Document Detail


De novo design of a tumor-penetrating peptide.
MedLine Citation:
PMID:  23151901     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Poor penetration of antitumor drugs into the extravascular tumor tissue is often a major factor limiting the efficacy of cancer treatments. Our group has recently described a strategy to enhance tumor penetration of chemotherapeutic drugs through use of iRGD peptide (CRGDK/RGPDC). This peptide comprises two sequence motifs: RGD, which binds to αvβ3/5 integrins on tumor endothelia and tumor cells, and a cryptic CendR motif (R/KXXR/K-OH). Once integrin binding has brought iRGD to the tumor, the peptide is proteolytically cleaved to expose the cryptic CendR motif. The truncated peptide loses affinity for its primary receptor and binds to neuropilin-1, activating a tissue penetration pathway that delivers the peptide along with attached or co-administered payload into the tumor mass. Here, we describe the design of a new tumor-penetrating peptide based on the current knowledge of homing sequences and internalizing receptors. The tumor-homing motif in the new peptide is the NGR sequence, which binds to endothelial CD13. The NGR sequence was placed in the context of a CendR motif (RNGR), and this sequence was embedded in the iRGD framework. The resulting peptide (CRNGRGPDC, iNGR) homed to tumor vessels and penetrated into tumor tissue more effectively than the standard NGR peptide. iNGR induced greater tumor penetration of coupled nanoparticles and co-administered compounds than NGR. Doxorubicin given together with iNGR was significantly more efficacious than the drug alone. These results show that a tumor-specific, tissue-penetrating peptide can be constructed from known sequence elements. This principle may be useful in designing tissue-penetrating peptides for other diseases.
Authors:
Luca Alberici; Lise Roth; Kazuki N Sugahara; Lilach Agemy; Venkata R Kotamraju; Tambet Teesalu; Claudio Bordignon; Catia Traversari; Gian-Paolo Rizzardi; Erkki Ruoslahti
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-11-14
Journal Detail:
Title:  Cancer research     Volume:  73     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-18     Completed Date:  2013-03-26     Revised Date:  2014-01-23    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  804-12     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Antineoplastic Agents / therapeutic use*
Cell Line, Tumor
Drug Delivery Systems / methods*
Drug Design
Humans
Mice
Neoplasms / drug therapy*
Oligopeptides / therapeutic use*
Protein Binding
Grant Support
ID/Acronym/Agency:
CA30199/CA/NCI NIH HHS; P30 CA030199/CA/NCI NIH HHS; R01 CA 152327/CA/NCI NIH HHS; R01 CA152327/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/NGR peptide; 0/Oligopeptides; 0/cysteinyl-arginyl-asparagyl-glycyl-arginyl-glycyl-prolyl-aspartyl-cysteine
Comments/Corrections

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