Oral Cancer Immunotherapy through a Simvastatin-Loaded Colloidal Dispersion System for the Generation of Sustained Antitumor Immunity

Seong A. Kim; Gi hoon Nam; Young Rang Bae; Saurav Kumar Jha; Seohyun Kim; Yoonjeong Choi; Yeji Lee; Minsu Kwon; Cheolhyun Jeong; Youngro Byun; Jin Woo Park; In San Kim

doi:10.1002/adtp.202100025

Oral Cancer Immunotherapy through a Simvastatin-Loaded Colloidal Dispersion System for the Generation of Sustained Antitumor Immunity

Seong A. Kim, Gi hoon Nam, Young Rang Bae, Saurav Kumar Jha, Seohyun Kim, Yoonjeong Choi, Yeji Lee, Minsu Kwon, Cheolhyun Jeong, Youngro Byun, Jin Woo Park, In San Kim

KU-KIST Graduate School of Converging Science and Technology

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

1 Citation (Scopus)

Abstract

Statins exhibit anticancer pleiotropic effects, such as the induction tumor-specific apoptosis and the promotion antitumor immunity. However, due to low bioavailability, high doses are required to trigger such antitumor effects. In this study, an oral delivery system to improve bioavailability of simvastatin (SIMVA) is prepared and its application in combination with an oral anticancer formulation is investigated. A colloidal dispersion (CD) of SIMVA is prepared using N^α-deoxycholyl-l-lysyl-methylester (DL) to enhance a solubility and permeation (SIMVA/DL-CD). Preparation of SIMVA/DL-CD markedly increases the solubility and in vitro artificial membrane permeability of SIMVA by 291- and 4.68-fold, respectively, compared to SIMVA in 5% dimethyl sulfoxide. The oral absorption of SIMVA/DL-CD (20 mg kg⁻¹ SIMVA) is significantly enhanced and its oral bioavailability is tenfold higher compared to that of free SIMVA. An in vivo study in CT26 tumor-bearing mice receiving SIMVA/DL-CD reveals substantial tumor growth suppression through upregulated anticancer immunity. In particular, the combination of oral SIMVA/DL-CD and oxaliplatin powder formulation elicits considerable tumor-suppressive effects and CD8⁺ T cell immunity. Furthermore, this combination therapy sensitizes antiprogramed cell death protein-1 monoclonal antibody-resistant tumors to checkpoint blockade. The current findings highlight the therapeutic potential of oral SIMVA/DL-CD as an effective anticancer immunotherapy.

Original language	English
Article number	2100025
Journal	Advanced Therapeutics
Volume	4
Issue number	8
DOIs	https://doi.org/10.1002/adtp.202100025
Publication status	Published - 2021 Aug

Bibliographical note

Funding Information:
S.AK., G.-h.N., and Y.R.B. contributed equally to this study. The authors thank the animal facility at KIST for the assistance, Labcore Inc. for FFPE preparation, PrismCDX for mIHC and image acquisition, and Wiley Editing Services for English language editing. The authors greatly appreciated using the Convergence Research Laboratory (established by the Mokpo National University Innovation Support Project in 2020) to conduct this research. This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government Ministry of Science and Information and Communication Technology (MSIT; Grant Nos. 2017R1A3B1023418 and 2020R1F1A1069889), by the KU-KIST School Project, and by the KIST Institutional Program.

Funding Information:
S.AK., G.‐h.N., and Y.R.B. contributed equally to this study. The authors thank the animal facility at KIST for the assistance, Labcore Inc. for FFPE preparation, PrismCDX for mIHC and image acquisition, and Wiley Editing Services for English language editing. The authors greatly appreciated using the Convergence Research Laboratory (established by the Mokpo National University Innovation Support Project in 2020) to conduct this research. This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government Ministry of Science and Information and Communication Technology (MSIT; Grant Nos. 2017R1A3B1023418 and 2020R1F1A1069889), by the KU‐KIST School Project, and by the KIST Institutional Program.

Publisher Copyright:
© 2021 Wiley-VCH GmbH

Keywords

colloidal dispersion
immunotherapy
oral delivery
oxaliplatin
simvastatin

ASJC Scopus subject areas

Medicine (miscellaneous)
Pharmacology
Pharmaceutical Science
Genetics(clinical)
Biochemistry, medical
Pharmacology (medical)

UN SDGs

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

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10.1002/adtp.202100025

Cite this

@article{38978e7d37794eca85bf728328c176e2,

title = "Oral Cancer Immunotherapy through a Simvastatin-Loaded Colloidal Dispersion System for the Generation of Sustained Antitumor Immunity",

abstract = "Statins exhibit anticancer pleiotropic effects, such as the induction tumor-specific apoptosis and the promotion antitumor immunity. However, due to low bioavailability, high doses are required to trigger such antitumor effects. In this study, an oral delivery system to improve bioavailability of simvastatin (SIMVA) is prepared and its application in combination with an oral anticancer formulation is investigated. A colloidal dispersion (CD) of SIMVA is prepared using Nα-deoxycholyl-l-lysyl-methylester (DL) to enhance a solubility and permeation (SIMVA/DL-CD). Preparation of SIMVA/DL-CD markedly increases the solubility and in vitro artificial membrane permeability of SIMVA by 291- and 4.68-fold, respectively, compared to SIMVA in 5% dimethyl sulfoxide. The oral absorption of SIMVA/DL-CD (20 mg kg−1 SIMVA) is significantly enhanced and its oral bioavailability is tenfold higher compared to that of free SIMVA. An in vivo study in CT26 tumor-bearing mice receiving SIMVA/DL-CD reveals substantial tumor growth suppression through upregulated anticancer immunity. In particular, the combination of oral SIMVA/DL-CD and oxaliplatin powder formulation elicits considerable tumor-suppressive effects and CD8+ T cell immunity. Furthermore, this combination therapy sensitizes antiprogramed cell death protein-1 monoclonal antibody-resistant tumors to checkpoint blockade. The current findings highlight the therapeutic potential of oral SIMVA/DL-CD as an effective anticancer immunotherapy.",

keywords = "colloidal dispersion, immunotherapy, oral delivery, oxaliplatin, simvastatin",

author = "Kim, {Seong A.} and Nam, {Gi hoon} and Bae, {Young Rang} and Jha, {Saurav Kumar} and Seohyun Kim and Yoonjeong Choi and Yeji Lee and Minsu Kwon and Cheolhyun Jeong and Youngro Byun and Park, {Jin Woo} and Kim, {In San}",

note = "Funding Information: S.AK., G.-h.N., and Y.R.B. contributed equally to this study. The authors thank the animal facility at KIST for the assistance, Labcore Inc. for FFPE preparation, PrismCDX for mIHC and image acquisition, and Wiley Editing Services for English language editing. The authors greatly appreciated using the Convergence Research Laboratory (established by the Mokpo National University Innovation Support Project in 2020) to conduct this research. This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government Ministry of Science and Information and Communication Technology (MSIT; Grant Nos. 2017R1A3B1023418 and 2020R1F1A1069889), by the KU-KIST School Project, and by the KIST Institutional Program. Funding Information: S.AK., G.‐h.N., and Y.R.B. contributed equally to this study. The authors thank the animal facility at KIST for the assistance, Labcore Inc. for FFPE preparation, PrismCDX for mIHC and image acquisition, and Wiley Editing Services for English language editing. The authors greatly appreciated using the Convergence Research Laboratory (established by the Mokpo National University Innovation Support Project in 2020) to conduct this research. This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government Ministry of Science and Information and Communication Technology (MSIT; Grant Nos. 2017R1A3B1023418 and 2020R1F1A1069889), by the KU‐KIST School Project, and by the KIST Institutional Program. Publisher Copyright: {\textcopyright} 2021 Wiley-VCH GmbH",

year = "2021",

month = aug,

doi = "10.1002/adtp.202100025",

language = "English",

volume = "4",

journal = "Advanced Therapeutics",

issn = "2366-3987",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "8",

}

TY - JOUR

T1 - Oral Cancer Immunotherapy through a Simvastatin-Loaded Colloidal Dispersion System for the Generation of Sustained Antitumor Immunity

AU - Kim, Seong A.

AU - Nam, Gi hoon

AU - Bae, Young Rang

AU - Jha, Saurav Kumar

AU - Kim, Seohyun

AU - Choi, Yoonjeong

AU - Lee, Yeji

AU - Kwon, Minsu

AU - Jeong, Cheolhyun

AU - Byun, Youngro

AU - Park, Jin Woo

AU - Kim, In San

N1 - Funding Information: S.AK., G.-h.N., and Y.R.B. contributed equally to this study. The authors thank the animal facility at KIST for the assistance, Labcore Inc. for FFPE preparation, PrismCDX for mIHC and image acquisition, and Wiley Editing Services for English language editing. The authors greatly appreciated using the Convergence Research Laboratory (established by the Mokpo National University Innovation Support Project in 2020) to conduct this research. This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government Ministry of Science and Information and Communication Technology (MSIT; Grant Nos. 2017R1A3B1023418 and 2020R1F1A1069889), by the KU-KIST School Project, and by the KIST Institutional Program. Funding Information: S.AK., G.‐h.N., and Y.R.B. contributed equally to this study. The authors thank the animal facility at KIST for the assistance, Labcore Inc. for FFPE preparation, PrismCDX for mIHC and image acquisition, and Wiley Editing Services for English language editing. The authors greatly appreciated using the Convergence Research Laboratory (established by the Mokpo National University Innovation Support Project in 2020) to conduct this research. This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government Ministry of Science and Information and Communication Technology (MSIT; Grant Nos. 2017R1A3B1023418 and 2020R1F1A1069889), by the KU‐KIST School Project, and by the KIST Institutional Program. Publisher Copyright: © 2021 Wiley-VCH GmbH

PY - 2021/8

Y1 - 2021/8

N2 - Statins exhibit anticancer pleiotropic effects, such as the induction tumor-specific apoptosis and the promotion antitumor immunity. However, due to low bioavailability, high doses are required to trigger such antitumor effects. In this study, an oral delivery system to improve bioavailability of simvastatin (SIMVA) is prepared and its application in combination with an oral anticancer formulation is investigated. A colloidal dispersion (CD) of SIMVA is prepared using Nα-deoxycholyl-l-lysyl-methylester (DL) to enhance a solubility and permeation (SIMVA/DL-CD). Preparation of SIMVA/DL-CD markedly increases the solubility and in vitro artificial membrane permeability of SIMVA by 291- and 4.68-fold, respectively, compared to SIMVA in 5% dimethyl sulfoxide. The oral absorption of SIMVA/DL-CD (20 mg kg−1 SIMVA) is significantly enhanced and its oral bioavailability is tenfold higher compared to that of free SIMVA. An in vivo study in CT26 tumor-bearing mice receiving SIMVA/DL-CD reveals substantial tumor growth suppression through upregulated anticancer immunity. In particular, the combination of oral SIMVA/DL-CD and oxaliplatin powder formulation elicits considerable tumor-suppressive effects and CD8+ T cell immunity. Furthermore, this combination therapy sensitizes antiprogramed cell death protein-1 monoclonal antibody-resistant tumors to checkpoint blockade. The current findings highlight the therapeutic potential of oral SIMVA/DL-CD as an effective anticancer immunotherapy.

AB - Statins exhibit anticancer pleiotropic effects, such as the induction tumor-specific apoptosis and the promotion antitumor immunity. However, due to low bioavailability, high doses are required to trigger such antitumor effects. In this study, an oral delivery system to improve bioavailability of simvastatin (SIMVA) is prepared and its application in combination with an oral anticancer formulation is investigated. A colloidal dispersion (CD) of SIMVA is prepared using Nα-deoxycholyl-l-lysyl-methylester (DL) to enhance a solubility and permeation (SIMVA/DL-CD). Preparation of SIMVA/DL-CD markedly increases the solubility and in vitro artificial membrane permeability of SIMVA by 291- and 4.68-fold, respectively, compared to SIMVA in 5% dimethyl sulfoxide. The oral absorption of SIMVA/DL-CD (20 mg kg−1 SIMVA) is significantly enhanced and its oral bioavailability is tenfold higher compared to that of free SIMVA. An in vivo study in CT26 tumor-bearing mice receiving SIMVA/DL-CD reveals substantial tumor growth suppression through upregulated anticancer immunity. In particular, the combination of oral SIMVA/DL-CD and oxaliplatin powder formulation elicits considerable tumor-suppressive effects and CD8+ T cell immunity. Furthermore, this combination therapy sensitizes antiprogramed cell death protein-1 monoclonal antibody-resistant tumors to checkpoint blockade. The current findings highlight the therapeutic potential of oral SIMVA/DL-CD as an effective anticancer immunotherapy.

KW - colloidal dispersion

KW - immunotherapy

KW - oral delivery

KW - oxaliplatin

KW - simvastatin

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U2 - 10.1002/adtp.202100025

DO - 10.1002/adtp.202100025

M3 - Article

AN - SCOPUS:85107091813

SN - 2366-3987

VL - 4

JO - Advanced Therapeutics

JF - Advanced Therapeutics

IS - 8

M1 - 2100025

ER -

Oral Cancer Immunotherapy through a Simvastatin-Loaded Colloidal Dispersion System for the Generation of Sustained Antitumor Immunity

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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