Document Detail

Modification of a Dioxygen Carrier, HemoCD, with PEGylated Dendrons for Extension of Circulation Time in the Bloodstream.
MedLine Citation:
PMID:  23136812     Owner:  NLM     Status:  Publisher    
A supramolecular diatomic receptor, hemoCD, was modified with PEGylated dendrons to extend its circulation time in the bloodstream. The core component was 4-oxo-4-[[4-(10,15,20-tris(4-sulfonatophenyl)-21H,23H-porphin-5-yl)phenyl]amino]butanoic acid (Por-COOH). The building block of the dendrons was Fmoc-4-amino-4-(2-carboxyethyl)heptanedioic acid (FmocTA), which was condensed with α-amino-ω-methoxy-poly(ethylene glycol) (PEG5000-NH2) to yield an FmocG1-dendron. After deprotection, the G1-dendron was condensed with Por-COOH to yield G1-Por. A precursor (FmocNA) of an FmocG2-dendron was prepared via a condensation reaction of 4-amino-4-(2-t-butoxycarbonylethyl)heptanedioic acid di-t-butyl ester (TA-E) with FmocTA followed by hydrolysis of the resultant nona-carboxylic acid nona-t-butyl ester. Condensation of FmocNA with PEG5000-NH2 yielded an FmocG2-dendron. After deprotection, the G2-dendron was condensed with Por-COOH to yield G2-Por. The ferrous complexes of G1- and G2-Pors formed stable 1:1 inclusion complexes with Py3CD, a per-O-methylated β-cyclodextrin dimer with a pyridine linker, in aqueous solution yielding supramolecular complexes designated as G1-hemoCD and G2-hemoCD, respectively. Both G1- and G2-hemoCDs bound molecular oxygen, with the O(2) affinities (P(1/2)) of hemoCD, G1-, and G2-hemoCDs at pH 7.4 and 37 °C being 22, 20, and 20 Torr, respectively. The modification of hemoCD with the dendrons did not cause destabilization of the O(2) adducts via autoxidation, as indicated by their half-lives (t(1/2)) of 6.8, 6.1, and 5.5 h for hemoCD, G1-, and G2-hemoCDs, respectively. The blood concentration-time curves of G1- and G2-hemoCDs injected into the bloodstream of rats exhibited two phases, with the half-lives of the fast and slow decays being 0.45 and 5.3 h, respectively, for G1-hemoCD, and 0.20 and 12.8 h, respectively, for G2-hemoCD. The half-lives of hemoCD were 0.02 and 0.50 h, respectively. The circulation time of hemoCD was markedly extended by its modification with the PEGylated dendrons, which was very effective in protecting hemoCD against opsonization for uptake by the reticuloendothelial system.
Koji Kano; Keiichi Karasugi; Hiroaki Kitagishi
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-8
Journal Detail:
Title:  Bioconjugate chemistry     Volume:  -     ISSN:  1520-4812     ISO Abbreviation:  Bioconjug. Chem.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-9     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9010319     Medline TA:  Bioconjug Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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