A stapled peptide antagonist of MDM2 carried by polymeric micelles sensitizes glioblastoma to temozolomide treatment through p53 activation.
A stapled peptide antagonist of MDM2 carried by polymeric micelles sensitizes glioblastoma to temozolomide treatment through p53 activation.
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DOI：
10.1016/j.jconrel.2015.09.061
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发表时间：
2015-11-28
期刊：
影响因子：
--
通讯作者：
Lu W
中科院分区：
文献类型：
--
作者：
Chen X;Tai L;Gao J;Qian J;Zhang M;Li B;Xie C;Lu L;Lu W;Lu W
拮抗MDM2和MDMX以激活肿瘤抑制蛋白p53是治疗多形性胶质母细胞瘤（GBM）的一种有吸引力的治疗模式。然而，p53激活剂有效穿过血脑屏障和/或血脑肿瘤屏障并特异性靶向肿瘤细胞的能力较差，这方面的挑战仍然存在。为了解决这些问题，我们开发了一种环RGD肽共轭聚（-乙二醇）-共聚乳酸聚合物胶束（RGD- m），该胶束携带MDM2和MDMX （sPMI）的钉接肽拮抗剂。采用膜水合法制备了RGD-M/sPMI包封效率高、负载能力强、粒径分布理想的多肽载胶团。胶束包封可显著提高sPMI的溶解度，从而减轻其血清隔离。体外研究表明，RGD-M/sPMI通过激活p53信号通路，在血清存在的情况下有效抑制胶质瘤细胞的增殖。此外，RGD-M/sPMI在裸鼠异种移植瘤模型中对人胶质母细胞瘤具有有效的肿瘤生长抑制活性。重要的是，RGD-M/sPMI联合替莫唑胺（GBM的标准化疗药物）在实验动物中提高了对胶质母细胞瘤的抗肿瘤疗效。我们的结果验证了p53激活剂与替莫唑胺联合治疗GBM是一种更有效的治疗方法。
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.
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DOI：
10.1073/pnas.1003919107
发表时间：
2010-10-19
影响因子：
11.1
作者：
Ding, Hui;Inoue, Satoshi;Ljubimova, Julia Y.
通讯作者：
Ljubimova, Julia Y.
DOI：
10.1073/pnas.1303002110
发表时间：
2013-09-03
影响因子：
11.1
作者：
Chang, Yong S.;Graves, Bradford;Sawyer, Tomi K.
通讯作者：
Sawyer, Tomi K.
DOI：
10.1073/pnas.1203789109
发表时间：
2012-07-17
影响因子：
11.1
作者：
Graves, Bradford;Thompson, Thelma;Vassilev, Lyubomir T.
通讯作者：
Vassilev, Lyubomir T.
影响因子：
16.6
作者：
Li, Chong;Pazgier, Marzena;Liu, Min;Lu, Wei-Yue;Lu, Wuyuan
通讯作者：
Lu, Wuyuan
影响因子：
4.7
作者：
Martin S;Janouskova H;Dontenwill M
通讯作者：
Dontenwill M