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

• Published in: Journal of controlled release Vol. 258; pp. 43 - 55
• Main Authors: Sun, Jingjing, Liu, Yanhua, Chen, Yichao, Zhao, Wenchen, Zhai, Qianyu, Rathod, Sanjay, Huang, Yixian, Tang, Suoqin, Kwon, Yong Tae, Fernandez, Christian, Venkataramanan, Raman, Li, Song
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 28.07.2017
• Subjects: Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - pharmacokinetics; Antibiotics, Antineoplastic - therapeutic use; Cell Line, Tumor; Cell Survival - drug effects; Co-delivery; Dasatinib; Dasatinib - administration & dosage; Dasatinib - pharmacokinetics; Dasatinib - therapeutic use; Delayed-Action Preparations - chemistry; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - pharmacokinetics; Doxorubicin - therapeutic use; Drug Delivery Systems; Female; Humans; Mice, Inbred BALB C; Micelles; Neoplasms - drug therapy; Neoplasms - pathology; Oxidation-Reduction; Polyethylene Glycols - chemistry; Prodrug micelles; Prodrugs - administration & dosage; Prodrugs - pharmacokinetics; Prodrugs - therapeutic use; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - therapeutic use; Redox responsive; Prodrug micelles; Dasatinib; Redox responsive; Co-delivery; Doxorubicin
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2017.05.006

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 (10mM 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. [Display omitted]