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Doxorubicin/heparin composite nanoparticles for caspase-activated prodrug chemotherapy

Authors
Ul Khaliq, NisarSandra, Febrina CarolinaPark, Dal YongLee, Jae YoungOh, Keun SangKim, DongkyuByun, YoungroKim, In-SanKwon, Ick ChanKim, Sang YoonYuk, Soon Hong
Issue Date
9월-2016
Publisher
ELSEVIER SCI LTD
Keywords
Doxorubicin-induced apoptosis-targeted; chemotherapy; Doxorubicin prodrug; Caspase-3; The composite nanoparticles; Doxorubicin; Heparin
Citation
BIOMATERIALS, v.101, pp.131 - 142
Indexed
SCIE
SCOPUS
Journal Title
BIOMATERIALS
Volume
101
Start Page
131
End Page
142
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/87663
DOI
10.1016/j.biomaterials.2016.05.056
ISSN
0142-9612
Abstract
Caspase-activated prodrug chemotherapy is introduced and demonstrated using the composite nano particles (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. (C) 2016 Elsevier Ltd. All rights reserved.
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