Doxorubicin delivered by a redox-responsive dasatinib-containing polymeric prodrug carrier for combination therapy

Jingjing Sun, Yanhua Liu, Yichao Chen, Wenchen Zhao, Qianyu Zhai, Sanjay Rathod, Yixian Huang, Suoqin Tang, Yongtae Kwon, Christian Fernandez, Raman Venkataramanan, Song Li

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Two novel prodrug polymers POEG-b-PSSDas (redox-sensitive) and POEG-b-PCCDas (redox-insensitive), which consist of poly(oligo(ethylene glycol) methacrylate) (POEG) hydrophilic blocks and dasatinib (DAS, an oncogenic tyrosine kinases inhibitor) conjugated hydrophobic blocks, were designed as dual-functional carriers for codelivery with doxorubicin (DOX). Both carriers retained antitumor activity of DAS and could form mixed micelles with DOX. Compared to POEG-b-PCCDas micelles, incorporation of disulfide linkage into POEG-b-PSSDas micelles facilitated efficient cleavage of DAS from prodrug micelles in tumor cells/tissues, leading to a higher level of anti-tumor activity in vitro and in vivo. In addition, DOX-loaded POEG-b-PSSDas micelles exhibited triggered DOX release under a redox environment (10 mM glutathione, GSH), and demonstrated enhanced cytotoxicity against 4T1.2 and PC3 cell lines compared to DOX and DOX-loaded POEG-b-PCCDas micelles. More importantly, DOX-loaded POEG-b-PSSDas micelles were more effective in inhibiting the tumor growth and prolonging the survival rate in an aggressive murine breast cancer model (4T1.2) compared to DOX-loaded POEG-b-PCCDas micelles and a micellar formulation co-loaded with DOX and DAS. This redox-responsive prodrug micellar system provides an attractive strategy for effective combination of tumor targeted therapy and traditional chemotherapy, which warrants further investigation.

Original languageEnglish
Pages (from-to)43-55
Number of pages13
JournalJournal of Controlled Release
Volume258
DOIs
StatePublished - 28 Jul 2017

Fingerprint

amsonic acid
Prodrugs
Micelles
Protein-Tyrosine Kinases
Doxorubicin
Oxidation-Reduction
Therapeutics
Neoplasms

Keywords

  • Co-delivery
  • Dasatinib
  • Doxorubicin
  • Prodrug micelles
  • Redox responsive

Cite this

Sun, Jingjing ; Liu, Yanhua ; Chen, Yichao ; Zhao, Wenchen ; Zhai, Qianyu ; Rathod, Sanjay ; Huang, Yixian ; Tang, Suoqin ; Kwon, Yongtae ; Fernandez, Christian ; Venkataramanan, Raman ; Li, Song. / Doxorubicin delivered by a redox-responsive dasatinib-containing polymeric prodrug carrier for combination therapy. In: Journal of Controlled Release. 2017 ; Vol. 258. pp. 43-55.
@article{9b3a9965a71d4bc3be3d5eab1aa0ec7a,
title = "Doxorubicin delivered by a redox-responsive dasatinib-containing polymeric prodrug carrier for combination therapy",
abstract = "Two novel prodrug polymers POEG-b-PSSDas (redox-sensitive) and POEG-b-PCCDas (redox-insensitive), which consist of poly(oligo(ethylene glycol) methacrylate) (POEG) hydrophilic blocks and dasatinib (DAS, an oncogenic tyrosine kinases inhibitor) conjugated hydrophobic blocks, were designed as dual-functional carriers for codelivery with doxorubicin (DOX). Both carriers retained antitumor activity of DAS and could form mixed micelles with DOX. Compared to POEG-b-PCCDas micelles, incorporation of disulfide linkage into POEG-b-PSSDas micelles facilitated efficient cleavage of DAS from prodrug micelles in tumor cells/tissues, leading to a higher level of anti-tumor activity in vitro and in vivo. In addition, DOX-loaded POEG-b-PSSDas micelles exhibited triggered DOX release under a redox environment (10 mM glutathione, GSH), and demonstrated enhanced cytotoxicity against 4T1.2 and PC3 cell lines compared to DOX and DOX-loaded POEG-b-PCCDas micelles. More importantly, DOX-loaded POEG-b-PSSDas micelles were more effective in inhibiting the tumor growth and prolonging the survival rate in an aggressive murine breast cancer model (4T1.2) compared to DOX-loaded POEG-b-PCCDas micelles and a micellar formulation co-loaded with DOX and DAS. This redox-responsive prodrug micellar system provides an attractive strategy for effective combination of tumor targeted therapy and traditional chemotherapy, which warrants further investigation.",
keywords = "Co-delivery, Dasatinib, Doxorubicin, Prodrug micelles, Redox responsive",
author = "Jingjing Sun and Yanhua Liu and Yichao Chen and Wenchen Zhao and Qianyu Zhai and Sanjay Rathod and Yixian Huang and Suoqin Tang and Yongtae Kwon and Christian Fernandez and Raman Venkataramanan and Song Li",
year = "2017",
month = "7",
day = "28",
doi = "10.1016/j.jconrel.2017.05.006",
language = "English",
volume = "258",
pages = "43--55",
journal = "Journal of Controlled Release",
issn = "0168-3659",
publisher = "Elsevier",

}

Sun, J, Liu, Y, Chen, Y, Zhao, W, Zhai, Q, Rathod, S, Huang, Y, Tang, S, Kwon, Y, Fernandez, C, Venkataramanan, R & Li, S 2017, 'Doxorubicin delivered by a redox-responsive dasatinib-containing polymeric prodrug carrier for combination therapy', Journal of Controlled Release, vol. 258, pp. 43-55. https://doi.org/10.1016/j.jconrel.2017.05.006

Doxorubicin delivered by a redox-responsive dasatinib-containing polymeric prodrug carrier for combination therapy. / Sun, Jingjing; Liu, Yanhua; Chen, Yichao; Zhao, Wenchen; Zhai, Qianyu; Rathod, Sanjay; Huang, Yixian; Tang, Suoqin; Kwon, Yongtae; Fernandez, Christian; Venkataramanan, Raman; Li, Song.

In: Journal of Controlled Release, Vol. 258, 28.07.2017, p. 43-55.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Doxorubicin delivered by a redox-responsive dasatinib-containing polymeric prodrug carrier for combination therapy

AU - Sun, Jingjing

AU - Liu, Yanhua

AU - Chen, Yichao

AU - Zhao, Wenchen

AU - Zhai, Qianyu

AU - Rathod, Sanjay

AU - Huang, Yixian

AU - Tang, Suoqin

AU - Kwon, Yongtae

AU - Fernandez, Christian

AU - Venkataramanan, Raman

AU - Li, Song

PY - 2017/7/28

Y1 - 2017/7/28

N2 - Two novel prodrug polymers POEG-b-PSSDas (redox-sensitive) and POEG-b-PCCDas (redox-insensitive), which consist of poly(oligo(ethylene glycol) methacrylate) (POEG) hydrophilic blocks and dasatinib (DAS, an oncogenic tyrosine kinases inhibitor) conjugated hydrophobic blocks, were designed as dual-functional carriers for codelivery with doxorubicin (DOX). Both carriers retained antitumor activity of DAS and could form mixed micelles with DOX. Compared to POEG-b-PCCDas micelles, incorporation of disulfide linkage into POEG-b-PSSDas micelles facilitated efficient cleavage of DAS from prodrug micelles in tumor cells/tissues, leading to a higher level of anti-tumor activity in vitro and in vivo. In addition, DOX-loaded POEG-b-PSSDas micelles exhibited triggered DOX release under a redox environment (10 mM glutathione, GSH), and demonstrated enhanced cytotoxicity against 4T1.2 and PC3 cell lines compared to DOX and DOX-loaded POEG-b-PCCDas micelles. More importantly, DOX-loaded POEG-b-PSSDas micelles were more effective in inhibiting the tumor growth and prolonging the survival rate in an aggressive murine breast cancer model (4T1.2) compared to DOX-loaded POEG-b-PCCDas micelles and a micellar formulation co-loaded with DOX and DAS. This redox-responsive prodrug micellar system provides an attractive strategy for effective combination of tumor targeted therapy and traditional chemotherapy, which warrants further investigation.

AB - Two novel prodrug polymers POEG-b-PSSDas (redox-sensitive) and POEG-b-PCCDas (redox-insensitive), which consist of poly(oligo(ethylene glycol) methacrylate) (POEG) hydrophilic blocks and dasatinib (DAS, an oncogenic tyrosine kinases inhibitor) conjugated hydrophobic blocks, were designed as dual-functional carriers for codelivery with doxorubicin (DOX). Both carriers retained antitumor activity of DAS and could form mixed micelles with DOX. Compared to POEG-b-PCCDas micelles, incorporation of disulfide linkage into POEG-b-PSSDas micelles facilitated efficient cleavage of DAS from prodrug micelles in tumor cells/tissues, leading to a higher level of anti-tumor activity in vitro and in vivo. In addition, DOX-loaded POEG-b-PSSDas micelles exhibited triggered DOX release under a redox environment (10 mM glutathione, GSH), and demonstrated enhanced cytotoxicity against 4T1.2 and PC3 cell lines compared to DOX and DOX-loaded POEG-b-PCCDas micelles. More importantly, DOX-loaded POEG-b-PSSDas micelles were more effective in inhibiting the tumor growth and prolonging the survival rate in an aggressive murine breast cancer model (4T1.2) compared to DOX-loaded POEG-b-PCCDas micelles and a micellar formulation co-loaded with DOX and DAS. This redox-responsive prodrug micellar system provides an attractive strategy for effective combination of tumor targeted therapy and traditional chemotherapy, which warrants further investigation.

KW - Co-delivery

KW - Dasatinib

KW - Doxorubicin

KW - Prodrug micelles

KW - Redox responsive

UR - http://www.scopus.com/inward/record.url?scp=85019140893&partnerID=8YFLogxK

U2 - 10.1016/j.jconrel.2017.05.006

DO - 10.1016/j.jconrel.2017.05.006

M3 - Article

C2 - 28501705

AN - SCOPUS:85019140893

VL - 258

SP - 43

EP - 55

JO - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

ER -