Oligoarginine-based prodrugs with self-cleavable spacers for caco-2 cell permeation. | |
MedLine Citation:
|
PMID: 18981599 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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. |
Authors:
|
Kentaro Takayama; Yuka Suehisa; Takuya Fujita; Jeffrey-Tri Nguyen; Shiroh Futaki; Akira Yamamoto; Yoshiaki Kiso; Yoshio Hayashi |
Related Documents
:
|
2600659 - Intestinal absorption of stearic acid after consumption of high fat meals in humans. 2805169 - Studies on sustained-release suppositories. ii. evaluation of polymer electrolyte conta... 3167089 - A comment on the evaluation of equilibrium constants for alpha-tocopherol interactions ... 12197999 - Zinc absorption from a low-phytic acid maize. 10103229 - Initial reactions in the biodegradation of 1-chloro-4-nitrobenzene by a newly isolated ... 17134679 - Inhibition of the intestinal absorption of bile acids using cationic derivatives: mecha... 15333909 - Fluorescence-based on-line detection as an analytical tool in rna electrophoresis. 2028499 - Hypothermia prevents ischemia-induced increases in hippocampal glycine concentrations i... 3942729 - Effect of extracellular potassium on amino acid transport and membrane potential in fet... |
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 |
Affiliation:
|
Institute for Chemical Research, Kyoto University, Kyoto, Japan. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
MeSH Terms | |
Descriptor/Qualifier:
|
Arginine
/
chemistry* Caco-2 Cells Cell Membrane Permeability Half-Life Humans Hydrogen-Ion Concentration Indicators and Reagents Microscopy, Confocal Oligopeptides / chemistry* Prodrugs / chemistry* Spectrometry, Fluorescence Spectrometry, Mass, Fast Atom Bombardment |
Chemical | |
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
Previous Document: Engineering of plant polyketide biosynthesis.
Next Document: Spectrophotometric and atomic absorption determination of ramipril, enalapril maleate and fosinopril...