Doxorubicin/heparin composite nanoparticles for caspase-activated prodrug chemotherapy

Nisar Ul Khaliq, Febrina Carolina Sandra, Dal Yong Park, Jae Young Lee, Keun Sang Oh, Dongkyu Kim, Youngro Byun, In-San Kim, Ick Chan Kwon, Sang Yoon Kim, Soon Hong Yuk

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Caspase-activated prodrug chemotherapy is introduced and demonstrated using the composite nanoparticles (NPs), which deliver doxorubicin (DOX) and DEVD-S-DOX together to the tumor tissue. DEVD-S-DOX, DOX linked to a peptide moiety (DEVD), is a prodrug that is cleaved into free DOX by caspase-3 upon apoptosis. DEVD-S-DOX has no therapeutic efficacy, but it changes into free DOX with the expression of caspase-3. With the accumulation of the composite NPs in the tumor tissue by the enhanced permeation and retention (EPR) effect, a small exposure of DOX in the tumor cells initiated apoptosis in a localized area of the tumor tissue, which induced caspase-3 activation. Cleavage of DEVD-S-DOX into free DOX by caspase-3 continued with repetitive activation of caspase-3 and cleavage of DEVD-S-DOX at the tumor site. The composite NPs were characterized with transmittance electron microscopy (TEM) and particle size analyzer. We then evaluated the nanoparticle drug release, therapeutic efficacy, and in vivo biodistribution for tumor targeting using a non-invasive live animal imaging technology and the quantification of DOX with high performance liquid chromatography. DOX-induced apoptosis-targeted chemotherapy (DIATC) was verified by in vitro/in vivo DEVD-S-DOX response to free DOX and cellular uptake behavior of the composite NPs with flow cytometry analysis. Significant antitumor efficacy with minimal cardiotoxicity was also observed, which supported DIATC for improved chemotherapy.

Original languageEnglish
Pages (from-to)131-142
Number of pages12
JournalBiomaterials
Volume101
DOIs
Publication statusPublished - 2016 Sep 1

Fingerprint

Chemotherapy
Prodrugs
Caspases
Nanoparticles
Doxorubicin
Tumors
Cell death
Drug Therapy
Composite materials
Tissue
Caspase 3
Chemical activation
Flow cytometry
Apoptosis
High performance liquid chromatography
Neoplasms
Permeation
Peptides
Electron microscopy
doxorubicin-heparin

Keywords

  • Caspase-3
  • Doxorubicin
  • Doxorubicin prodrug
  • Doxorubicin-induced apoptosis-targeted chemotherapy
  • Heparin
  • The composite nanoparticles

ASJC Scopus subject areas

  • Biomaterials
  • Bioengineering
  • Ceramics and Composites
  • Mechanics of Materials
  • Biophysics

Cite this

Khaliq, N. U., Sandra, F. C., Park, D. Y., Lee, J. Y., Oh, K. S., Kim, D., ... Yuk, S. H. (2016). Doxorubicin/heparin composite nanoparticles for caspase-activated prodrug chemotherapy. Biomaterials, 101, 131-142. https://doi.org/10.1016/j.biomaterials.2016.05.056

Doxorubicin/heparin composite nanoparticles for caspase-activated prodrug chemotherapy. / Khaliq, Nisar Ul; Sandra, Febrina Carolina; Park, Dal Yong; Lee, Jae Young; Oh, Keun Sang; Kim, Dongkyu; Byun, Youngro; Kim, In-San; Kwon, Ick Chan; Kim, Sang Yoon; Yuk, Soon Hong.

In: Biomaterials, Vol. 101, 01.09.2016, p. 131-142.

Research output: Contribution to journalArticle

Khaliq, NU, Sandra, FC, Park, DY, Lee, JY, Oh, KS, Kim, D, Byun, Y, Kim, I-S, Kwon, IC, Kim, SY & Yuk, SH 2016, 'Doxorubicin/heparin composite nanoparticles for caspase-activated prodrug chemotherapy', Biomaterials, vol. 101, pp. 131-142. https://doi.org/10.1016/j.biomaterials.2016.05.056
Khaliq, Nisar Ul ; Sandra, Febrina Carolina ; Park, Dal Yong ; Lee, Jae Young ; Oh, Keun Sang ; Kim, Dongkyu ; Byun, Youngro ; Kim, In-San ; Kwon, Ick Chan ; Kim, Sang Yoon ; Yuk, Soon Hong. / Doxorubicin/heparin composite nanoparticles for caspase-activated prodrug chemotherapy. In: Biomaterials. 2016 ; Vol. 101. pp. 131-142.
@article{977ac39c8e764d489656c006ab1552a3,
title = "Doxorubicin/heparin composite nanoparticles for caspase-activated prodrug chemotherapy",
abstract = "Caspase-activated prodrug chemotherapy is introduced and demonstrated using the composite nanoparticles (NPs), which deliver doxorubicin (DOX) and DEVD-S-DOX together to the tumor tissue. DEVD-S-DOX, DOX linked to a peptide moiety (DEVD), is a prodrug that is cleaved into free DOX by caspase-3 upon apoptosis. DEVD-S-DOX has no therapeutic efficacy, but it changes into free DOX with the expression of caspase-3. With the accumulation of the composite NPs in the tumor tissue by the enhanced permeation and retention (EPR) effect, a small exposure of DOX in the tumor cells initiated apoptosis in a localized area of the tumor tissue, which induced caspase-3 activation. Cleavage of DEVD-S-DOX into free DOX by caspase-3 continued with repetitive activation of caspase-3 and cleavage of DEVD-S-DOX at the tumor site. The composite NPs were characterized with transmittance electron microscopy (TEM) and particle size analyzer. We then evaluated the nanoparticle drug release, therapeutic efficacy, and in vivo biodistribution for tumor targeting using a non-invasive live animal imaging technology and the quantification of DOX with high performance liquid chromatography. DOX-induced apoptosis-targeted chemotherapy (DIATC) was verified by in vitro/in vivo DEVD-S-DOX response to free DOX and cellular uptake behavior of the composite NPs with flow cytometry analysis. Significant antitumor efficacy with minimal cardiotoxicity was also observed, which supported DIATC for improved chemotherapy.",
keywords = "Caspase-3, Doxorubicin, Doxorubicin prodrug, Doxorubicin-induced apoptosis-targeted chemotherapy, Heparin, The composite nanoparticles",
author = "Khaliq, {Nisar Ul} and Sandra, {Febrina Carolina} and Park, {Dal Yong} and Lee, {Jae Young} and Oh, {Keun Sang} and Dongkyu Kim and Youngro Byun and In-San Kim and Kwon, {Ick Chan} and Kim, {Sang Yoon} and Yuk, {Soon Hong}",
year = "2016",
month = "9",
day = "1",
doi = "10.1016/j.biomaterials.2016.05.056",
language = "English",
volume = "101",
pages = "131--142",
journal = "Biomaterials",
issn = "0142-9612",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - Doxorubicin/heparin composite nanoparticles for caspase-activated prodrug chemotherapy

AU - Khaliq, Nisar Ul

AU - Sandra, Febrina Carolina

AU - Park, Dal Yong

AU - Lee, Jae Young

AU - Oh, Keun Sang

AU - Kim, Dongkyu

AU - Byun, Youngro

AU - Kim, In-San

AU - Kwon, Ick Chan

AU - Kim, Sang Yoon

AU - Yuk, Soon Hong

PY - 2016/9/1

Y1 - 2016/9/1

N2 - Caspase-activated prodrug chemotherapy is introduced and demonstrated using the composite nanoparticles (NPs), which deliver doxorubicin (DOX) and DEVD-S-DOX together to the tumor tissue. DEVD-S-DOX, DOX linked to a peptide moiety (DEVD), is a prodrug that is cleaved into free DOX by caspase-3 upon apoptosis. DEVD-S-DOX has no therapeutic efficacy, but it changes into free DOX with the expression of caspase-3. With the accumulation of the composite NPs in the tumor tissue by the enhanced permeation and retention (EPR) effect, a small exposure of DOX in the tumor cells initiated apoptosis in a localized area of the tumor tissue, which induced caspase-3 activation. Cleavage of DEVD-S-DOX into free DOX by caspase-3 continued with repetitive activation of caspase-3 and cleavage of DEVD-S-DOX at the tumor site. The composite NPs were characterized with transmittance electron microscopy (TEM) and particle size analyzer. We then evaluated the nanoparticle drug release, therapeutic efficacy, and in vivo biodistribution for tumor targeting using a non-invasive live animal imaging technology and the quantification of DOX with high performance liquid chromatography. DOX-induced apoptosis-targeted chemotherapy (DIATC) was verified by in vitro/in vivo DEVD-S-DOX response to free DOX and cellular uptake behavior of the composite NPs with flow cytometry analysis. Significant antitumor efficacy with minimal cardiotoxicity was also observed, which supported DIATC for improved chemotherapy.

AB - Caspase-activated prodrug chemotherapy is introduced and demonstrated using the composite nanoparticles (NPs), which deliver doxorubicin (DOX) and DEVD-S-DOX together to the tumor tissue. DEVD-S-DOX, DOX linked to a peptide moiety (DEVD), is a prodrug that is cleaved into free DOX by caspase-3 upon apoptosis. DEVD-S-DOX has no therapeutic efficacy, but it changes into free DOX with the expression of caspase-3. With the accumulation of the composite NPs in the tumor tissue by the enhanced permeation and retention (EPR) effect, a small exposure of DOX in the tumor cells initiated apoptosis in a localized area of the tumor tissue, which induced caspase-3 activation. Cleavage of DEVD-S-DOX into free DOX by caspase-3 continued with repetitive activation of caspase-3 and cleavage of DEVD-S-DOX at the tumor site. The composite NPs were characterized with transmittance electron microscopy (TEM) and particle size analyzer. We then evaluated the nanoparticle drug release, therapeutic efficacy, and in vivo biodistribution for tumor targeting using a non-invasive live animal imaging technology and the quantification of DOX with high performance liquid chromatography. DOX-induced apoptosis-targeted chemotherapy (DIATC) was verified by in vitro/in vivo DEVD-S-DOX response to free DOX and cellular uptake behavior of the composite NPs with flow cytometry analysis. Significant antitumor efficacy with minimal cardiotoxicity was also observed, which supported DIATC for improved chemotherapy.

KW - Caspase-3

KW - Doxorubicin

KW - Doxorubicin prodrug

KW - Doxorubicin-induced apoptosis-targeted chemotherapy

KW - Heparin

KW - The composite nanoparticles

UR - http://www.scopus.com/inward/record.url?scp=84973144071&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84973144071&partnerID=8YFLogxK

U2 - 10.1016/j.biomaterials.2016.05.056

DO - 10.1016/j.biomaterials.2016.05.056

M3 - Article

C2 - 27286189

AN - SCOPUS:84973144071

VL - 101

SP - 131

EP - 142

JO - Biomaterials

JF - Biomaterials

SN - 0142-9612

ER -