| Parallel in vivo and in vitro selection using phage display identifies protease-dependent tumor-targeting peptides. | |
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MedLine Citation:
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PMID: 20460372 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We recently developed activatable cell-penetrating peptides (ACPPs) that target contrast agents to in vivo sites of matrix metalloproteinase activity, such as tumors. Here we use parallel in vivo and in vitro selection with phage display to identify novel tumor-homing ACPPs with no bias for primary sequence or target protease. Specifically, phage displaying a library of ACPPs were either injected into tumor-bearing mice, followed by isolation of cleaved phage from dissected tumor, or isolated based on selective cleavage by extracts of tumor versus normal tissue. Selected sequences were synthesized as fluorescently labeled peptides, and tumor-specific cleavage was confirmed by digestion with tissue extracts. The most efficiently cleaved peptide contained the substrate sequence RLQLKL and labeled tumors and metastases from several cancer models with up to 5-fold contrast. This uniquely identified ACPP was not cleaved by matrix metalloproteinases or various coagulation factors but was efficiently cleaved by plasmin and elastases, both of which have been shown to be aberrantly overexpressed in tumors. The identification of an ACPP that targets tumor expressed proteases without rational design highlights the value of unbiased selection schemes for the development of potential therapeutic agents. |
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Authors:
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Mike Whitney; Jessica L Crisp; Emilia S Olson; Todd A Aguilera; Larry A Gross; Lesley G Ellies; Roger Y Tsien |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-05-11 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-07-12 Completed Date: 2010-08-06 Revised Date: 2010-09-28 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 22532-41 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, University of California at San Diego, La Jolla, California 92093, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Animals Drug Delivery Systems / methods* Mice Molecular Sequence Data Neoplasms / metabolism* Peptide Hydrolases / metabolism* Peptide Library* Peptides / chemistry, pharmacology* Tissue Extracts |
| Grant Support | |
ID/Acronym/Agency:
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CA118182/CA/NCI NIH HHS; //Howard Hughes Medical Institute |
| Chemical | |
Reg. No./Substance:
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0/Peptide Library; 0/Peptides; 0/Tissue Extracts; EC 3.4.-/Peptide Hydrolases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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