Document Detail


Trastuzumab-polyethylenimine-polyethylene glycol conjugates for targeting Her2-expressing tumors.
MedLine Citation:
PMID:  16984128     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In this study, we describe the synthesis and characterization of a conjugate consisting of poly(ethylene glycol 2,000 Da)(10)-graft-poly(ethylene imine 25 kDa) (PEG-PEI) covalently coupled to Trastuzumab (Herceptin) via N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP) for specific gene delivery to Her2-expressing cell lines. The efficiency of DNA condensation was studied using an ethidium bromide exclusion assay and demonstrated negligible differences compared to PEG-PEI. Conjugate complex sizes were determined by dynamic light scattering to be in the range 130-180 nm. zeta potentials at different N/P ratios were close to neutral. Flow cytometry and confocal microscopy revealed efficient binding and uptake of Trastuzumab-PEI-PEG complexes using Her2-positive SK-BR-3 cells. In contrast, binding and uptake into Her2-negative OVCAR-3 cells was negligible. In good correlation with these findings, reporter gene expression using targeted complexes in SK-BR-3 cells was up to sevenfold higher than that of unmodified PEG-PEI complexes. With the use OVCAR-3 cells, no significant difference in expression efficiencies could be observed between conjugate and PEG-PEI complexes. Inhibition experiments with free Trastuzumab showed a significant decrease in reporter gene expression using SK-BR-3 cells but no decrease using OVCAR-3 cells, strongly supporting a specific Her2-receptor-mediated uptake mechanism. Our results suggest that Trastuzumab-PEI-PEG might be a promising new bioconjugate for targeted gene transfer to Her2-positive tumor cells in vivo.
Authors:
Oliver Germershaus; Thomas Merdan; Udo Bakowsky; Martin Behe; Thomas Kissel
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Bioconjugate chemistry     Volume:  17     ISSN:  1043-1802     ISO Abbreviation:  Bioconjug. Chem.     Publication Date:    2006 Sep-Oct
Date Detail:
Created Date:  2006-09-20     Completed Date:  2007-05-15     Revised Date:  2013-05-08    
Medline Journal Info:
Nlm Unique ID:  9010319     Medline TA:  Bioconjug Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1190-9     Citation Subset:  IM    
Affiliation:
Department of Pharmaceutics and Biopharmacy, Philipps University Marburg, Ketzerbach 63, 35032 Marburg, Germany.
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MeSH Terms
Descriptor/Qualifier:
Antibodies, Monoclonal / chemistry*,  metabolism
Antibodies, Monoclonal, Humanized
Antineoplastic Agents / chemical synthesis,  chemistry*,  metabolism
Cell Line, Tumor
Gene Transfer Techniques*
Genes, Reporter
Genetic Therapy / methods
Humans
Molecular Structure
Neoplasms / metabolism
Particle Size
Polyethylene Glycols / chemistry*
Polyethyleneimine / chemistry*
Receptor, erbB-2 / metabolism*
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antibodies, Monoclonal, Humanized; 0/Antineoplastic Agents; 0/Polyethylene Glycols; 9002-98-6/Polyethyleneimine; EC 2.7.10.1/Receptor, erbB-2; P188ANX8CK/trastuzumab

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