Imaging of Urokinase-Type Plasminogen Activator Receptor Expression Using a 64Cu-Labeled Linear Peptide Antagonist by microPET

Li, Zibo; Niu, Gang; Wang, Hui; He, Lina; Yang, Lily; Ploug, Michael; Chen, Xiaoyuan

doi:10.1158/1078-0432.ccr-07-4434

Cited by 71 publications

(67 citation statements)

References 42 publications

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“…This peptide was further optimized by combinatorial chemistry, resulting in a more stable, affinity-matured 9-mer peptidomimetic analog that bound uPAR with a K D of approximately 0.4 nM (Ploug et al 2001). In a recent study, this peptidomimetic was conjugated to DOTA, radiolabeled with 64 Cu, and used to image U87MG human glioblastoma xenografts in mice by PET (Li et al 2008).…”

Section: Molecular Imaging Agents Obtained Using Cell Lines Expressinmentioning

confidence: 99%

Phage display and molecular imaging: expanding fields of vision in living subjects

Cochran

2010

Biotechnology and Genetic Engineering Reviews

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In vivo molecular imaging enables non-invasive visualization of biological processes within living subjects, and holds great promise for diagnosis and monitoring of disease. The ability to create new agents that bind to molecular targets and deliver imaging probes to desired locations in the body is critically important to further advance this field. To address this need, phage display, an established technology for the discovery and development of novel binding agents, is increasingly becoming a key component of many molecular imaging research programs. This review discusses the expanding role played by phage display in the field of molecular imaging with a focus on in vivo applications. Furthermore, new methodological advances in phage display that can be directly applied to the discovery and development of molecular imaging agents are described. Various phage library selection strategies are summarized and compared, including selections against purified target, intact cells, and ex vivo tissue, plus in vivo homing strategies. An outline of the process for converting polypeptides obtained from phage display library selections into successful in vivo imaging agents is provided, including strategies to optimize in vivo performance. Additionally, the use To whom correspondence may be addressed (cochran1@stanford.edu) Abbreviations: scFv, single chain variable fragment; Fab, fragment antigen binding; ELISA, Enzyme-Linked Immunosorbent Assay; NEB, New England Biolabs; PET, positron emission tomography; SPECT, single photon emission computed tomography; NIR, near infrared; PEG, polyethylene glycol; SPARC, secreted protein acidic and rich in cysteine; VCAM-1, vascular cell adhesion molecule; MRI, magnetic resonance imaging; DOTA, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; IC 50 , half maximal inhibitory concentration; CT, computed tomography; K D , equilibrium dissociation constant; EGFR, epidermal growth factor receptor; EGFR-ECD, EGFR extracellular domain; Aβ 42 , amyloid-beta; MMP, matrix metalloprotease; uPAR, urokinase-type plasminogen activator receptor; VEGF, vascular endothelial growth factor; IL-11, Interleukin-11; IL-11αR, Interleukin-11 α-receptor. 58F.V. CoChran and J.r. CoChran of phage particles as imaging agents is also described. In the latter part of the review, a survey of phage-derived in vivo imaging agents is presented, and important recent examples are highlighted. Other imaging applications are also discussed, such as the development of peptide tags for site-specific protein labeling and the use of phage as delivery agents for reporter genes. The review concludes with a discussion of how phage display technology will continue to impact both basic science and clinical applications in the field of molecular imaging.

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Section: Molecular Imaging Agents Obtained Using Cell Lines Expressinmentioning

confidence: 99%

Phage display and molecular imaging: expanding fields of vision in living subjects

Cochran

2010

Biotechnology and Genetic Engineering Reviews

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“…Following this line of evidence, several intervention strategies targeting uPAR have been developed, and some have shown promising therapeutic effects in preclinical mouse model systems (10 -13). To assist their further clinical translation, a non-invasive imaging modality for visualizing uPAR expression in vivo using positron emission tomography has been developed recently (13)(14)(15).…”

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confidence: 99%

A Flexible Multidomain Structure Drives the Function of the Urokinase-type Plasminogen Activator Receptor (uPAR)

Mertens

Kjærgaard

Mysling

et al. 2012

Journal of Biological Chemistry

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Background:The urokinase receptor (uPAR) is a modular receptor containing three LU domains. Results: Ligand-free uPAR is inherently flexible with a detached N-terminal domain (DI). Conclusion: Allosteric regulation of uPAR is driven by uPA-induced compaction of the intact receptor and a concomitant stabilization of DI. Significance: This flexibility and ligand-induced allostery are expected to impact future studies on uPAR function and targeted intervention.

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“…Accordingly, uPAR has been proposed as a promising molecular target for intervention and/or cytotoxin-based cancer therapies (14,17,18). With the goal of future monitoring efficacy of such treatment modalities, we have developed a high affinity peptide antagonist of the human uPA⅐uPAR interaction (19), which has proven well suited for non-invasive in vivo imaging of uPAR by positron emission tomography (20).…”

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confidence: 99%

Structure-based Engineering of Species Selectivity in the Interaction between Urokinase and Its Receptor

Lin

Gårdsvoll

Huai

et al. 2010

Journal of Biological Chemistry

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131

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The high affinity interaction between the urokinase-type plasminogen activator (uPA) and its glycolipid-anchored receptor (uPAR) is decisive for cell surface-associated plasminogen activation. Because plasmin activity controls fibrinolysis in a variety of pathological conditions, including cancer and wound healing, several intervention studies have focused on targeting the uPA⅐uPAR interaction in vivo. Evaluations of such studies in xenotransplanted tumor models are, however, complicated by the pronounced species selectivity in this interaction. We now report the molecular basis underlying this difference by solving the crystal structure for the murine uPA⅐uPAR complex and demonstrate by extensive surface plasmon resonance studies that the kinetic rate constants for this interaction can be swapped completely between these orthologs by exchanging only two residues. This study not only discloses the structural basis required for a successful rational design of the species selectivity in the uPA⅐uPAR interaction, which is highly relevant for functional studies in mouse models, but it also suggests the possible development of general inhibitors that will target the uPA⅐uPAR interaction across species barriers.The urokinase-type plasminogen activator receptor (uPAR) 3 is a glycolipid-anchored membrane protein (1) that recognizes the serine protease urokinase-type plasminogen activator (uPA) and its zymogen (pro-uPA) with very high affinity and specificity (2). This interaction is exclusively mediated by the N-terminal growth factor-like domain (GFD 1-48 ) of uPA, and it is indispensable for the focalized uPA-mediated plasminogen activation that occurs at cell surfaces both in vitro (3, 4) and in vivo (5-7). Several independent studies have correlated uPAR expression in vivo to e.g. neutrophil infiltration (8 -10) and to various pathological conditions such as cancer invasion and metastasis (11-13), hepatic fibrin deposition (14, 15), and kidney barrier function (16). Accordingly, uPAR has been proposed as a promising molecular target for intervention and/or cytotoxin-based cancer therapies (14,17,18). With the goal of future monitoring efficacy of such treatment modalities, we have developed a high affinity peptide antagonist of the human uPA⅐uPAR interaction (19), which has proven well suited for non-invasive in vivo imaging of uPAR by positron emission tomography (20).The extracellular domains of uPAR comprise three homologous Ly-6/uPAR (LU)-type modules, all of which adopt the three-fingered folding topology that is defined by the structures of the single domain snake venom ␣-neurotoxins (21-23). Crystal structures recently solved for human uPAR in complex with the abovementioned peptide antagonist (24), the N-terminal fragment (ATF) of uPA (25), or the somatomedin B (SMB) domain of vitronectin (26) all confirm this topology, and more importantly, they consistently reveal the presence of a large hydrophobic uPA-binding cavity in uPAR that requires all three LU domains for its assembly. In total, Ͼ2000 Å 2 of solve...

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Imaging of Urokinase-Type Plasminogen Activator Receptor Expression Using a 64Cu-Labeled Linear Peptide Antagonist by microPET

Cited by 71 publications

References 42 publications

Phage display and molecular imaging: expanding fields of vision in living subjects

Phage display and molecular imaging: expanding fields of vision in living subjects

A Flexible Multidomain Structure Drives the Function of the Urokinase-type Plasminogen Activator Receptor (uPAR)

Structure-based Engineering of Species Selectivity in the Interaction between Urokinase and Its Receptor

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