Document Detail


Cell-penetrating TAT peptide in drug delivery systems: proteolytic stability requirements.
MedLine Citation:
PMID:  21438724     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The stability and activity of the HIV cell-penetrating TAT peptide (TATp) on the surface of TATp-modified micelles and liposomes in relation to its proteolytic cleavage was investigated. TATp moieties were attached to the surface of these nanocarriers using TATp modified with a conjugate of phosphatidyl ethanolamine with a 'short' PEG (PEG-PE). Following pre-incubation with trypsin, elastase, or collagenase, the proteolytic stability of TATp on the surface of these modified carriers was studied by HPLC with fluorescence detection using fluorenylmethyl chloroformate (FMOC) labeling. All tested enzymes produced a dose-dependent cleavage of TATp as shown by the presence of TATp Arg-Arg fragments. Inhibition of TATp cleavage occurred when these TATp-micelles were modified by the addition of longer PEG-PE blocks, indicating an effective shielding of TATp from proteolysis by these blocks. TATp-modified carriers were also tested for their ability to accumulate in EL-4, HeLa, and B16-F10 cells. Trypsin treatment of TATp-modified liposomes and micelles resulted in decreased uptake and cell interaction, as measured by fluorescence microscopy and fluorescence-activated cell sorting techniques. Furthermore, a decrease in the cytotoxicity of TATp-modified liposomes loaded with doxorubicin (Doxil) was observed following trypsin treatment. In conclusion, steric shielding of TATp is essential to ensure its in vivo therapeutic function.
Authors:
Erez Koren; Anjali Apte; Rupa R Sawant; Jacob Grunwald; Vladimir P Torchilin
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-03-26
Journal Detail:
Title:  Drug delivery     Volume:  18     ISSN:  1521-0464     ISO Abbreviation:  Drug Deliv     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-06-09     Completed Date:  2011-09-29     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  9417471     Medline TA:  Drug Deliv     Country:  England    
Other Details:
Languages:  eng     Pagination:  377-84     Citation Subset:  IM    
Affiliation:
Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, Massachusetts 02115, USA. e.koren@neu.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibiotics, Antineoplastic / administration & dosage,  pharmacology
Cell Line, Tumor
Cell-Penetrating Peptides / chemistry
Chromatography, High Pressure Liquid
Dose-Response Relationship, Drug
Doxorubicin / administration & dosage*,  pharmacology
Drug Carriers / chemistry*
Drug Delivery Systems*
HeLa Cells
Humans
Melanoma, Experimental / drug therapy,  pathology
Mice
Neoplasms / drug therapy,  pathology
Phosphatidylethanolamines / chemistry
Polyethylene Glycols / chemistry
Protein Stability
Trypsin / metabolism
tat Gene Products, Human Immunodeficiency Virus / chemistry*
Grant Support
ID/Acronym/Agency:
R01 CA121838/CA/NCI NIH HHS; R01 CA121838/CA/NCI NIH HHS; R01 CA128486/CA/NCI NIH HHS; R01 CA128486/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Cell-Penetrating Peptides; 0/Drug Carriers; 0/Phosphatidylethanolamines; 0/Polyethylene Glycols; 0/tat Gene Products, Human Immunodeficiency Virus; 23214-92-8/Doxorubicin; EC 3.4.21.4/Trypsin
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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