Optical Imaging of Matrix Metalloproteinase–2 Activity in Tumors: Feasibility Study in a Mouse Model

Bremer, Christoph; Bredow, Sebastian; Mahmood, Umar; Weissleder, Ralph; Tung, Ching–Hsuan

doi:10.1148/radiol.2212010368

Cited by 241 publications

(192 citation statements)

References 34 publications

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“…We next tested whether ACPPs could light up proteaseexpressing human tumor xenografts in whole mice. We chose HT-1080 tumors in the axilla of nude mice because these tumors express both MMP-2 and MMP-9 and have been used to test other MMP-2 cleavable contrast agents (22,26). Adding a PEG tail to the peptide proved helpful to prevent excessively rapid excretion; PEGs of 5, 11, and 21 kDa gave plasma half-lives of Ϸ5, 15, and 38 min, respectively, consistent with trends reported in ref.…”

Section: Mmp-2 Cleavable Acpps Concentrate In Human Tumors Xenograftedsupporting

confidence: 63%

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Tumor imaging by means of proteolytic activation of cell-penetrating peptides

Jiang

Olson

Nguyen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

752

713

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We have devised and tested a new strategy for selectively delivering molecules to tumor cells. Cellular association of polyargininebased, cell-penetrating peptides (CPPs) is effectively blocked when they are fused to an inhibitory domain made up of negatively charged residues. We call these fusions activatable CPPs (ACPPs) because cleavage of the linker between the polycationic and polyanionic domains, typically by a protease, releases the CPP portion and its attached cargo to bind to and enter cells. Association with cultured cells typically increases 10-fold or more upon linker cleavage. In mice xenografted with human tumor cells secreting matrix metalloproteinases 2 and 9, ACPPs bearing a far-red-fluorescent cargo show in vivo contrast ratios of 2-3 and a 3.1-fold increase in standard uptake value for tumors relative to contralateral normal tissue or control peptides with scrambled linkers. Ex vivo slices of freshly resected human squamous cell carcinomas give similar or better contrast ratios. Because CPPs are known to import a wide variety of nonoptical contrast and therapeutic agents, ACPPs offer a general strategy toward imaging and treating disease processes associated with linker-cleaving activities such as extracellular proteases.cancer ͉ molecular imaging ͉ polycation ͉ transduction

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Section: Mmp-2 Cleavable Acpps Concentrate In Human Tumors Xenograftedsupporting

confidence: 63%

“…Currently, at least 26 members of the MMP family have been identified. They play a crucial role in extracellular matrix degradation, tissue invasion, and metastasis (21)(22)(23)(24)(25)(26).…”

mentioning

confidence: 99%

Tumor imaging by means of proteolytic activation of cell-penetrating peptides

Jiang

Olson

Nguyen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

752

713

View full text Add to dashboard Cite

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“…An example of the signal sensitivity that can be achieved using these agents is the visualization of MMP-2 activity [50], [51], and [52]. In vitro, the authors observed an 850% increase in NIR fl uorescence intensity when the probe was cleaved and specifi c activation could be blocked by MMP-2 inhibitors.…”

Section: Activatable Probesmentioning

confidence: 99%

A systematic approach to the development of fluorescent contrast agents for optical imaging of mouse cancer models

Kovar

Simpson

Schutz-Geschwender

et al. 2007

Analytical Biochemistry

140

142

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“…The modular design allows one to create probes for different proteases. To date, several smart probes are designed for various proteases which include cathepsins [36], matrix metalloproteases [60], thrombin [61] and plasminogen activator [62,63]. The success of these probes in the preclinical research setting led to the first application of such agents in the clinic.…”

Section: (I) Role Of Optical Molecular Imaging In the Development Of mentioning

confidence: 99%

Optical imaging for the new grammar of drug discovery

Krucker¹,

Sandanaraj²

2011

Phil. Trans. R. Soc. A.

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Optical technologies used in biomedical research have undergone tremendous development in the last decade and enabled important insight into biochemical, cellular and physiological phenomena at the microscopic and macroscopic level. Historically in drug discovery, to increase throughput in screening, or increase efficiency through automation of image acquisition and analysis in pathology, efforts in imaging were focused on the reengineering of established microscopy solutions. However, with the emergence of the new grammar for drug discovery, other requirements and expectations have created unique opportunities for optical imaging. The new grammar of drug discovery provides rules for translating the wealth of genomic and proteomic information into targeted medicines with a focus on complex interactions of proteins. This paradigm shift requires highly specific and quantitative imaging at the molecular level with tools that can be used in cellular assays, animals and finally translated into patients. The development of fluorescent targeted and activatable 'smart' probes, fluorescent proteins and new reporter gene systems as functional and dynamic markers of molecular events in vitro and in vivo is therefore playing a pivotal role. An enabling optical imaging platform will combine optical hardware refinement with a strong emphasis on creating and validating highly specific chemical and biological tools.

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Optical Imaging of Matrix Metalloproteinase–2 Activity in Tumors: Feasibility Study in a Mouse Model

Abstract: It is feasible to image MMP-2 enzyme activity in vivo by using near-infrared optical imaging technology and "smart" matrix metalloproteinase-sensitive probes.

Cited by 241 publications

References 34 publications

Tumor imaging by means of proteolytic activation of cell-penetrating peptides

Tumor imaging by means of proteolytic activation of cell-penetrating peptides

A systematic approach to the development of fluorescent contrast agents for optical imaging of mouse cancer models

Optical imaging for the new grammar of drug discovery

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