway. This research provides more reliable evidence for the "gut-heart axis dialogue" and explores potential therapeutic approaches for MIRI. • For the first time, the idea that bombesin can improve cardiac function after ischemia-reperfusion was proposed. • It was verified that bombesin can reduce myocardial ischemia-reperfusion injury by activating the Keap1/Nrf2/HO-1 antioxidant stress pathway. • Exploring and finding the target of myocardial protection from the "gastrointestinal-heart axis" approach provides a feasible way for subsequent research on myocardial protection from gastrointestinal hormones. [ABSTRACT FROM AUTHOR]
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- 2024
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35. Structural insights into ligand recognition, selectivity, and activation of bombesin receptor subtype-3.
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Li, Changyao, Xu, Youwei, Su, Wenxin, He, Xinheng, Li, Jingru, Li, Xinzhu, Xu, H. Eric, and Yin, Wanchao
- Abstract
Bombesin receptor subtype-3 (BRS3) is an important orphan G protein-coupled receptor that regulates energy homeostasis and insulin secretion. As a member of the bombesin receptor (BnR) family, the lack of known endogenous ligands and high-resolution structure has hindered the understanding of BRS3 signaling and function. We present two cryogenic electron microscopy (cryo-EM) structures of BRS3 in complex with the heterotrimeric G q protein in its active states: one bound to the pan-BnR agonist BA1 and the other bound to the synthetic BRS3-specific agonist MK-5046. These structures reveal the architecture of the orthosteric ligand pocket underpinning molecular recognition and provide insights into the structural basis for BRS3's selectivity and low affinity for bombesin peptides. Examination of conserved micro-switches suggests a shared activation mechanism among BnRs. Our findings shed light on BRS3's ligand selectivity and signaling mechanisms, paving the way for exploring its therapeutic potential for diabetes, obesity, and related metabolic disorders. [Display omitted] • Structures of BRS3-G q complexes with ligands BA1 and MK-5046 were determined • Key residues in the ligand-binding pocket for BRS3 activation were identified • Ligand selectivity basis for bombesin receptors was detailed • Binding pocket insights guide rational drug design for BRS3 in diabetes and obesity treatment Li, Xu et al. report cryogenic electron microscopy structures of agonist-bound human bombesin receptor subtype-3 (BRS3) coupled with G protein, revealing insights into ligand recognition, selectivity, and receptor activation. The structures provide a basis for understanding BRS3's role in metabolic regulation and designing modulators targeting this receptor. [ABSTRACT FROM AUTHOR]
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- 2024
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36. An Insight into Neuropeptides Inhibitors in the Biology of Colorectal Cancer: Opportunity and Translational Perspectives.
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Srivastava, Ankit, Rikhari, Deeksha, Pradhan, Biswajita, Bharadwaj, Kaushik Kumar, Gaballo, Antonio, Quarta, Alessandra, Jena, Mrutyunjay, Srivastava, Sameer, and Ragusa, Andrea
- Subjects
NEUROPEPTIDES ,COLORECTAL cancer ,G protein coupled receptors ,PERIPHERAL nervous system ,CANCER cell proliferation ,CANCER cells ,RHODOPSIN - Abstract
Neuropeptides are mainly secreted from the human central and peripheral nervous systems. Neuropeptides bind to its cognate rhodopsin-like G-protein coupled receptor (GPCR) and perform various physiological functions. Conventional cancer treatments in clinical practice still present many drawbacks due to the lack of selectivity toward the target cell, drug-resistance, and side-effects, thus pushing for the development of new therapeutic agents and therapies. Recent research suggests that neuropeptides influence cancer cell proliferation, invasion, metastasis, and angiogenesis and, therefore, they could be exploited as a target for novel anticancer therapies. Very recently, targeted approaches that inhibit neuropeptides and their associated receptors are being developed in cancer treatment. This review focuses on various neuropeptides and their potential utility as drug targets by different inhibitors as a recently identified approach to cancer prevention, with particular emphasis on colorectal cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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37. Assessment of the bound conformation of bombesin to the BB1 and BB2 receptors
- Author
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Universitat Politècnica de Catalunya. Departament d'Enginyeria Química, Universitat Politècnica de Catalunya. GBMI - Grup de Biotecnologia Molecular i Industrial, Vila i Julià, Guillem, Rubio Martinez, Jaime, Pérez González, Juan Jesús, Universitat Politècnica de Catalunya. Departament d'Enginyeria Química, Universitat Politècnica de Catalunya. GBMI - Grup de Biotecnologia Molecular i Industrial, Vila i Julià, Guillem, Rubio Martinez, Jaime, and Pérez González, Juan Jesús
- Abstract
Bombesin is an endogenous peptide involved in a wide spectrum of physiological activities ranging from satiety, control of circadian rhythm and thermoregulation in the central nervous system, to stimulation of gastrointestinal hormone release, activation of macrophages and effects on development in peripheral tissues. Actions of the peptide are mediated through the two high affinity G-protein coupled receptors BB1R and BB2R. Under pathophysiological conditions, these receptors are overexpressed in many different types of tumors, such as prostate cancer, breast cancer, small and non-small cell lung cancer and pancreatic cancer. This observation has been used for designing cell markers, but it has not been yet exploited for therapeutical purposes. Despite the enormous biological interest of the peptide, little is known about the stereochemical features that contribute to their activity. On the one hand, mutagenesis studies identified a few receptor residues important for high bombesin affinity and on the other, a few studies focused on the relevance of diverse residues of the peptide for receptor activation. Models of the peptide bound to BB1R and BB2R can be helpful to improve our understanding of the stereochemical features granting bombesin activity. Accordingly, the present study describes the computational process followed to construct such models by means of Steered Molecular Dynamics, using models of the peptide and its receptors. Present results provide new insights into the structure-activity relationships of bombesin and its receptors, as well as render an explanation for the differential binding affinity observed towards BB1R and BB2R. Finally, these models can be further exploited to help for designing novel small molecule peptidomimetics with improved pharmacokinetics profile., This study was supported by the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR)- Generalitat de Catalunya (2021SGR00350 and 2021SGR00342), and Spanish Structures and Excellence María de Maeztu Program, grant number CEX2021-001202-M., Peer Reviewed, Postprint (author's final draft)
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- 2024
38. Linking GERD and the Peptide Bombesin: A New Therapeutic Strategy to Modulate Inflammatory, Oxidative Stress and Clinical Biochemistry Parameters.
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Ardizzone A, Scuderi SA, Crupi L, Campolo M, Paterniti I, Capra AP, and Esposito E
- Abstract
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.
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- 2024
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39. Bombesin Peptide Conjugated Water-Soluble Chitosan Gallate—A New Nanopharmaceutical Architecture for the Rapid One-Pot Synthesis of Prostate Tumor Targeted Gold Nanoparticles
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Tangthong T, Piroonpan T, Thipe VC, Khoobchandani M, Katti K, Katti KV, and Pasanphan W
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water-soluble chitosan ,gallic acid ,bombesin ,one-pot synthesis ,gold nanoparticle ,prostate cancer ,Medicine (General) ,R5-920 - Abstract
Theeranan Tangthong,1,2 Thananchai Piroonpan,2 Velaphi C Thipe,3,4 Menka Khoobchandani,4,5 Kavita Katti,4,5 Kattesh V Katti,4– 6 Wanvimol Pasanphan1,2 1Department of Materials Science, Faculty of Science, Kasetsart University, Chatuchak, Bangkok, 10900, Thailand; 2Center of Radiation Processing for Polymer Modification and Nanotechnology (CRPN), Department of Materials Science, Faculty of Science, Kasetsart University Chatuchak, Bangkok, 10900, Thailand; 3Department of Chemistry, University of Missouri, Columbia, MO, 65211, USA; 4Institute of Green Nanotechnology, University of Missouri, Columbia, MO, 65211, USA; 5Department of Radiology, University of Missouri, Columbia, MO, 65211, USA; 6Department of Physics, University of Missouri, Columbia, MO, 65211, USACorrespondence: Wanvimol PasanphanDepartment of Materials Science, Faculty of Science, Kasetsart University, 50 Ngam Wong Wan Road, Lat Yao, Chatuchak, Bangkok, 10900, ThailandTel +66 2562 5555 (Ext. 646518)Email wanvimol.p@ku.ac.thKattesh V KattiInstitute of Green Nanotechnology, University of Missouri, Columbia, MO, 65211, USATel +1 573 882-5656Fax +1 573 884-5679Email KattiK@health.missouri.eduPurpose: We report herein bombesin peptide conjugated water-soluble chitosan gallate as a template for rapid one-pot synthesis of gold nanoparticles (AuNPs) with capabilities to target receptors on prostate cancer cells.Methods: Water-soluble chitosan (WCS), anchored with gallic acid (GA) and LyslLys3 (1,4,7,10-tetraazacyclo dodecane-1,4,7,10-tetraacetic acid) bombesin 1– 14 (DBBN) peptide, provides a tumor targeting nanomedicine agent. WCS nanoplatforms provide attractive strategies with built-in capabilities to reduce gold (III) to gold nanoparticles with stabilizing and tumor-targeting capabilities. WCS-GA-DBBN encapsulation around gold nanoparticles affords optimum in vitro stability.Results: The DBBN content in the WCS-GA-DBBN sample was ∼ 27%w/w. The antioxidant activities of WCS-GA and WCS-GA-DBBN nanocolloids were enhanced by 12 times as compared to the nascent WCS. AuNPs with a desirable hydrodynamic diameter range of 40– 60 nm have been efficiently synthesized using WCS-GA and WCS-GA-DBBN platforms. The AuNPs were stable over 4 days after preparation and ∼ 3 days after subjecting to all relevant biological fluids. The AuNPs capped with WCS-GA-DBBN peptide exhibited superior cellular internalization into prostate tumor (PC-3) cells with evidence of receptor mediated endocytosis.Conclusion: The AuNPs capped with WCS-GA-DBBN exhibited selective affinity toward prostate cancer cells. AuNPs conjugated with WCS-GA-DBBN serve as a new generation of theranostic agents for treating various neoplastic diseases, thus opening-up new applications in oncology.Keywords: water-soluble chitosan, gallic acid, bombesin, one-pot synthesis, gold nanoparticle, prostate cancer
- Published
- 2021
40. Antimicrobial Profile from Frog Skin Peptides
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Bombesin ,Skin ,Biological sciences ,Health - Abstract
2024 JUL 16 (NewsRx) -- By a News Reporter-Staff News Editor at Life Science Weekly -- According to news reporting based on a preprint abstract, our journalists obtained the following [...]
- Published
- 2024
41. 64 Cu-SAR-Bombesin PET-CT Imaging in the Staging of Estrogen/Progesterone Receptor Positive, HER2 Negative Metastatic Breast Cancer Patients: Safety, Dosimetry and Feasibility in a Phase I Trial.
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Wong, Keith, Sheehan-Dare, Gemma, Nguyen, Andrew, Ho, Bao, Liu, Victor, Lee, Jonathan, Brown, Lauren, Dear, Rachel, Chan, Lyn, Sharma, Shikha, Malaroda, Alessandra, Smith, Isabelle, Lim, Elgene, and Emmett, Louise
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METASTATIC breast cancer , *PROGESTERONE receptors , *POSITRON emission tomography computed tomography , *CANCER patients , *RADIATION dosimetry , *CANCER cells , *OPTICALLY stimulated luminescence , *POSITRON emission tomography - Abstract
Breast cancers are most frequently oestrogen receptor (ER) and progesterone receptor (PR) positive and [18F]Fluorodeoxyglucose PET-CT (FDG) has lower sensitivity for these subtypes. The gastrin-releasing peptide receptor (GRPR) is overexpressed in ER+/PR+ breast cancers. This study assessed the safety and potential of [64Cu]Cu-Sarcophagine (SAR)-Bombesin PET/CT (BBN) in re-staging metastatic ER+/PR+/human epidermal growth-factor-2-negative (HER2-) breast cancer. Seven patients with metastatic ER+/PR+/HER2- breast cancer undergoing staging underwent [64Cu]Cu-SAR-BBN PET-CT. Bloods, vital signs and electrocardiogram, blood tracer-clearance and dosimetry were undertaken. GRPR status was assessed in available metastatic biopsy samples. Staging with conventional imaging ([18F]FDG, bone scan and diagnostic CT) was within 3 weeks of [64Cu]Cu-SAR-BBN PET/CT. PET scans were assessed visually and quantitatively. Seven patients underwent imaging. One of the seven had de-novo metastatic breast cancer and six of the seven recurrent metastatic disease. Two of the seven had lobular subtype. No adverse events were reported. All seven patients were positive on conventional imaging (six of seven on FDG). [64Cu]Cu-SAR-BBN imaging was positive in five of the seven. Both [64Cu]Cu-SAR-BBN-negative patients had disease identified on [18F]FDG. One patient was [64Cu]Cu-SAR-BBN positive/[18F]FDG negative. Four of seven patients were [64Cu]Cu-SAR-BBN positive/[18F]FDG positive. In these four, mean SUVmax was higher for [64Cu]Cu-SAR-BBN than [18F]FDG (SUVmax 15 vs. 12). In the classical lobular subtype (two of seven), [64Cu]Cu-SAR-BBN was more avid compared to [18F]FDG (SUVmax 20 vs. 11, and 20 vs. <3). Dosimetry calculations estimated whole-body effective dose for 200 MBq of [64Cu]Cu-SAR-BBN to be 1.9 mSv. [64Cu]Cu-SAR-BBN PET/CT appears safe and may have diagnostic value in metastatic ER+/PR+/HER2- breast cancer, particularly the lobular subtype. Further evaluation is warranted. [ABSTRACT FROM AUTHOR]
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- 2022
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42. University of Messina Researcher Has Published New Study Findings on Acid Reflux Disease (Linking GERD and the Peptide Bombesin: A New Therapeutic Strategy to Modulate Inflammatory, Oxidative Stress and Clinical Biochemistry Parameters).
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- 2024
43. In vitro and in vivo evaluation of Bombesin-MMAE conjugates for targeted tumour therapy.
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Gomena, Jacopo, Modena, Daniela, Cordella, Paola, Vári, Balázs, Ranđelović, Ivan, Borbély, Adina, Bottani, Michela, Vári-Mező, Diána, Halmos, Gábor, Juhász, Éva, Steinkühler, Christian, Tóvári, József, and Mező, Gábor
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BIOSYNTHESIS , *PEPTIDE drugs , *DRUG administration , *PROSTATE cancer , *BREAST cancer - Abstract
Targeted tumour therapy has proved to be an efficient alternative to overcome the limitations of conventional chemotherapy. The upregulation of the bombesin receptor 2 (BB2) in several malignancies and the advantages offered by peptide drug conjugates over antibody drug conjugates in terms of production and tumour targeting motivated us to synthesise and test bombesin conjugates armed with the tubulin binder monomethyl auristatin E. The widely used Val-Cit-PABC was initially included as cathepsin cleavable self-immolative linker for the release of the free drug. However, the poor stability of the Val-Cit-conjugates in mouse plasma encouraged us to consider the optimised alternatives Glu-Val-Cit-PABC and Glu-Gly-Cit-PABC. Conjugate BN-EVcM1 , featuring Glu-Val-Cit-PABC, combined suitable stability (t (½) in mouse and human plasma: 8.4 h and 4.6 h, respectively), antiproliferative activity in vitro (IC 50 = 29.6 nM on the human prostate cancer cell line PC-3) and the full release of the free payload within 24 h. Three conjugates, namely BN-EGcM1 , BN-EVcM1 and BN-EVcM2 , improved the accumulation of MMAE in PC-3 human prostate cancer xenograft mice models, compared to the administration of the free drug. Among them, BN-EVcM1 also stood out for the significantly extended survival of mice in in vivo acute efficacy studies and for the significant inhibition of the growth of a PC-3 tumour in mice in both acute and chronic efficacy studies. [Display omitted] • The bombesin receptor BB2 is an attractive target for targeted tumour therapy. • We describe the synthesis and biological activity of bombesin-MMAE conjugates. • Structure optimisation afforded highly active and plasma-stable constructs, suitable for in vivo investigation. • Three conjugates improved the accumulation of the payload at the tumour site in mice. • Two conjugates extended mice survival and significantly inhibited tumour growth in mice. [ABSTRACT FROM AUTHOR]
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- 2024
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44. Synergistic antipruritic effects of gamma aminobutyric acid A and B agonists in a mouse model of atopic dermatitis
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Cevikbas, Ferda, Braz, Joao M, Wang, Xidao, Solorzano, Carlos, Sulk, Mathias, Buhl, Timo, Steinhoff, Martin, and Basbaum, Allan I
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Biomedical and Clinical Sciences ,Neurosciences ,Transplantation ,Animals ,Antipruritics ,Baclofen ,Dermatitis ,Atopic ,Disease Models ,Animal ,Drug Synergism ,GABA-A Receptor Agonists ,GABA-B Receptor Agonists ,Gastrin-Releasing Peptide ,Glutamate Decarboxylase ,Interleukins ,Interneurons ,Male ,Median Eminence ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Muscimol ,RNA ,Messenger ,Receptors ,Bombesin ,Receptors ,GABA-A ,Receptors ,GABA-B ,Receptors ,Neurokinin-1 ,Skin ,Spinal Cord ,Stem Cell Transplantation ,Atopic dermatitis ,baclofen ,chronic itch ,GABA ,GABAergic progenitor cell transplants ,muscimol ,pruritogens ,Immunology ,Allergy - Abstract
BackgroundDespite recent insights into the pathophysiology of acute and chronic itch, chronic itch remains an often intractable condition. Among major contributors to chronic itch is dysfunction of spinal cord gamma aminobutyric acidergic (GABAergic) inhibitory controls.ObjectivesWe sought to test the hypothesis that selective GABA agonists as well as cell transplant-derived GABA are antipruritic against acute itch and in a transgenic mouse model of atopic dermatitis produced by overexpression of the TH2 cell-associated cytokine, IL-31 (IL-31Tg mice).MethodsWe injected wild-type and IL-31Tg mice with combinations of GABA-A (muscimol) or GABA-B (baclofen) receptor agonists 15 to 20 minutes prior to injection of various pruritogens (histamine, chloroquine, or endothelin-1) and recorded spontaneous scratching before and after drug administration. We also tested the antipruritic properties of intraspinal transplantation of precursors of GABAergic interneurons in the IL-31Tg mice.ResultsSystemic muscimol or baclofen are antipruritic against both histamine-dependent and -independent pruritogens, but the therapeutic window using either ligand alone was very small. In contrast, combined subthreshold doses of baclofen and muscimol produced a significant synergistic antipruritic effect, with no sedation. Finally, transplant-mediated long-term enhancement of GABAergic signaling not only reduced spontaneous scratching in the IL-31Tg mice but also dramatically resolved the associated skin lesions.ConclusionsAlthough additional research is clearly needed, existing approved GABA agonists should be considered in the management of chronic itch, notably atopic dermatitis.
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- 2017
45. Targeting the Gastrin-Releasing Peptide Receptor (GRP-R) in Cancer Therapy: Development of Bombesin-Based Peptide–Drug Conjugates
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Jacopo Gomena, Balázs Vári, Rita Oláh-Szabó, Beáta Biri-Kovács, Szilvia Bősze, Adina Borbély, Ádám Soós, Ivan Ranđelović, József Tóvári, and Gábor Mező
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bombesin ,gastrin-releasing peptide receptor ,targeted tumour therapy ,peptide–drug conjugates ,prostate cancer ,breast cancer ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Targeted tumour therapy has proved to be an efficient alternative to overcome the limitations of conventional chemotherapy. Among several receptors upregulated in cancer cells, the gastrin-releasing peptide receptor (GRP-R) has recently emerged as a promising target for cancer imaging, diagnosing and treatment due to its overexpression on cancerous tissues such as breast, prostate, pancreatic and small-cell lung cancer. Herein, we report on the in vitro and in vivo selective delivery of the cytotoxic drug daunorubicin to prostate and breast cancer, by targeting GRP-R. Exploiting many bombesin analogues as homing peptides, including a newly developed peptide, we produced eleven daunorubicin-containing peptide–drug conjugates (PDCs), acting as drug delivery systems to safely reach the tumour environment. Two of our bioconjugates revealed remarkable anti-proliferative activity, an efficient uptake by all three tested human breast and prostate cancer cell lines, high stability in plasma and a prompt release of the drug-containing metabolite by lysosomal enzymes. Moreover, they revealed a safe profile and a consistent reduction of the tumour volume in vivo. In conclusion, we highlight the importance of GRP-R binding PDCs in targeted cancer therapy, with the possibility of further tailoring and optimisation.
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- 2023
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46. Nanostrategies for Therapeutic and Diagnostic Targeting of Gastrin-Releasing Peptide Receptor
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Beata Paulina Rurarz, Małgorzata Bukowczyk, Natalia Gibka, Agnieszka Wanda Piastowska-Ciesielska, Urszula Karczmarczyk, and Piotr Ulański
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gastrin-releasing peptide receptor ,GRPR ,bombesin receptor subtype 2 ,BB2 ,bombesin ,targeted therapy ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Advances in nanomedicine bring the attention of researchers to the molecular targets that can play a major role in the development of novel therapeutic and diagnostic modalities for cancer management. The choice of a proper molecular target can decide the efficacy of the treatment and endorse the personalized medicine approach. Gastrin-releasing peptide receptor (GRPR) is a G-protein-coupled membrane receptor, well known to be overexpressed in numerous malignancies including pancreatic, prostate, breast, lung, colon, cervical, and gastrointestinal cancers. Therefore, many research groups express a deep interest in targeting GRPR with their nanoformulations. A broad spectrum of the GRPR ligands has been described in the literature, which allows tuning of the properties of the final formulation, particularly in the field of the ligand affinity to the receptor and internalization possibilities. Hereby, the recent advances in the field of applications of various nanoplatforms that are able to reach the GRPR-expressing cells are reviewed.
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- 2023
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47. Enhanced gold nanoparticle-tumor cell recognition by albumin multilayer coating
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E. Achilli, C.Y. Flores, C.F. Temprana, S. del V. Alonso, M. Radrizzani, and M. Grasselli
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Gold nanoparticles ,Albumin ,Protein corona ,Bombesin ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Background: In a biological environment, nanoparticles are rapidly coated with serum proteins, which affects the NPs transport through biological medium, cellular uptake and response, all of which can impair therapeutic efficiency. Reduction of non-specific adsorption of proteins is mandatory to overcome this drawback. Aim: We propose to use albumin to prepare a multilayer coating of NPs to reduce the non-specific protein interactions in biological media. Materials & methods: Biohybrid NPs (bioHNPs) prepared by coating gold NPs with a multilayer of albumin and finally decorated with Bombesin-related peptides (BD-bioHNPs). Results: BioHNPs/biological media interaction was characterized by physicochemical and biological techniques under near-physiological conditions. A significant reduction of the Corona effect and enhanced in vitro uptake to PC-3 cells was demonstrated for BD-bioHNPs. Conclusion: This methodology to prepare decorated bioHNPs allows the preparation of ‘stealth’ NPs with improved cell targeting and the ability to avoid non-specific interactions with the biological media.
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- 2022
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48. The peptidergic control circuit for sighing.
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Li, Peng, Janczewski, Wiktor A, Yackle, Kevin, Kam, Kaiwen, Pagliardini, Silvia, Krasnow, Mark A, and Feldman, Jack L
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Respiratory Center ,Neurons ,Animals ,Mice ,Inbred C57BL ,Mice ,Rats ,Rats ,Sprague-Dawley ,Gastrin-Releasing Peptide ,Bombesin ,Neurokinin B ,Receptors ,Bombesin ,Emotions ,Signal Transduction ,Respiration ,Female ,Male ,Ribosome Inactivating Proteins ,Type 1 ,In Vitro Techniques ,Saporins ,General Science & Technology - Abstract
Sighs are long, deep breaths expressing sadness, relief or exhaustion. Sighs also occur spontaneously every few minutes to reinflate alveoli, and sighing increases under hypoxia, stress, and certain psychiatric conditions. Here we use molecular, genetic, and pharmacologic approaches to identify a peptidergic sigh control circuit in murine brain. Small neural subpopulations in a key breathing control centre, the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG), express bombesin-like neuropeptide genes neuromedin B (Nmb) or gastrin-releasing peptide (Grp). These project to the preBötzinger Complex (preBötC), the respiratory rhythm generator, which expresses NMB and GRP receptors in overlapping subsets of ~200 neurons. Introducing either neuropeptide into preBötC or onto preBötC slices, induced sighing or in vitro sigh activity, whereas elimination or inhibition of either receptor reduced basal sighing, and inhibition of both abolished it. Ablating receptor-expressing neurons eliminated basal and hypoxia-induced sighing, but left breathing otherwise intact initially. We propose that these overlapping peptidergic pathways comprise the core of a sigh control circuit that integrates physiological and perhaps emotional input to transform normal breaths into sighs.
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- 2016
49. Voxel-based comparison of [68Ga]Ga-RM2-PET/CT and [68Ga]Ga-PSMA-11-PET/CT with histopathology for diagnosis of primary prostate cancer
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Thomas Franz Fassbender, Florian Schiller, Constantinos Zamboglou, Vanessa Drendel, Selina Kiefer, Cordula A. Jilg, Anca-Ligia Grosu, and Michael Mix
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Prostate cancer ,GRPR ,Bombesin ,RM2 ,PSMA ,PET/CT ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 - Abstract
Abstract Background Focal therapies or focally escalated therapies of primary prostate cancer are becoming more and more important. This increases the need to identify the exact extension of the intraprostatic tumor and possible dominant intraprostatic lesions by imaging techniques. While the prostate-specific membrane antigen (PSMA) is already a well-established target for imaging of prostate cancer cells, the gastrin-releasing peptide receptor (GRPR) seems to provide interesting additional information. Histopathology was used to examine the extent to which the single and combined image information of PET scans targeting GRPR and PSMA might lead to better tumor delineation. Methods Eight patients with histologically proven primary prostate cancer underwent two positron emission tomography with computer tomography scans, [68Ga]Ga-RM2-PET/CT (RM2-PET) and [68Ga]Ga-PSMA-11-PET/CT (PSMA-PET), prior to radical prostatectomy. RM2-PET data were correlated voxel-wise to a voxel-based model of the histopathologic tumor volume information. The results were compared to, correlated to, and combined with the correlation of PSMA-PET data analyzed analogously. Results In 4/8 patients, RM2-PET showed a higher signal in histologically proven tumor regions compared to PSMA. There were also tumor regions where PSMA-PET showed a higher signal than GRPR in 4/8 patients. A voxel-wise correlation of RM2-PET against histopathology yielded similar results compared to the correlation of PSMA-PET against histopathology, while PSMA-PET is the slightly better performing imaging technique. The combined information of both tracers yielded the best overall result, although this effect was not statistically significant compared to RM2-PET alone. Conclusions Qualitative and quantitative findings in this preliminary study with 8 patients indicate that RM2-PET and PSMA-PET partially show not only the same, but also distinct regions of prostate cancer. Patients with pPCa might profit from information given by tracers targeting GRPR and PSMA simultaneously, in terms of a better delineation of the gross tumor volume.
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- 2020
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50. Bombesin receptor-targeted liposomes for enhanced delivery to lung cancer cells
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Mohammad J. Akbar, Pâmela C. Lukasewicz Ferreira, Melania Giorgetti, Leanne Stokes, and Christopher J. Morris
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bombesin ,grpr ,liposome ,lung cancer ,targeting ,Technology ,Chemical technology ,TP1-1185 ,Science ,Physics ,QC1-999 - Abstract
Background: Gastrin-releasing peptide is a member of the bombesin family of peptides. Its cognate receptor, gastrin releasing peptide receptor (GRPR), is widely expressed in cancers of the lung, pancreas and ovaries. Gastrin releasing peptide (GRP) is an autocrine growth factor in small cell lung cancer, which has very poor patient outcomes. High affinity antagonist peptides have been developed for in vivo cancer imaging. In this report we decorated pegylated liposomes with a GRPR antagonist peptide and studied its interaction with, and accumulation within, lung cancer cells.Results: An N-terminally cysteine modified GRPR antagonist (termed cystabn) was synthesised and shown to inhibit cell growth in vitro. Cystabn was used to prepare a targeted 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG2000) lipid conjugate that was formulated into liposomes. The liposomes displayed desirable colloidal properties and good stability under storage conditions. Flow cytometric and microscopic studies showed that fluorescently labelled cystabn-decorated liposomes accumulated more extensively in GRPR over-expressing cells than matched liposomes that contained no cystabn targeting motif.Conclusion: The use of GRPR antagonistic peptides for nanoparticle targeting has potential for enhancing drug accumulation in resistant cancer cells.
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- 2019
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