Ratiometric Activatable Cell‐Penetrating Peptides Provide Rapid In Vivo Readout of Thrombin Activation

Whitney, Michael; Savariar, Elamprakash N.; Friedman, Beth; Levin, Rachel A.; Crisp, Jessica L.; Glasgow, Heather L.; Lefkowitz, Roy B.; Adams, Stephen; Steinbach, Paul; Nashi, Nadia; Nguyen, Quyen T.; Tsien, Roger Y.

doi:10.1002/anie.201205721

Cited by 98 publications

(91 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although there are reports of increased MMP-9 levels in patients with asthma who undergo antigen challenge (25), there are no current reports on the maintenance of MMP-2/9 activity throughout chronic airway remodeling. A beneficial feature of the ACPP design is that the linker sequence can easily be replaced with a substrate for any other extracellular protease that has a known cleavage sequence; the chemical approaches for the cleavage sequences reported in this paper have all been previously published (10,24,41,46,47). Thus ACPPs can be used to examine other extracellular proteases that have proposed activity in asthma.…”

Section: Discussionmentioning

confidence: 91%

“…More recently, the development of ratiometric ACPPs has improved cancer detection (41) and allowed for in vivo assessment of thrombin activation (47). However, the usefulness of ACPPs has not previously been evaluated in allergic airway inflammation or asthma.…”

Section: Discussionmentioning

confidence: 99%

“…To evaluate whether other extracellular proteases are upregulated in the lungs of acutely challenged mice, we used RACPPs that are selective for neutrophil elastase (41,46) and thrombin (47), which were generated by modifying the cleavable linker to alter the substrate specificity (Fig. 6).…”

Section: Evaluating Protease Activity With Racpps For a Variety Of Sumentioning

confidence: 99%

See 2 more Smart Citations

Detection and monitoring of localized matrix metalloproteinase upregulation in a murine model of asthma

Felsen¹,

Savariar²,

Whitney³

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

Self Cite

View full text Add to dashboard Cite

Extracellular proteases including matrix metalloproteinases (MMPs) are speculated to play a significant role in chronic lung diseases, such as asthma. Although increased protease expression has been correlated with lung pathogenesis, the relationship between localized enzyme activity and disease progression remains poorly understood. We report the application of MMP-2/9 activatable cell-penetrating peptides (ACPPs) and their ratiometric analogs (RACPPs) for in vivo measurement of protease activity and distribution in the lungs of mice that were challenged with the allergen ovalbumin. MMP-2/9 activity was increased greater than twofold in whole, dissected lungs from acutely challenged mice compared with control mice (P=1.8×10(-4)). This upregulation of MMP-2/9 activity was localized around inflamed airways with 1.6-fold higher protease-dependent ACPP uptake surrounding diseased airways compared with adjacent, pathologically normal lung parenchyma (P=0.03). MMP-2/9 activity detected by ACPP cleavage colocalized with gelatinase activity measured with in situ dye-quenched gelatin. For comparison, neutrophil elastase activity and thrombin activity, detected with elastase- and thrombin-cleavable RACPPs, respectively, were not significantly elevated in acutely allergen-challenged mouse lungs. The results demonstrate that ACPPs, like the MMP-2/9-activated and related ACPPs, allow for real-time detection of protease activity in a murine asthma model, which should improve our understanding of protease activation in asthma disease progression and help elucidate new therapy targets or act as a mechanism for therapeutic drug delivery.

show abstract

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Detection and monitoring of localized matrix metalloproteinase upregulation in a murine model of asthma

Felsen¹,

Savariar²,

Whitney³

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

Self Cite

View full text Add to dashboard Cite

show abstract

“…24 approach has also been used for detection of thrombin activation in which a CPP was made active by thrombin, allowing the CPP to be internalized in nearby cells, which can lead to better treatment of atherosclerosis and strokes (Whitney et al 2013). Another exciting approach has been the development of chemically sensitive linkers to produce other novel activatable CPPs.…”

Section: Accepted Manuscriptmentioning

confidence: 98%

Cell-penetrating peptides transport therapeutics into cells

Ramsey

Flynn

2015

Pharmacology & Therapeutics

219

181

View full text Add to dashboard Cite

Nearly 30years ago, certain small, relatively nontoxic peptides were discovered to be capable of traversing the cell membrane. These cell-penetrating peptides, as they are now called, have been shown to not only be capable of crossing the cell membrane themselves but can also carry many different therapeutic agents into cells, including small molecules, plasmid DNA, siRNA, therapeutic proteins, viruses, imaging agents, and other various nanoparticles. Many cell-penetrating peptides have been derived from natural proteins, but several other cell-penetrating peptides have been developed that are either chimeric or completely synthetic. How cell-penetrating peptides are internalized into cells has been a topic of debate, with some peptides seemingly entering cells through an endocytic mechanism and others by directly penetrating the cell membrane. Although the entry mechanism is still not entirely understood, it seems to be dependent on the peptide type, the peptide concentration, the cargo the peptide transports, and the cell type tested. With new intracellular disease targets being discovered, cell-penetrating peptides offer an exciting approach for delivering drugs to these intracellular targets. There are hundreds of cell-penetrating peptides being studied for drug delivery, and ongoing studies are demonstrating their success both in vitro and in vivo.

show abstract

“…Sensors based on the changes of fluorescence intensity were susceptible to test conditions such as environmental pH, sensor concentration, excitation wavelength, etc. The errors originated from the test conditions could be overcome by a ratiometric strategy which allowed for a built-in correction to overcome the errors come from environments effects, especially the variations in sensors concentration [56][57][58]. So only the response time was explored.…”

Section: Performance Of Cds@eu/gmp As Nanosensor Toward Dpa Detectionmentioning

confidence: 99%

Ratiometric fluorescent detection of biomakers for biological warfare agents with carbon dots chelated europium-based nanoscale coordination polymers

Song

Chen

et al. 2015

Sensors and Actuators B: Chemical

View full text Add to dashboard Cite

Ratiometric Activatable Cell‐Penetrating Peptides Provide Rapid In Vivo Readout of Thrombin Activation

Cited by 98 publications

References 31 publications

Detection and monitoring of localized matrix metalloproteinase upregulation in a murine model of asthma

Detection and monitoring of localized matrix metalloproteinase upregulation in a murine model of asthma

Cell-penetrating peptides transport therapeutics into cells

Ratiometric fluorescent detection of biomakers for biological warfare agents with carbon dots chelated europium-based nanoscale coordination polymers

Contact Info

Product

Resources

About