Document Detail

Oligoarginine-based prodrugs with self-cleavable spacers for caco-2 cell permeation.
MedLine Citation:
PMID:  18981599     Owner:  NLM     Status:  MEDLINE    
In the development of oligoarginine-based prodrugs with self-cleavable spacers for intestinal absorption, we previously reported a series of spacers with variable half-lives of parent compound release based on a neighboring group participation mechanism from an amino acid side-chain structure next to the succinyl moiety. In the present study, to diversify the half-life of the spacer, we first synthesized several additional fluorescein isothiocyanate ethanolamine (FE)-heptaarginine conjugates (4d--g) and evaluated their conversion time. To investigate the overall cellular uptake of FE-heptaarginine conjugates, the cellular uptakes of FE-heptaarginines 4a and 4b possessing the longest and shortest half-lives, respectively, were evaluated using HeLa cells by confocal microscopy and flow cytometry. Conjugate 4a with a longer half-life was more efficiently taken up by the cells than conjugate 4b. However, in term of the transport rate of parent FE 1 in in vitro Caco-2 cell permeation assay, conjugate 4b with a short half-life could function more efficiently that conjugate 4a. To understand the reason for this discrepant finding, fluorescence on the basal side medium after treatment with conjugate 4b in the permeation assay was determined. It became apparent that the fluorescence was mostly from the parent FE 1 itself, and not conjugate 4b, suggesting that the conjugate was cleaved inside the cells. Moreover, the conversion time of conjugate 4b (t1/2=9.4 min at pH 7.4) was significantly extended in slightly acidic media. These results suggest that the conversion rate was slowed in the relatively acidic endosomal environment where the conjugate was transferred after endocytosis, and resulted in a favorable migration time across the cells. The other conjugates, including conjugate 4a, were more stable inside of the cell, resulting in very long conversion times that were ineffective in increasing the permeation rate. Therefore, spacers with shorter half lives, in order to produce a larger amount of the parent compound inside the cells are promising development for effective oligoarginine-based cargo-transporter systems to enhance intestinal absorption of parent drugs with low permeability.
Kentaro Takayama; Yuka Suehisa; Takuya Fujita; Jeffrey-Tri Nguyen; Shiroh Futaki; Akira Yamamoto; Yoshiaki Kiso; Yoshio Hayashi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Chemical & pharmaceutical bulletin     Volume:  56     ISSN:  0009-2363     ISO Abbreviation:  Chem. Pharm. Bull.     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2008-11-04     Completed Date:  2009-01-29     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0377775     Medline TA:  Chem Pharm Bull (Tokyo)     Country:  Japan    
Other Details:
Languages:  eng     Pagination:  1515-20     Citation Subset:  IM    
Institute for Chemical Research, Kyoto University, Kyoto, Japan.
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MeSH Terms
Arginine / chemistry*
Caco-2 Cells
Cell Membrane Permeability
Hydrogen-Ion Concentration
Indicators and Reagents
Microscopy, Confocal
Oligopeptides / chemistry*
Prodrugs / chemistry*
Spectrometry, Fluorescence
Spectrometry, Mass, Fast Atom Bombardment
Reg. No./Substance:
0/Indicators and Reagents; 0/Oligopeptides; 0/Prodrugs; 74-79-3/Arginine

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

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