Document Detail


Targeting a genetically engineered elastin-like polypeptide to solid tumors by local hyperthermia.
MedLine Citation:
PMID:  11245464     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Elastin-like polypeptides (ELPs) are biopolymers of the pentapeptide repeat Val-Pro-Gly-Xaa-Gly that undergo an inverse temperature phase transition. They are soluble in aqueous solutions below their transition temperature (T1) but hydrophobically collapse and aggregate at temperatures greater than T1. We hypothesized that ELPs conjugated to drugs would enable thermally targeted drug delivery to solid tumors if their T1 were between body temperature and the temperature in a locally heated region. To test this hypothesis, we synthesized a thermally responsive ELP with a T1 of 41 degrees C and a thermally unresponsive control ELP in Escherichia coli using recombinant DNA techniques. In vivo fluorescence videomicroscopy and radiolabel distribution studies of ELP delivery to human tumors (SKOV-3 ovarian carcinoma and D-54MG glioma) implanted in nude mice demonstrated that hyperthermic targeting of the thermally responsive ELP for 1 h provides a approximately 2-fold increase in tumor localization compared to the same polypeptide without hyperthermia. We observed aggregates of the thermally responsive ELP by fluorescence videomicroscopy within the heated tumor microvasculature but not in control experiments, which demonstrates that the phase transition of the thermally responsive ELP carrier can be engineered to occur in vivo at a specified temperature. By exploiting the phase transition-induced aggregation of these polypeptides, this method provides a new way to thermally target polymer-drug conjugates to solid tumors.
Authors:
D E Meyer; G A Kong; M W Dewhirst; M R Zalutsky; A Chilkoti
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  61     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2001 Feb 
Date Detail:
Created Date:  2001-03-13     Completed Date:  2001-03-29     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1548-54     Citation Subset:  IM    
Affiliation:
Department of Biomedical Engineering, Duke University, Durham, NC 27708-0281, USA.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Base Sequence
Drug Stability
Elastin / chemistry,  genetics,  pharmacokinetics*
Female
Glioma / metabolism*
Humans
Hyperthermia, Induced*
Mice
Mice, Inbred BALB C
Mice, Nude
Microscopy, Fluorescence
Microscopy, Video
Molecular Sequence Data
Ovarian Neoplasms / metabolism*
Peptides / chemistry,  genetics,  pharmacokinetics*
Protein Engineering
Temperature
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
CA42745/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Peptides; 9007-58-3/Elastin

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


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