A stapled peptide antagonist of MDM2 carried by polymeric micelles sensitizes glioblastoma to temozolomide treatment through p53 activation

JOURNAL OF CONTROLLED RELEASE

卷:218

Article

Chen, Xishan^1,2,6  Tai, Lingyu^1,3,6  Gao, Jie^1,6  Qian, Jianchang^1,6  Zhang, Mingfei^1,6  Li, Beibei^1,6  Xie, Cao^1,6  Lu, Linwei⁴  Lu, Wuyuan²  Lu, Weiyue^1,5,6,7 

[1] Fudan Univ, Sch Pharm, Dept Pharmaceut, Shanghai 201203, Peoples R China

[2] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Inst Human Virol, Baltimore, MD 21201 USA

[3] Shenyang Pharmaceut Univ, Sch Pharm, Shenyang 110016, Peoples R China

[4] Fudan Univ, Huashan Hosp, Dept Integrat Med, Inst Integrat Med, Shanghai 200041, Peoples R China

[5] Fudan Univ, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China

[6] Fudan Univ, Minist Educ, Key Lab Smart Drug Delivery, Shanghai 201203, Peoples R China

[7] Fudan Univ, State Key Lab Mol Engn Polymers, Shanghai 200433, Peoples R China

关键词: Stapled peptide;    p53;    Micelle;    Glioma-targeting delivery;    Chemosensitization;    Temozolomide;   

DOI  :  10.1016/j.jconrel.2015.09.061

来源: Elsevier

【 摘 要 】

Antagonizing MDM2 and MDMX to activate the tumor suppressor protein p53 is an attractive therapeutic paradigm for the treatment of glioblastoma multiforme (GBM). However, challenges remain with respect to the poor ability of p53 activators to efficiently cross the blood-brain barrier and/or blood-brain tumor barrier and to specifically target tumor cells. To circumvent these problems, we developed a cyclic RGD peptide-conjugated poly(ethylene glycol)-co-poly(lactic acid) polymeric micelle (RGD-M) that carried a stapled peptide antagonist of both MDM2 and MDMX (sPMI). The peptide-carrying micelle RGD-M/sPMI was prepared via film-hydration method with high encapsulation efficiency and loading capacity as well as ideal size distribution. Micelle encapsulation dramatically increased the solubility of sPMI, thus alleviating its serum sequestration. In vitro studies showed that RGD-M/sPMI efficiently inhibited the proliferation of glioma cells in the presence of serum by activating the p53 signaling pathway. Further, RGD-M/sPMI exerted potent tumor growth inhibitory activity against human glioblastoma in nude mouse xenograft models. Importantly, the combination of RGD-M/sPMI and temozolomide - a standard chemotherapy drug for GBM increased antitumor efficacy against glioblastoma in experimental animals. Our results validate a combination therapy using p53 activators with temozolomide as a more effective treatment for GBM. (C) 2015 Elsevier B.V. All rights reserved.

【 授权许可】

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