scholarly journals Synthesis, Physicochemical and Biological Study of Gallium-68- and Lutetium-177-Labeled VEGF-A165/NRP-1 Complex Inhibitors Based on Peptide A7R and Branched Peptidomimetic

Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 100
Author(s):  
Katarzyna Masłowska ◽  
Ewa Witkowska ◽  
Dagmara Tymecka ◽  
Paweł Krzysztof Halik ◽  
Aleksandra Misicka ◽  
...  
Keyword(s):  
Biological Study ◽  
Vascular Endothelial ◽  
Good Efficiency ◽  
Promising Strategy ◽  
Therapeutic Uses ◽  
Neuropilin 1 ◽  
Surface Receptor ◽  
Tumor Growth And Metastasis ◽  
Gallium 68 ◽  
Endothelial Growth Factor

Neuropilin-1 (NRP-1) is a surface receptor found on many types of cancer cells. The overexpression of NRP-1 and its interaction with vascular endothelial growth factor-165 (VEGF165) are associated with tumor growth and metastasis. Therefore, compounds that block the VEGF165/NRP-1 interaction represent a promising strategy to image and treat NRP-1-related pathologies. The aim of the presented work was to design and synthesize radioconjugates of two known peptide-type inhibitors of the VEGF165/NRP-1 complex: A7R peptide and its shorter analog, the branched peptidomimetic Lys(hArg)-Dab-Pro-Arg. Both peptide-type inhibitors were coupled to a radionuclide chelator (DOTA) via a linker (Ahx) and so radiolabeled with Ga-68 and Lu-177 radionuclides, for diagnostic and therapeutic uses, respectively. The synthesized radioconjugates were tested for their possible use as theranostic-like radiopharmaceuticals for the imaging and therapy of cancers that overexpress NRP-1. The obtained results indicate good efficiency of the radiolabeling reaction and satisfactory stability, at least 3t1/2 for the 68Ga- and 1t1/2 for the 177Lu-radiocompounds, in solutions mimicking human body fluids. However, enzymatic degradation of both the studied inhibitors caused insufficient stability of the radiocompounds in human serum, indicating that further modifications are needed to sufficiently stabilize the peptidomimetics with inhibitory properties against VEGF165/NRP-1 complex formation.

scholarly journals Selective upregulation of vascular endothelial growth factor receptors neuropilin-1 and -2 in human neuroblastoma

Cancer ◽  
2001 ◽  
Vol 94 (1) ◽  
pp. 258-263 ◽  
Author(s):  
Mitra Fakhari ◽  
Dieter Pullirsch ◽  
Dietmar Abraham ◽  
Kurosh Paya ◽  
Reinhold Hofbauer ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Growth Factor Receptors ◽  
Vascular Endothelial ◽  
Human Neuroblastoma ◽  
Neuropilin 1 ◽  
Endothelial Growth Factor

scholarly journals Neuropilin-1 Mediates Collapsin-1/Semaphorin III Inhibition of Endothelial Cell Motility

1999 ◽  
Vol 146 (1) ◽  
pp. 233-242 ◽  
Author(s):  
Hua-Quan Miao ◽  
Shay Soker ◽  
Leonard Feiner ◽  
José Luis Alonso ◽  
Jonathan A. Raper ◽  
...  
Keyword(s):  
Binding Sites ◽  
Aortic Ring ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Binding Assays ◽  
Angiogenesis Assay ◽  
Neuropilin 1 ◽  
Endothelial Growth Factor ◽  
Neuronal Guidance

Neuropilin-1 (NRP1) is a receptor for two unrelated ligands with disparate activities, vascular endothelial growth factor-165 (VEGF165), an angiogenesis factor, and semaphorin/collapsins, mediators of neuronal guidance. To determine whether semaphorin/collapsins could interact with NRP1 in nonneuronal cells, the effects of recombinant collapsin-1 on endothelial cells (EC) were examined. Collapsin-1 inhibited the motility of porcine aortic EC (PAEC) expressing NRP1 alone; coexpressing KDR and NRP1 (PAEC/KDR/NRP1), but not parental PAEC; or PAEC expressing KDR alone. The motility of PAEC expressing NRP1 was inhibited by 65–75% and this inhibition was abrogated by anti-NRP1 antibody. In contrast, VEGF165 stimulated the motility of PAEC/KDR/NRP1. When VEGF165 and collapsin-1 were added simultaneously to PAEC/KDR/NRP1, dorsal root ganglia (DRG), and COS-7/NRP1 cells, they competed with each other in EC motility, DRG collapse, and NRP1-binding assays, respectively, suggesting that the two ligands have overlapping NRP1 binding sites. Collapsin-1 rapidly disrupted the formation of lamellipodia and induced depolymerization of F-actin in an NRP1-dependent manner. In an in vitro angiogenesis assay, collapsin-1 inhibited the capillary sprouting of EC from rat aortic ring segments. These results suggest that collapsin-1 can inhibit EC motility as well as axon motility, that these inhibitory effects on motility are mediated by NRP1, and that VEGF165 and collapsin-1 compete for NRP1-binding sites.

scholarly journals αvβ3 Integrin Limits the Contribution of Neuropilin-1 to Vascular Endothelial Growth Factor-induced Angiogenesis

2009 ◽  
Vol 284 (49) ◽  
pp. 33966-33981 ◽  
Author(s):  
Stephen D. Robinson ◽  
Louise E. Reynolds ◽  
Vassiliki Kostourou ◽  
Andrew R. Reynolds ◽  
Rita Graça da Silva ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Αvβ3 Integrin ◽  
Vascular Endothelial ◽  
Neuropilin 1 ◽  
Endothelial Growth Factor

scholarly journals Inhibition of endothelial FAK activity prevents tumor metastasis by enhancing barrier function

2014 ◽  
Vol 204 (2) ◽  
pp. 247-263 ◽  
Author(s):  
Christine Jean ◽  
Xiao Lei Chen ◽  
Ju-Ock Nam ◽  
Isabelle Tancioni ◽  
Sean Uryu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Stromal Cells ◽  
Barrier Function ◽  
Tumor Metastasis ◽  
Vascular Endothelial ◽  
Vascular Endothelial Cadherin ◽  
Tumor Growth And Metastasis ◽  
Endothelial Growth Factor

Pharmacological focal adhesion kinase (FAK) inhibition prevents tumor growth and metastasis, via actions on both tumor and stromal cells. In this paper, we show that vascular endothelial cadherin (VEC) tyrosine (Y) 658 is a target of FAK in tumor-associated endothelial cells (ECs). Conditional kinase-dead FAK knockin within ECs inhibited recombinant vascular endothelial growth factor (VEGF-A) and tumor-induced VEC-Y658 phosphorylation in vivo. Adherence of VEGF-expressing tumor cells to ECs triggered FAK-dependent VEC-Y658 phosphorylation. Both FAK inhibition and VEC-Y658F mutation within ECs prevented VEGF-initiated paracellular permeability and tumor cell transmigration across EC barriers. In mice, EC FAK inhibition prevented VEGF-dependent tumor cell extravasation and melanoma dermal to lung metastasis without affecting primary tumor growth. As pharmacological c-Src or FAK inhibition prevents VEGF-stimulated c-Src and FAK translocation to EC adherens junctions, but FAK inhibition does not alter c-Src activation, our experiments identify EC FAK as a key intermediate between c-Src and the regulation of EC barrier function controlling tumor metastasis.

scholarly journals The Hepatic Microenvironment and TRAIL-R2 Impact Outgrowth of Liver Metastases in Pancreatic Cancer after Surgical Resection

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 745 ◽  
Author(s):  
Lauritz Miarka ◽  
Charlotte Hauser ◽  
Ole Helm ◽  
Dörthe Holdhof ◽  
Silje Beckinger ◽  
...  
Keyword(s):  
Liver Metastases ◽  
Surgical Resection ◽  
Tumor Resection ◽  
Ductal Adenocarcinoma ◽  
Vascular Endothelial ◽  
Liver Inflammation ◽  
Tumor Growth And Metastasis ◽  
Endothelial Growth Factor ◽  
The Impact

Most patients with pancreatic ductal adenocarcinoma (PDAC) undergoing curative resection relapse within months, often with liver metastases. The hepatic microenvironment determines induction and reversal of dormancy during metastasis. Both tumor growth and metastasis depend on the Tumor necrosis factor (TNF)-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2). This study investigated the interplay of TRAIL-R2 and the hepatic microenvironment in liver metastases formation and the impact of surgical resection. Although TRAIL-R2-knockdown (PancTu-I shTR2) decreased local relapses and number of macroscopic liver metastases after primary tumor resection in an orthotopic PDAC model, the number of micrometastases was increased. Moreover, abdominal surgery induced liver inflammation involving activation of hepatic stellate cells (HSCs) into hepatic myofibroblasts (HMFs). In coculture with HSCs, proliferation of PancTu-I shTR2 cells was significantly lower compared to PancTu-I shCtrl cells, an effect still observed after switching coculture from HSC to HMF, mimicking surgery-mediated liver inflammation and enhancing cell proliferation. CXCL-8/IL-8 blockade diminished HSC-mediated growth inhibition in PancTu-I shTR2 cells, while Vascular Endothelial Growth Factor (VEGF) neutralization decreased HMF-mediated proliferation. Overall, this study points to an important role of TRAIL-R2 in PDAC cells in the interplay with the hepatic microenvironment during metastasis. Resection of primary PDAC seems to induce liver inflammation, which might contribute to outgrowth of liver metastases.

scholarly journals Tuftsin Binds Neuropilin-1 through a Sequence Similar to That Encoded by Exon 8 of Vascular Endothelial Growth Factor

2005 ◽  
Vol 281 (9) ◽  
pp. 5702-5710 ◽  
Author(s):  
Mathew A. von Wronski ◽  
Natarajan Raju ◽  
Radhakrishna Pillai ◽  
Nancy J. Bogdan ◽  
Edmund R. Marinelli ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vascular Endothelial ◽  
Neuropilin 1 ◽  
Endothelial Growth Factor

In vivo administration of vascular endothelial growth factor (VEGF) and its antagonist, soluble neuropilin-1, predicts a role of VEGF in the progression of acute myeloid leukemia in vivo

Blood ◽  
2002 ◽  
Vol 100 (13) ◽  
pp. 4622-4628 ◽  
Author(s):  
Gunter Schuch ◽  
Marcelle Machluf ◽  
Georg Bartsch ◽  
Masashi Nomi ◽  
Henri Richard ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Vascular Endothelial Growth Factor ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Vascular Endothelial ◽  
Neuropilin 1 ◽  
Endothelial Growth Factor ◽  
Acute Myeloid

Recent findings implied that the progression of hematologic malignancies, like that of solid tumors, is dependent on neovascularization. Recent studies on patients with acute myeloid leukemia (AML) showed increased levels of leukocyte-associated vascular endothelial growth factor (VEGF) and neovascularization of the bone marrow. Murine (32D, M1) and human (HEL, U937, and UKE-1) leukemic cell lines and freshly isolated leukemic cells were analyzed for the expression of VEGF and VEGF receptor mRNA. The expression of VEGF and VEGF receptors KDR and neuropilin-1 (NRP-1) was detected in these cells. In a murine chloroma model, delivery of VEGF165using microencapsulation technology resulted in enhanced tumor growth and vascularization, whereas treatment with a VEGF antagonist soluble NRP-1 (sNRP-1) inhibited tumor angiogenesis and growth. In a systemic leukemia model, survival of mice injected with adenovirus (Ad) encoding for Fc-sNRP-1 (sNRP-1 dimer) was significantly prolonged as compared with mice injected with Ad-LacZ. Further analyses showed a reduction in circulating leukemic cells and infiltration of liver and spleen as well as bone marrow neovascularization and cellularity. Taken together, these results demonstrate that angiogenic factors such as VEGF promote AML progression in vivo. The use of VEGF antagonists as an antiangiogenesis approach offers a potential treatment for AML. Finally, our novel in vivo drug delivery model may be useful for testing the activities of other peptide antiangiogenic factors.

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