Influence of hydrolysis susceptibility and hydrophobicity of Sn-38 nano-prodrugs on their anticancer activity

Yoshitaka Koseki; Yoshikazu Ikuta; Liman Cong; Mayumi Takano; Hiroshi Tada; Mika Watanabe; Kohsuke Gonda; Takanori Ishida; Noriaki Ohuchi; Keita Tanita; Farsai Taemaitree; Anh Thi Ngoc Dao; Tsunenobu Onodera; Hidetoshi Oikawa; Hitoshi Kasai

doi:10.1246/bcsj.20190088

Influence of hydrolysis susceptibility and hydrophobicity of Sn-38 nano-prodrugs on their anticancer activity

Yoshitaka Koseki, Yoshikazu Ikuta, Liman Cong, Mayumi Takano, Hiroshi Tada, Mika Watanabe, Kohsuke Gonda, Takanori Ishida, Noriaki Ohuchi, Keita Tanita, Farsai Taemaitree, Anh Thi Ngoc Dao, Tsunenobu Onodera, Hidetoshi Oikawa, Hitoshi Kasai

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

Abstract

In the field of drug delivery, controllability of drug release site and duration are among the most important factors to manipulate the drug efficacy and side effects. In this paper, a series of nano-prodrugs (NPs) composed of anticancer agent SN-38 and various substituent groups were synthesized and fabricated. By increasing the hydrophobicity of the prodrug molecule (calculated logP values exceeded ca. 7) through changing the substituent group, the hydrolysis susceptibility of SN-38 NPs in mouse serum was drastically decreased, thus prolonged the blood retention time of the NPs. In light of this knowledge and the dispersion stability in aqueous media, SN-38 NP modified with cholesterol (SN-38-chol NPs) was selected to be the optimal candidate among the screened NPs. The in vivo pharmacological effect of SN-38-chol NP was about 10 times higher than irinotecan, the clinically used solubilized prodrug analog of SN-38. In addition, SN-38-chol NP has low side effects in evaluating intestinal damage. These NPs possess great potential for clinical application and promise to be a next-generation of drug for cancer treatment.

Original language	English
Pages (from-to)	1305-1313
Number of pages	9
Journal	Bulletin of the Chemical Society of Japan
Volume	92
Issue number	8
DOIs	https://doi.org/10.1246/bcsj.20190088
Publication status	Published - 2019

Keywords

Drug delivery
Hydrolysis susceptibility
Nano-prodrugs

ASJC Scopus subject areas

Chemistry(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1246/bcsj.20190088

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Koseki, Y., Ikuta, Y., Cong, L., Takano, M., Tada, H., Watanabe, M., Gonda, K., Ishida, T., Ohuchi, N., Tanita, K., Taemaitree, F., Dao, A. T. N., Onodera, T., Oikawa, H., & Kasai, H. (2019). Influence of hydrolysis susceptibility and hydrophobicity of Sn-38 nano-prodrugs on their anticancer activity. Bulletin of the Chemical Society of Japan, 92(8), 1305-1313. https://doi.org/10.1246/bcsj.20190088

Koseki, Y, Ikuta, Y, Cong, L, Takano, M, Tada, H, Watanabe, M, Gonda, K , Ishida, T, Ohuchi, N, Tanita, K, Taemaitree, F, Dao, ATN, Onodera, T, Oikawa, H & Kasai, H 2019, 'Influence of hydrolysis susceptibility and hydrophobicity of Sn-38 nano-prodrugs on their anticancer activity', Bulletin of the Chemical Society of Japan, vol. 92, no. 8, pp. 1305-1313. https://doi.org/10.1246/bcsj.20190088

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title = "Influence of hydrolysis susceptibility and hydrophobicity of Sn-38 nano-prodrugs on their anticancer activity",

abstract = "In the field of drug delivery, controllability of drug release site and duration are among the most important factors to manipulate the drug efficacy and side effects. In this paper, a series of nano-prodrugs (NPs) composed of anticancer agent SN-38 and various substituent groups were synthesized and fabricated. By increasing the hydrophobicity of the prodrug molecule (calculated logP values exceeded ca. 7) through changing the substituent group, the hydrolysis susceptibility of SN-38 NPs in mouse serum was drastically decreased, thus prolonged the blood retention time of the NPs. In light of this knowledge and the dispersion stability in aqueous media, SN-38 NP modified with cholesterol (SN-38-chol NPs) was selected to be the optimal candidate among the screened NPs. The in vivo pharmacological effect of SN-38-chol NP was about 10 times higher than irinotecan, the clinically used solubilized prodrug analog of SN-38. In addition, SN-38-chol NP has low side effects in evaluating intestinal damage. These NPs possess great potential for clinical application and promise to be a next-generation of drug for cancer treatment.",

keywords = "Drug delivery, Hydrolysis susceptibility, Nano-prodrugs",

author = "Yoshitaka Koseki and Yoshikazu Ikuta and Liman Cong and Mayumi Takano and Hiroshi Tada and Mika Watanabe and Kohsuke Gonda and Takanori Ishida and Noriaki Ohuchi and Keita Tanita and Farsai Taemaitree and Dao, {Anh Thi Ngoc} and Tsunenobu Onodera and Hidetoshi Oikawa and Hitoshi Kasai",

note = "Funding Information: We would like to thank Prof. Tatsuya Murakami of the Graduate School of Engineering, Toyama Prefectural University and Prof. Hiroshi Yabu of IMRAM, Tohoku University for support of in vitro and in vivo experiments. We also thank Ms. Yuki Koseki for the illustrations. This study was supported by the Asahi Glass Foundation, the Cooperative Research Program of “Network Joint Research Center for Materials and Devices”, the Research Program of “Dynamic Alliance for Open Innovation Bridging Human, Environment and Materials” in “Network Joint Research Center for Materials and Devices”, Tohoku University Research Institutes Ensemble Grant for young researchers, and a Grant-in-Aid for Scientific Research (A). Publisher Copyright: {\textcopyright} 2019 The Chemical Society of Japan. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2019",

doi = "10.1246/bcsj.20190088",

language = "English",

volume = "92",

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T1 - Influence of hydrolysis susceptibility and hydrophobicity of Sn-38 nano-prodrugs on their anticancer activity

AU - Koseki, Yoshitaka

AU - Ikuta, Yoshikazu

AU - Cong, Liman

AU - Takano, Mayumi

AU - Tada, Hiroshi

AU - Watanabe, Mika

AU - Gonda, Kohsuke

AU - Ishida, Takanori

AU - Ohuchi, Noriaki

AU - Tanita, Keita

AU - Taemaitree, Farsai

AU - Dao, Anh Thi Ngoc

AU - Onodera, Tsunenobu

AU - Oikawa, Hidetoshi

AU - Kasai, Hitoshi

N1 - Funding Information: We would like to thank Prof. Tatsuya Murakami of the Graduate School of Engineering, Toyama Prefectural University and Prof. Hiroshi Yabu of IMRAM, Tohoku University for support of in vitro and in vivo experiments. We also thank Ms. Yuki Koseki for the illustrations. This study was supported by the Asahi Glass Foundation, the Cooperative Research Program of “Network Joint Research Center for Materials and Devices”, the Research Program of “Dynamic Alliance for Open Innovation Bridging Human, Environment and Materials” in “Network Joint Research Center for Materials and Devices”, Tohoku University Research Institutes Ensemble Grant for young researchers, and a Grant-in-Aid for Scientific Research (A). Publisher Copyright: © 2019 The Chemical Society of Japan. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2019

Y1 - 2019

N2 - In the field of drug delivery, controllability of drug release site and duration are among the most important factors to manipulate the drug efficacy and side effects. In this paper, a series of nano-prodrugs (NPs) composed of anticancer agent SN-38 and various substituent groups were synthesized and fabricated. By increasing the hydrophobicity of the prodrug molecule (calculated logP values exceeded ca. 7) through changing the substituent group, the hydrolysis susceptibility of SN-38 NPs in mouse serum was drastically decreased, thus prolonged the blood retention time of the NPs. In light of this knowledge and the dispersion stability in aqueous media, SN-38 NP modified with cholesterol (SN-38-chol NPs) was selected to be the optimal candidate among the screened NPs. The in vivo pharmacological effect of SN-38-chol NP was about 10 times higher than irinotecan, the clinically used solubilized prodrug analog of SN-38. In addition, SN-38-chol NP has low side effects in evaluating intestinal damage. These NPs possess great potential for clinical application and promise to be a next-generation of drug for cancer treatment.

AB - In the field of drug delivery, controllability of drug release site and duration are among the most important factors to manipulate the drug efficacy and side effects. In this paper, a series of nano-prodrugs (NPs) composed of anticancer agent SN-38 and various substituent groups were synthesized and fabricated. By increasing the hydrophobicity of the prodrug molecule (calculated logP values exceeded ca. 7) through changing the substituent group, the hydrolysis susceptibility of SN-38 NPs in mouse serum was drastically decreased, thus prolonged the blood retention time of the NPs. In light of this knowledge and the dispersion stability in aqueous media, SN-38 NP modified with cholesterol (SN-38-chol NPs) was selected to be the optimal candidate among the screened NPs. The in vivo pharmacological effect of SN-38-chol NP was about 10 times higher than irinotecan, the clinically used solubilized prodrug analog of SN-38. In addition, SN-38-chol NP has low side effects in evaluating intestinal damage. These NPs possess great potential for clinical application and promise to be a next-generation of drug for cancer treatment.

KW - Drug delivery

KW - Hydrolysis susceptibility

KW - Nano-prodrugs

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M3 - Article

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SN - 0009-2673

VL - 92

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EP - 1313

JO - Bulletin of the Chemical Society of Japan

JF - Bulletin of the Chemical Society of Japan

IS - 8

ER -

Influence of hydrolysis susceptibility and hydrophobicity of Sn-38 nano-prodrugs on their anticancer activity

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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