Development of an advanced nanoformulation for the intracellular delivery of a caspase-3 selective activity-based probe

Francesco Cogo, Peter Smyth, Roberta Burden, Daniel B. Longley, Richard Williams, Michael Johnston, Marcin Poreba, Wioletta Rut, Katarzyna Groborz, Guy Salvesen, Marcin Drag, Christopher J. Scott

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Abstract

The ability to label active caspase-3 represents a useful pharmacodynamic strategy to determine the efficacy of anti-tumour drugs. Activity-based probes (ABPs) provide a method for the labelling of activated caspases and the recent development of hybrid combinatorial substrate libraries (HyCoSuL) has allowed for the generation of highly selective ABPs to discriminately label these proteases. Here using this approach, a novel caspase-3 selective ABP (CS1) has been developed and validated in apoptotic cells to selectively bind caspase-3 over the closely related caspase-7. However, a critical bottleneck for ABPs is their cell penetrance and therefore this cell-impermeable CS1 probe was subsequently formulated into PLGA-based nanoparticles (CS1-NPs). We demonstrate the ability of these particles to be taken up by the cells and facilitate intracellular delivery of the ABP to effectively label caspase 3 in response to apoptotic stimuli. This work forms the foundation of a novel approach for the labelling of caspase 3 and may have downstream utility to measure real time apoptosis in tumours and other organs.
Original languageEnglish
JournalNanoscale - Royal Society of Chemistry
Early online date13 Dec 2018
DOIs
Publication statusEarly online date - 13 Dec 2018

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Caspase 3
Labels
Labeling
Tumors
Pharmacodynamics
Caspase 7
Cell death
Caspases
Peptide Hydrolases
Cells
Apoptosis
Nanoparticles
Substrates
Pharmaceutical Preparations

Cite this

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title = "Development of an advanced nanoformulation for the intracellular delivery of a caspase-3 selective activity-based probe",
abstract = "The ability to label active caspase-3 represents a useful pharmacodynamic strategy to determine the efficacy of anti-tumour drugs. Activity-based probes (ABPs) provide a method for the labelling of activated caspases and the recent development of hybrid combinatorial substrate libraries (HyCoSuL) has allowed for the generation of highly selective ABPs to discriminately label these proteases. Here using this approach, a novel caspase-3 selective ABP (CS1) has been developed and validated in apoptotic cells to selectively bind caspase-3 over the closely related caspase-7. However, a critical bottleneck for ABPs is their cell penetrance and therefore this cell-impermeable CS1 probe was subsequently formulated into PLGA-based nanoparticles (CS1-NPs). We demonstrate the ability of these particles to be taken up by the cells and facilitate intracellular delivery of the ABP to effectively label caspase 3 in response to apoptotic stimuli. This work forms the foundation of a novel approach for the labelling of caspase 3 and may have downstream utility to measure real time apoptosis in tumours and other organs.",
author = "Francesco Cogo and Peter Smyth and Roberta Burden and Longley, {Daniel B.} and Richard Williams and Michael Johnston and Marcin Poreba and Wioletta Rut and Katarzyna Groborz and Guy Salvesen and Marcin Drag and Scott, {Christopher J.}",
year = "2018",
month = "12",
day = "13",
doi = "10.1039/C8NR07859A",
language = "English",
journal = "Nanoscale - Royal Society of Chemistry",
issn = "2040-3364",
publisher = "Royal Society of Chemistry",

}

Development of an advanced nanoformulation for the intracellular delivery of a caspase-3 selective activity-based probe. / Cogo, Francesco; Smyth, Peter; Burden, Roberta; Longley, Daniel B.; Williams, Richard; Johnston, Michael; Poreba, Marcin ; Rut, Wioletta; Groborz, Katarzyna; Salvesen, Guy; Drag, Marcin; Scott, Christopher J.

In: Nanoscale - Royal Society of Chemistry, 13.12.2018.

Research output: Contribution to journalArticle

TY - JOUR

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AU - Cogo, Francesco

AU - Smyth, Peter

AU - Burden, Roberta

AU - Longley, Daniel B.

AU - Williams, Richard

AU - Johnston, Michael

AU - Poreba, Marcin

AU - Rut, Wioletta

AU - Groborz, Katarzyna

AU - Salvesen, Guy

AU - Drag, Marcin

AU - Scott, Christopher J.

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