Oligoarginine-Based Prodrugs with Self-Cleavable Spacers for Caco-2 Cell Permeation

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概要

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• 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 (t_<1/2>=9.4min 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.

• 公益社団法人日本薬学会の論文
• 2008-11-01

著者

• YAMAMOTO Akira

  Department of Biopharmaceutics, Kyoto Pharmaceutical University

• Kiso Y

  Department Of Medicinal Chemistry Kyoto Pharmaceutical University

• Nguyen Jeffrey-tri

  Department Of Medicinal Chemistry Center For Frontier Research In Medicinal Science And 21^<st>

• HAYASHI Yoshio

  Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and 21st Centur

• KISO Yoshiaki

  Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and 21st Centur

• FUJITA Takuya

  Department of Biopharmaceutics, Kyoto Pharmaceutical University

• Hayashi Yoshio

  Department Of Medicinal Chemistry Kyoto Pharmaceutical University

• Kinoshita Yuko

  Department Of Oriental Medicine Nihon University School Of Medicine

• Fujita T

  Division Of Oral Cytology And Cell Biology Department Of Developmental And Reconstructive Medicine N

• FUJITA Takuya

  Ritsumeikan University College of Information Science and Engeneering

• FUTAKI Shiroh

  Institute for Chemical Research, Kyoto University

• Fujita T

  Ritsumeikan University College Of Information Science And Engeneering

• Fujita Takuya

  Department Of Basic Pharmaceutics Faculty Of Pharmaceutical Sciences Kyoto University

• TAKAYAMA Kentaro

  Institute for Chemical Research, Kyoto University

• SUEHISA Yuka

  Department of Biopharmaceutics, 21st Century COE Program, Kyoto Pharmaceutical University

• Fujita T

  Showa College Of Pharmaceutical Sciences

• Suehisa Yuka

  Department Of Biopharmaceutics 21st Century Coe Program Kyoto Pharmaceutical University

• Kiso Yoshiaki

  Department Of Medicinal Chemistry Center For Frontier Research In Medicinal Science 21st Century Coe

• Futaki Shiroh

  Institute For Chemical Research Kyoto University

• Futaki Shiroh

  Institute For Chemical Research Kyoto University:sorst Jst

• Fukushima Tohru

  Department Of Pharmacology Faculty Of Pharmaceutical Sciences Setsunan University

• Takayama Kentaro

  Institute For Chemical Research Kyoto University:department Of Biopharmaceutics 21st Century Coe Pro

• Takayama Kentaro

  Institute For Chemical Research Kyoto University

• Hayashi Yoshio

  Department Of Electrical And Electronic Engineering Kitami Institute Of Technology

• Yamaguchi H

  Department Of Oral Molecular Pathology Institute Of Health Bioscience The University Of Tokushima Gr

• Yamamoto Akira

  Department Of Biopharmaceutics Kyoto Pharmaceutical University

• Yamamoto Akira

  Department Of Anatomy School Of Medicine University Of Tokushuma

• Hayashi Yoshio

  Department Of Medicinal Chemistry Center For Frontier Research In Medicinal Science Kyoto Pharmaceut

• Yamamoto Akira

  Department Of Biopharmaceutics 21st Century Coe Program Kyoto Pharmaceutical University

• Hayashi Yoshio

  Department Of Chemistry Faculty Of Science Kanazawa University

• Yamamoto Akira

  Department Of Anatomy School Of Medicine University Of Tokushima

• KISO Yoshiaki

  Department of Ecological Engineering, Toyohashi University of Technology, JAPAN.

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