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

JOURNAL OF CONTROLLED RELEASE

卷:258

Article

Sun, Jingjing¹  Liu, Yanhua²  Chen, Yichao¹  Zhao, Wenchen¹  Zhai, Qianyu³  Rathod, Sanjay¹  Huang, Yixian¹  Tang, Suoqin³  Kwon, Yong Tae^1,4  Fernandez, Christian¹  Venkataramanan, Raman¹  Li, Song¹ 

[1] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Ctr Pharmacogenet, Pittsburgh, PA 15261 USA

[2] Ningxia Med Univ, Sch Pharm, Dept Pharmaceut, 1160 Shengli St, Yinchuan 750004, Peoples R China

[3] Gen Hosp Peoples Liberat Army, Dept Pediat, Beijing 100853, Peoples R China

[4] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Prot Metab Med Res Ctr, Seoul 110799, South Korea

关键词: Dasatinib;    Prodrug micelles;    Redox responsive;    Doxorubicin;    Co-delivery;   

DOI  :  10.1016/j.jconrel.2017.05.006

来源: Elsevier

【 摘 要 】

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-bPSSDas 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 DOXloaded 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.

【 授权许可】

Free