Document Detail


Relevance of folic acid/polymer ratio in targeted PEG-epirubicin conjugates.
MedLine Citation:
PMID:  20621587     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A series of PEG-epirubicin conjugates with different folic acid contents per polymer chain was synthesized in order to study the influence of polymer/targeting moiety ratio on selective cytotoxicity, cellular uptake and intracellular localization. Analogous carboxyl-terminated conjugates without folic acid were studied as control. The heterobifunctional HO-PEG-COOH was used as polymeric carrier, allowing the synthesis of conjugates with a good control over the chemical structure and the drug/polymer and polymer/targeting residue ratios. A dendron structure was synthesized at one end of the PEG chain with the aim to increase the number of folic acid molecules. L-2-aminoadipic acid was used as branching unit. The conjugates showed high stability under several physiological conditions. Biological evaluation was carried out in A549, HeLa and KB-3-1 human cell lines, as these cells have different levels of folate receptor (FR) expression. In particular A549 cells are FR negative (FR-), HeLa cells are FR positive (FR+) and KB-3-1 cells over-express FR (FR++). It was clearly shown that the biological activity of the conjugates was influenced by the presence and the number of folic acid molecules per polymer chain and by the level of FR expression on cell surface. Conjugates conformation in solution was also studied, as differences in size might well affect cell internalization. In the cell viability assay, conjugates without folic acid were unexpectedly more cytotoxic than the targeted conjugates, but their IC(50) values were similar in the three cell lines. Differently, the anti-proliferative activity of targeted derivatives markedly increased going from FR(-) to FR(++) cells. FACS and confocal microscopy studies showed greater cellular internalization with the targeted conjugates than with their non-targeted analogues; more importantly, this relationship is clearly dependent on folic acid content in the conjugates and FR expression level in the cell line used.
Authors:
Fabiana Canal; María J Vicent; Gianfranco Pasut; Oddone Schiavon
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-06-02
Journal Detail:
Title:  Journal of controlled release : official journal of the Controlled Release Society     Volume:  146     ISSN:  1873-4995     ISO Abbreviation:  J Control Release     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-09-06     Completed Date:  2011-01-11     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8607908     Medline TA:  J Control Release     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  388-99     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier B.V. All rights reserved.
Affiliation:
Pharmaceutical Sciences Dept., University of Padua, Via F. Marzolo 5, 35131 Padua, Italy.
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MeSH Terms
Descriptor/Qualifier:
Antibiotics, Antineoplastic / administration & dosage*,  chemistry,  pharmacokinetics,  pharmacology
Cell Line, Tumor
Cell Survival / drug effects
Drug Delivery Systems*
Epirubicin / administration & dosage*,  chemistry,  pharmacokinetics,  pharmacology
Folate Receptors, GPI-Anchored / metabolism*
Folic Acid / chemistry*
Humans
Neoplasms / drug therapy*
Polyethylene Glycols / chemistry*
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Folate Receptors, GPI-Anchored; 0/Polyethylene Glycols; 56420-45-2/Epirubicin; 59-30-3/Folic Acid

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


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