scholarly journals I111n-Labeled Cystine-Knot Peptides Based on the Agouti-Related Protein for Targeting Tumor Angiogenesis

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Lei Jiang ◽  
Zheng Miao ◽  
Richard H. Kimura ◽  
Adam P. Silverman ◽  
Gang Ren ◽  
...  
Keyword(s):  
Tumor Angiogenesis ◽  
Cell Uptake ◽  
Mouse Serum ◽  
Tumor Uptake ◽  
Related Protein ◽  
Cystine Knot ◽  
Biodistribution Studies ◽  
Agouti Related Protein ◽  
Phosphate Buffered Saline

Agouti-related protein (AgRP) is a 4-kDa cystine-knot peptide of human origin with four disulfide bonds and four solvent-exposed loops. The cell adhesion receptor integrinαvβ3is an important tumor angiogenesis factor that determines the invasiveness and metastatic ability of many malignant tumors. AgRP mutants have been engineered to bind to integrinαvβ3with high affinity and specificity using directed evolution. Here, AgRP mutants 7C and 6E were radiolabeled with111In and evaluated forin vivotargeting of tumor integrinαvβ3receptors. AgRP peptides were conjugated to the metal chelator 1, 4, 7, 10-tetra-azacyclododecane- N,N′,N″,N‴-tetraacetic acid (DOTA) and radiolabeled with111In. The stability of the radiopeptides111In-DOTA-AgRP-7C and111In-DOTA-AgRP-6E was tested in phosphate-buffered saline (PBS) and mouse serum, respectively. Cell uptake assays of the radiolabeled peptides were performed in U87MG cell lines. Biodistribution studies were performed to evaluate thein vivoperformance of the two resulting probes using mice bearing integrin-expressing U87MG xenograft tumors. Both AgRP peptides were easily labeled with111In in high yield and radiochemical purity (>99%). The two probes exhibited high stability in phosphate-buffered saline and mouse serum. Compared with111In-DOTA-AgRP-6E,111In-DOTA-AgRP-7C showed increased U87MG tumor uptake and longer tumor retention (5.74±1.60and1.29±0.02%ID/g at 0.5 and 24 h, resp.), which was consistent with measurements of cell uptake. Moreover, the tumor uptake of111In-DOTA-AgRP-7C was specifically inhibited by coinjection with an excess of the integrin-binding peptidomimetic c(RGDyK). Thus,111In-DOTA-AgRP-7C is a promising probe for targeting integrinαvβ3positive tumors in living subjects.

Design, Pharmacology, and NMR Structure of a Minimized Cystine Knot with Agouti-Related Protein Activity†

Biochemistry ◽  
2002 ◽  
Vol 41 (24) ◽  
pp. 7565-7572 ◽  
Author(s):  
Pilgrim J. Jackson ◽  
Joseph C. McNulty ◽  
Ying-Kui Yang ◽  
Darren A. Thompson ◽  
Biaoxin Chai ◽  
...  
Keyword(s):  
Nmr Structure ◽  
Related Protein ◽  
Protein Activity ◽  
Cystine Knot ◽  
Agouti Related Protein

scholarly journals Zr-89 Immuno-PET Targeting Ectopic ATP Synthase Enables In-Vivo Imaging of Tumor Angiogenesis

2019 ◽  
Vol 20 (16) ◽  
pp. 3928
Author(s):  
Bok-Nam Park ◽  
Ga-Hee Kim ◽  
Seung-A Ko ◽  
Ga-Hee Shin ◽  
Su-Jin Lee ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cellular Uptake ◽  
Tumor Angiogenesis ◽  
Breast Cancer Cells ◽  
Xenograft Model ◽  
Tumor Uptake ◽  
Positron Emission ◽  
Pc3 Cells

In this study, we synthesized a Zr-89-labeled anti-adenosine triphosphate synthase monoclonal antibody (ATPS mAb) for applications in immuno-positron emission tomography (PET) and evaluated its feasibility for angiogenesis imaging. The cellular uptake of Zr-89 ATPS mAb was measured after treatment of cancer cell lines in vitro, and its biodistribution was evaluated at 4, 24 and 48 h in vivo in mice bearing xenografts. PET images were acquired at 4, 24, 48, and 96 h after Zr-89 ATPS mAb administration. Tumor angiogenesis was analyzed using anti-CD31 immunofluorescence staining. The cellular uptake of Zr-89 ATPS mAb increased over time in MDA-MB-231 breast cancer cells but did not increase in PC3 prostate cancer cells. The tumor uptake of Zr-89 ATPS mAb at 24 h was 9.4 ± 0.9% ID/g for MDA-Mb-231 cells and was 3.8 ± 0.6% ID/g for PC3 cells (p = 0.004). Zr-89 ATPS mAb uptake in MDA-MB-231 xenografts was inhibited by the administration of cold ATPS mAb (4.4 ± 0.5% ID/g, p = 0.011). Zr-89 ATPS mAb uptake could be visualized by PET for up to 96 h in MDA-MB-231 tumors. In contrast, there was no distinct tumor uptake detected by PET in the PC3 xenograft model. CD31-positive tumor vessels were abundant in MDA-MB-231 tumors, whereas they were scarcely detected in PC3 tumors. In conclusion, ATPS mAb was successfully labeled with Zr-89, which could be used for immuno-PET imaging targeting tumor angiogenesis.

Synthesis of a new 18F labeled porphyrin for potential application in positron emission tomography. In vivo imaging and cellular uptake

RSC Advances ◽  
2015 ◽  
Vol 5 (120) ◽  
pp. 99540-99546 ◽  
Author(s):  
Ana V. C. Simões ◽  
Sara M. A. Pinto ◽  
Mário J. F. Calvete ◽  
Célia M. F. Gomes ◽  
Nuno C. Ferreira ◽  
...  
Keyword(s):  
In Vivo Imaging ◽  
Bladder Tumor ◽  
Radiochemical Purity ◽  
Cell Uptake ◽  
Emission Tomography ◽  
Human Bladder ◽  
Biodistribution Studies ◽  
Biodistribution Data ◽  
Positron Emission

Synthesis, labeling and initial biodistribution studies of a new [18F] radiolabeled meso-tetraphenylporphyrin (radiochemical purity >95%). Includes human bladder tumor cell uptake and biodistribution data.

The effects of agouti-related protein gene transfer in vivo by electroporation in mice

2004 ◽  
Vol 370 (2-3) ◽  
pp. 108-113 ◽  
Author(s):  
Lan Xiang ◽  
Atsushi Murai ◽  
Tatsuo Muramatsu
Keyword(s):  
Gene Transfer ◽  
Protein Gene ◽  
Related Protein ◽  
Agouti Related Protein

scholarly journals Synthesis and evaluation of radiolabeled, folic acid-PEG conjugated, amino silane coated magnetic nanoparticles in tumor bearing Balb/C mice

Nukleonika ◽  
2015 ◽  
Vol 60 (3) ◽  
pp. 497-502 ◽  
Author(s):  
Javad Razjouyan ◽  
Hamidreza Zolata ◽  
Omid Khayat ◽  
Fereidoun Nowshiravan ◽  
Nami Shadanpour ◽  
...  
Keyword(s):  
Folic Acid ◽  
Folate Receptor ◽  
Superparamagnetic Iron Oxide ◽  
Fibroblast Cell ◽  
Mouse Fibroblast ◽  
Tumor Uptake ◽  
Mri Imaging ◽  
Tumor Bearing ◽  
Biodistribution Studies

Abstract To design a potent agent for positron emission tomography/magnetic resonance imaging (PET/MRI) imaging and targeted magnetic hyperthermia-radioisotope cancer therapy radiolabeled surface modified superparamagnetic iron oxide nanoparticles (SPIONs) were used as nanocarriers. Folic acid was conjugated for increasing selective cellular binding and internalization through receptor-mediated endocytosis. SPIONs were synthesized by the thermal decomposition of tris (acetylacetonato) iron (III) to achieve narrow and uniform nanoparticles. To increase the biocompatibility of SPIONs, they were coated with (3-aminopropyl) triethoxysilane (APTES), and then conjugated with synthesized folic acid-polyethylene glycol (FA-PEG) through amine group of (3-aminopropyl) triethoxysilane. Finally, the particles were labeled with 64Cu (t1/2 = 12.7 h) using 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono (N-hydroxy succinimide ester) DOTA-NHS chelator. After the characterization of SPIONs, their cellular internalization was evaluated in folate receptor (FR) overexpressing KB (established from a HeLa cell contamination) and mouse fibroblast cell (MFB) lines. Eventually, active and passive targeting effects of complex were assessed in KB tumor-bearing Balb/C mice through biodistribution studies. Synthesized bare SPIONs had low toxicity effect on healthy cells, but surface modification increased their biocompatibility. Moreover, KB cells viability was reduced when using folate conjugated SPIONs due to FR-mediated endocytosis, while having little effect on healthy cells (MFB). Moreover, this radiotracer had tolerable in vivo characteristics and tumor uptake. In the receptor blocked case, tumor uptake was decreased, indicating FR-specific uptake in tumor tissue while enhanced permeability and retention effect was major mechanism for tumor uptake.

A novel radiofluorinated agouti-related protein for tumor angiogenesis imaging

Amino Acids ◽  
2012 ◽  
Vol 44 (2) ◽  
pp. 673-681 ◽  
Author(s):  
Han Jiang ◽  
Sarah J. Moore ◽  
Shuanglong Liu ◽  
Hongguang Liu ◽  
Zheng Miao ◽  
...  
Keyword(s):  
Tumor Angiogenesis ◽  
Related Protein ◽  
Agouti Related Protein

scholarly journals Agouti-Related Protein Is Posttranslationally Cleaved by Proprotein Convertase 1 to Generate Agouti-Related Protein (AGRP)83–132: Interaction between AGRP83–132 and Melanocortin Receptors Cannot Be Influenced by Syndecan-3

Endocrinology ◽  
2006 ◽  
Vol 147 (4) ◽  
pp. 1621-1631 ◽  
Author(s):  
John W. M. Creemers ◽  
Lynn E. Pritchard ◽  
Amy Gyte ◽  
Philippe Le Rouzic ◽  
Sandra Meulemans ◽  
...  
Keyword(s):  
Food Intake ◽  
Core Body Temperature ◽  
Full Length ◽  
Related Protein ◽  
Amino Terminal ◽  
Terminal Domain ◽  
Carboxyl Terminal ◽  
Agouti Related Protein

Agouti-related protein (AGRP) plays a key role in energy homeostasis. The carboxyl-terminal domain of AGRP acts as an endogenous antagonist of the melanocortin-4 receptor (MC4-R). It has been suggested that the amino-terminal domain of AGRP binds to syndecan-3, thereby modulating the effects of carboxyl-terminal AGRP at the MC4-R. This model assumes that AGRP is secreted as a full-length peptide. In this study we found that AGRP is processed intracellularly after Arg79-Glu80-Pro81-Arg82. The processing site suggests cleavage by proprotein convertases (PCs). RNA interference and overexpression experiments showed that PC1/3 is primarily responsible for cleavage in vitro, although both PC2 and PC5/6A can also process AGRP. Dual in situ hybridization demonstrated that PC1/3 is expressed in AGRP neurons in the rat hypothalamus. Moreover, hypothalamic extracts from PC1-null mice contained 3.3-fold more unprocessed full-length AGRP, compared with wild-type mice, based on combined HPLC and RIA analysis, demonstrating that PC1/3 plays a role in AGRP cleavage in vivo. We also found that AGRP83–132 is more potent an antagonist than full-length AGRP, based on cAMP reporter assays, suggesting that posttranslational cleavage is required to potentiate the effect of AGRP at the MC4-R. Because AGRP is cleaved into distinct amino-terminal and carboxyl-terminal peptides, we tested whether amino-terminal peptides modulate food intake. However, intracerebroventricular injection of rat AGRP25–47 and AGRP50–80 had no effect on body weight, food intake, or core body temperature. Because AGRP is cleaved before secretion, syndecan-3 must influence food intake independently of the MC4-R.

scholarly journals Exploiting the Concept of Multivalency with 68Ga- and 89Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Dominik Summer ◽  
Christine Rangger ◽  
Maximilian Klingler ◽  
Peter Laverman ◽  
Gerben M. Franssen ◽  
...  
Keyword(s):  
Metabolic Stability ◽  
Cell Uptake ◽  
Late Time ◽  
Biodistribution Studies ◽  
Imaging Probes ◽  
Gallium 68 ◽  
Late Time Point ◽  
Time Point

Cholecystokinin-2 receptors (CCK2R) are overexpressed in a variety of malignant diseases and therefore have gained certain attention for peptide receptor radionuclide imaging. Among extensive approaches to improve pharmacokinetics and metabolic stability of minigastrin (MG) based radioligands, the concept of multivalency for enhanced tumour targeting has not been investigated extensively. We therefore utilized fusarinine C (FSC) as chelating scaffold for novel mono-, di-, and trimeric bioconjugates for targeting CCK2R expression. FSC-based imaging probes were radiolabelled with positron emitting radionuclides (gallium-68 and zirconium-89) and characterized in vitro (log⁡D, IC50, and cell uptake) and in vivo (metabolic stability in BALB/c mice, biodistribution profile, and microPET/CT imaging in A431-CCK2R/A431-mock tumour xenografted BALB/c nude mice). Improved targeting did not fully correlate with the grade of multimerization. The divalent probe showed higher receptor affinity and increased CCK2R mediated cell uptake while the trimer remained comparable to the monomer. In vivo biodistribution studies 1 h after administration of the 68Ga-labelled radioligands confirmed this trend, but imaging at late time point (24 h) with 89Zr-labelled counterparts showed a clearly enhanced imaging contrast of the trimeric probe compared to the mono- and dimer. Furthermore, in vivo stability studies showed a higher metabolic stability for multimeric probes compared to the monomeric bioconjugate. In summary, we could show that FSC can be utilized as suitable scaffold for novel mono- and multivalent imaging probes for CCK2R-related malignancies with partly improved targeting properties for multivalent conjugates. The increased tumour accumulation of the trimer 24 h postinjection (p.i.) can be explained by slower clearance and increased metabolic stability of multimeric conjugates.

scholarly journals 89Zr-pembrolizumab biodistribution is influenced by PD-1-mediated uptake in lymphoid organs

2020 ◽  
Vol 8 (2) ◽  
pp. e000938 ◽  
Author(s):  
Elly L van der Veen ◽  
Danique Giesen ◽  
Linda Pot-de Jong ◽  
Annelies Jorritsma-Smit ◽  
Elisabeth G E De Vries ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lymph Nodes ◽  
Pet Imaging ◽  
Immune Checkpoint ◽  
Whole Body ◽  
Lymphoid Tissues ◽  
Tumor Uptake ◽  
Body Distribution ◽  
Biodistribution Studies

BackgroundTo better predict response to immune checkpoint therapy and toxicity in healthy tissues, insight in the in vivo behavior of immune checkpoint targeting monoclonal antibodies is essential. Therefore, we aimed to study in vivo pharmacokinetics and whole-body distribution of zirconium-89 (89Zr) labeled programmed cell death protein-1 (PD-1) targeting pembrolizumab with positron-emission tomography (PET) in humanized mice.MethodsHumanized (huNOG) and non-humanized NOG mice were xenografted with human A375M melanoma cells. PET imaging was performed on day 7 post 89Zr-pembrolizumab (10 µg, 2.5 MBq) administration, followed by ex vivo biodistribution studies. Other huNOG mice bearing A375M tumors received a co-injection of excess (90 µg) unlabeled pembrolizumab or 89Zr-IgG4 control (10 µg, 2.5 MBq). Tumor and spleen tissue were studied with autoradiography and immunohistochemically including PD-1.ResultsPET imaging and biodistribution studies showed high 89Zr-pembrolizumab uptake in tissues containing human immune cells, including spleen, lymph nodes and bone marrow. Tumor uptake of 89Zr-pembrolizumab was lower than uptake in lymphoid tissues, but higher than uptake in other organs. High uptake in lymphoid tissues could be reduced by excess unlabeled pembrolizumab. Tracer activity in blood pool was increased by addition of unlabeled pembrolizumab, but tumor uptake was not affected. Autoradiography supported PET findings and immunohistochemical staining on spleen and lymph node tissue showed PD-1 positive cells, whereas tumor tissue was PD-1 negative.Conclusion89Zr-pembrolizumab whole-body biodistribution showed high PD-1-mediated uptake in lymphoid tissues, such as spleen, lymph nodes and bone marrow, and modest tumor uptake. Our data may enable evaluation of 89Zr-pembrolizumab whole-body distribution in patients.

Bifunctional HPPH-N2S2-99mTc conjugates as tumor imaging agents: synthesis and biodistribution studies

2003 ◽  
Vol 07 (07) ◽  
pp. 500-507 ◽  
Author(s):  
Bing Ma ◽  
Guolin Li ◽  
Peter Kanter ◽  
Dominick Lamonica ◽  
Zachary Grossman ◽  
...  
Keyword(s):  
Half Life ◽  
Tumor Imaging ◽  
Post Injection ◽  
Tumor Uptake ◽  
In Vivo Biodistribution ◽  
Structure Activity ◽  
Biodistribution Studies ◽  
Activity Screening ◽  
Pyropheophorbide A

Pyropheophorbide-a and the corresponding 3-(1'-hexyloxyethyl)-3-devinyl derivative ( HPPH ), the tumor-avid photosensitizers were conjugated with mono- or di-bisaminoethanethiols ( N 2 S 2 ligand). The in vivo biodistribution study of the related 99m Tc complexes was performed in F-344 rats bearing Ward colon tumors at 4 h and 24 h post injection. These data show that the complexes are stable and among four tracers, HPPH di-99 m Tc N 2 S 2 conjugate reaches the highest tumor uptake (%ID/g). The larger tumors reach higher concentrations of the tracer. However, the short 6 h half life of 99 m Tc is incompatible with the 24 h imaging time, suggesting that the use of a longer-lived isotope such as 111 In could still provide a useful scanning agent, or that further structure-activity screening could yield an HPPH analog with more appropriate pharmacokinetics for tumor imaging with 99 m Tc .

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