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, Yong Tae Kwon, Christian Fernandez, Raman Venkataramanan, Song Li

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56 Scopus citations

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

Keywords

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

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