Carrier-free nanoparticles of cathepsin B-cleavable peptide-conjugated doxorubicin prodrug for cancer targeting therapy

Man Kyu Shim, Jooho Park, Hong Yeol Yoon, Sangmin Lee, Wooram Um, Jong Ho Kim, Sun Woong Kang, Joung Wook Seo, Soo Wang Hyun, Jae Hyung Park, Youngro Byun, Ick Chan Kwon, Kwang Meyung Kim

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Cancer nanomedicine using nanoparticle-based delivery systems has shown outstanding promise in recent decades for improving anticancer treatment. However, limited targeting efficiency, low drug loading efficiency and innate toxicity of nanoparticles have caused severe problems, leaving only a few available in the clinic. Here, we newly developed carrier-free nanoparticles of cathepsin B-cleavable peptide (Phe-Arg-Arg-Gly; FRRG)-conjugated doxorubicin (DOX) prodrug (FRRG-DOX) that formed a stable nanoparticle structure with an average diameter of 213 nm in aqueous condition. The carrier-free nanoparticles of FRRG-DOX induced cytotoxicity against cathepsin B-overexpressed tumor cells whereas the toxicity was minimized in normal cells. In particular, the FRRG-DOX nanoparticles showed the successful tumor-targeting ability and enhanced therapeutic efficiency in human colon adenocarcinoma (HT-29) tumor-bearing mice via enhanced permeation and retention (EPR) effect. Furthermore, FRRG-DOX nanoparticles did not present any severe toxicity, such as non-specific cell death and cardiac toxicity, in normal tissues due to minimal expression of cathepsin B. This carrier-free nanoparticles of FRRG-DOX can solve the unavoidable problems of current nanomedicine, such as lower targeting efficiency, toxicity of nanoparticles themselves, and difficulty in mass production that are fatally caused by natural and synthetic nano-sized carriers.

Original languageEnglish
Pages (from-to)376-389
Number of pages14
JournalJournal of Controlled Release
Volume294
DOIs
Publication statusPublished - 2019 Jan 28

Fingerprint

Cathepsin B
Prodrugs
Nanoparticles
Doxorubicin
Peptides
Neoplasms
Nanomedicine
Therapeutics
Colon
Adenocarcinoma
Cell Death

Keywords

  • Carrier-free nanoparticles
  • Cathepsin B-specfic prodrug
  • Nanomedicine
  • Tumor targeting therapy

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Carrier-free nanoparticles of cathepsin B-cleavable peptide-conjugated doxorubicin prodrug for cancer targeting therapy. / Shim, Man Kyu; Park, Jooho; Yoon, Hong Yeol; Lee, Sangmin; Um, Wooram; Kim, Jong Ho; Kang, Sun Woong; Seo, Joung Wook; Hyun, Soo Wang; Park, Jae Hyung; Byun, Youngro; Kwon, Ick Chan; Kim, Kwang Meyung.

In: Journal of Controlled Release, Vol. 294, 28.01.2019, p. 376-389.

Research output: Contribution to journalArticle

Shim, MK, Park, J, Yoon, HY, Lee, S, Um, W, Kim, JH, Kang, SW, Seo, JW, Hyun, SW, Park, JH, Byun, Y, Kwon, IC & Kim, KM 2019, 'Carrier-free nanoparticles of cathepsin B-cleavable peptide-conjugated doxorubicin prodrug for cancer targeting therapy', Journal of Controlled Release, vol. 294, pp. 376-389. https://doi.org/10.1016/j.jconrel.2018.11.032
Shim, Man Kyu ; Park, Jooho ; Yoon, Hong Yeol ; Lee, Sangmin ; Um, Wooram ; Kim, Jong Ho ; Kang, Sun Woong ; Seo, Joung Wook ; Hyun, Soo Wang ; Park, Jae Hyung ; Byun, Youngro ; Kwon, Ick Chan ; Kim, Kwang Meyung. / Carrier-free nanoparticles of cathepsin B-cleavable peptide-conjugated doxorubicin prodrug for cancer targeting therapy. In: Journal of Controlled Release. 2019 ; Vol. 294. pp. 376-389.
@article{79eb963696984760875a0b082a0bfb00,
title = "Carrier-free nanoparticles of cathepsin B-cleavable peptide-conjugated doxorubicin prodrug for cancer targeting therapy",
abstract = "Cancer nanomedicine using nanoparticle-based delivery systems has shown outstanding promise in recent decades for improving anticancer treatment. However, limited targeting efficiency, low drug loading efficiency and innate toxicity of nanoparticles have caused severe problems, leaving only a few available in the clinic. Here, we newly developed carrier-free nanoparticles of cathepsin B-cleavable peptide (Phe-Arg-Arg-Gly; FRRG)-conjugated doxorubicin (DOX) prodrug (FRRG-DOX) that formed a stable nanoparticle structure with an average diameter of 213 nm in aqueous condition. The carrier-free nanoparticles of FRRG-DOX induced cytotoxicity against cathepsin B-overexpressed tumor cells whereas the toxicity was minimized in normal cells. In particular, the FRRG-DOX nanoparticles showed the successful tumor-targeting ability and enhanced therapeutic efficiency in human colon adenocarcinoma (HT-29) tumor-bearing mice via enhanced permeation and retention (EPR) effect. Furthermore, FRRG-DOX nanoparticles did not present any severe toxicity, such as non-specific cell death and cardiac toxicity, in normal tissues due to minimal expression of cathepsin B. This carrier-free nanoparticles of FRRG-DOX can solve the unavoidable problems of current nanomedicine, such as lower targeting efficiency, toxicity of nanoparticles themselves, and difficulty in mass production that are fatally caused by natural and synthetic nano-sized carriers.",
keywords = "Carrier-free nanoparticles, Cathepsin B-specfic prodrug, Nanomedicine, Tumor targeting therapy",
author = "Shim, {Man Kyu} and Jooho Park and Yoon, {Hong Yeol} and Sangmin Lee and Wooram Um and Kim, {Jong Ho} and Kang, {Sun Woong} and Seo, {Joung Wook} and Hyun, {Soo Wang} and Park, {Jae Hyung} and Youngro Byun and Kwon, {Ick Chan} and Kim, {Kwang Meyung}",
year = "2019",
month = "1",
day = "28",
doi = "10.1016/j.jconrel.2018.11.032",
language = "English",
volume = "294",
pages = "376--389",
journal = "Journal of Controlled Release",
issn = "0168-3659",
publisher = "Elsevier",

}

TY - JOUR

T1 - Carrier-free nanoparticles of cathepsin B-cleavable peptide-conjugated doxorubicin prodrug for cancer targeting therapy

AU - Shim, Man Kyu

AU - Park, Jooho

AU - Yoon, Hong Yeol

AU - Lee, Sangmin

AU - Um, Wooram

AU - Kim, Jong Ho

AU - Kang, Sun Woong

AU - Seo, Joung Wook

AU - Hyun, Soo Wang

AU - Park, Jae Hyung

AU - Byun, Youngro

AU - Kwon, Ick Chan

AU - Kim, Kwang Meyung

PY - 2019/1/28

Y1 - 2019/1/28

N2 - Cancer nanomedicine using nanoparticle-based delivery systems has shown outstanding promise in recent decades for improving anticancer treatment. However, limited targeting efficiency, low drug loading efficiency and innate toxicity of nanoparticles have caused severe problems, leaving only a few available in the clinic. Here, we newly developed carrier-free nanoparticles of cathepsin B-cleavable peptide (Phe-Arg-Arg-Gly; FRRG)-conjugated doxorubicin (DOX) prodrug (FRRG-DOX) that formed a stable nanoparticle structure with an average diameter of 213 nm in aqueous condition. The carrier-free nanoparticles of FRRG-DOX induced cytotoxicity against cathepsin B-overexpressed tumor cells whereas the toxicity was minimized in normal cells. In particular, the FRRG-DOX nanoparticles showed the successful tumor-targeting ability and enhanced therapeutic efficiency in human colon adenocarcinoma (HT-29) tumor-bearing mice via enhanced permeation and retention (EPR) effect. Furthermore, FRRG-DOX nanoparticles did not present any severe toxicity, such as non-specific cell death and cardiac toxicity, in normal tissues due to minimal expression of cathepsin B. This carrier-free nanoparticles of FRRG-DOX can solve the unavoidable problems of current nanomedicine, such as lower targeting efficiency, toxicity of nanoparticles themselves, and difficulty in mass production that are fatally caused by natural and synthetic nano-sized carriers.

AB - Cancer nanomedicine using nanoparticle-based delivery systems has shown outstanding promise in recent decades for improving anticancer treatment. However, limited targeting efficiency, low drug loading efficiency and innate toxicity of nanoparticles have caused severe problems, leaving only a few available in the clinic. Here, we newly developed carrier-free nanoparticles of cathepsin B-cleavable peptide (Phe-Arg-Arg-Gly; FRRG)-conjugated doxorubicin (DOX) prodrug (FRRG-DOX) that formed a stable nanoparticle structure with an average diameter of 213 nm in aqueous condition. The carrier-free nanoparticles of FRRG-DOX induced cytotoxicity against cathepsin B-overexpressed tumor cells whereas the toxicity was minimized in normal cells. In particular, the FRRG-DOX nanoparticles showed the successful tumor-targeting ability and enhanced therapeutic efficiency in human colon adenocarcinoma (HT-29) tumor-bearing mice via enhanced permeation and retention (EPR) effect. Furthermore, FRRG-DOX nanoparticles did not present any severe toxicity, such as non-specific cell death and cardiac toxicity, in normal tissues due to minimal expression of cathepsin B. This carrier-free nanoparticles of FRRG-DOX can solve the unavoidable problems of current nanomedicine, such as lower targeting efficiency, toxicity of nanoparticles themselves, and difficulty in mass production that are fatally caused by natural and synthetic nano-sized carriers.

KW - Carrier-free nanoparticles

KW - Cathepsin B-specfic prodrug

KW - Nanomedicine

KW - Tumor targeting therapy

UR - http://www.scopus.com/inward/record.url?scp=85059456528&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059456528&partnerID=8YFLogxK

U2 - 10.1016/j.jconrel.2018.11.032

DO - 10.1016/j.jconrel.2018.11.032

M3 - Article

VL - 294

SP - 376

EP - 389

JO - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

ER -