Improved Antiglioblastoma Activity and BBB Permeability by Conjugation of Paclitaxel to a Cell-Penetrative MMP-2-Cleavable Peptide.
Improved Antiglioblastoma Activity and BBB Permeability by Conjugation of Paclitaxel to a Cell-Penetrative MMP-2-Cleavable Peptide.
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通过将紫杉醇与细胞缀合改善抗胶质母细胞瘤活性和 BBB 通透性 — 穿透性 MMP — 2 — 可裂解肽
DOI：
10.1002/advs.202001960
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Yu S
中科院分区：
文献类型：
--
作者：
Hua D;Tang L;Wang W;Tang S;Yu L;Zhou X;Wang Q;Sun C;Shi C;Luo W;Jiang Z;Li H;Yu S
为了解决胶质母细胞瘤（GBM）治疗中受体混杂和血脑屏障（BBB）渗透性差的问题，基于肽-药物偶联物的策略，开发了一种新型的双功能纳米复合物给药系统。在这项研究中，SynB3‐PVGLIG‐PTX是由基质金属蛋白酶‐2 （MMP‐2）设计和筛选出来的，它表现出最好的亲和力。MMP - 2敏感肽（PVGLIG）和细胞渗透肽（SynB3）结合形成双功能肽。此外，作为一种药物-肽纳米复合物，SynB3 - PVGLIG - PTX显示出高潜力形成具有良好溶解性的聚集，可以通过MMP - 2的裂解释放紫杉醇（PTX）。从功能角度来看，我们发现SynB3‐PVGLIG‐PTX能够特异性抑制体外MMP‐2存在下GBM细胞的增殖、迁移和侵袭，这与转染MMP‐2 siRNA的细胞不同。进一步的体内实验表明，SynB3‐PVGLIG‐PTX可以很容易地进入U87MG异种移植裸鼠的大脑，并且与PTX和替莫唑胺相比，SynB3‐PVGLIG‐PTX可以通过控制PTX的释放而对GBM产生更好的抑制作用。因此，SynB3‐PVGLIG‐PTX由于其特异性和血脑屏障通透性，可以作为一种新的药物装载递送系统用于治疗GBM。SynB3‐PVGLIG‐PTX与MMP‐2具有较强的亲和性，可以通过凝聚形成带正电荷的特殊结构来提高水溶性；在MMP‐2的切割过程中，SynB3‐PVGLIG‐PTX可控制PTX的释放，这表明SynB3‐PVGLIG‐PTX在GBM细胞中具有特异性的细胞毒性；SynB3‐PVGLIG‐PTX在体外和体内均能有效抑制GBM。
In order to solve the problems of receptor promiscuity and poor blood‐brain barrier (BBB) penetration in the treatment of glioblastomas (GBM), a novel dual‐functional nanocomplex drug delivery system is developed based on the strategy of peptide‐drug conjugates. In this study, SynB3‐PVGLIG‐PTX is designed and screened out by matrix metalloproteinase‐2 (MMP‐2), to which it exhibits the best affinity. The MMP‐2‐sensitive peptide (PVGLIG) and a cell‐penetration peptide (SynB3) are combined to form a dual‐functional peptide. Moreover, as a drug‐peptide nanocomplex, SynB3‐PVGLIG‐PTX exhibited a high potential to form an aggregation with good solubility that can release paclitaxel (PTX) through the cleavage of MMP‐2. From a functional perspective, it is found that SynB3‐PVGLIG‐PTX can specifically inhibit the proliferation, migration, and invasion of GBM cells in vitro in the presence of MMP‐2, in contrast to that observed in MMP‐2 siRNA transfected cells. Further investigation in vivo shows that SynB3‐PVGLIG‐PTX easily enters the brain of U87MG xenograft nude mice and can generate a better suppressive effect on GBM through a controlled release of PTX from SynB3‐PVGLIG‐PTX compared with PTX and temozolomide. Thus, it is proposed that SynB3‐PVGLIG‐PTX can be used as a novel drug‐loading delivery system to treat GBM due to its specificity and BBB permeability. SynB3‐PVGLIG‐PTX exhibits a strong affinity with MMP‐2, and it can enhance water solubility by agglomerating to form a special structure with a positive charge; a controlled release of PTX from SynB3‐PVGLIG‐PTX occurs upon cleavage of MMP‐2, implying that SynB3‐PVGLIG‐PTX has a specific cytotoxicity in GBM cells; SynB3‐PVGLIG‐PTX can effectively inhibit GBM in vitro and in vivo.
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使用具有三种不同连接的细胞穿透肽 synB3 改善内吗啡肽 1 的血脑屏障通透性。
影响因子：
5.8
作者：
Liu, Hui;Zhang, Wei;Wang, Rui
通讯作者：
Wang, Rui
DOI：
10.3390/ph5090991
发表时间：
2012-09-12
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Regberg J;Srimanee A;Langel U
通讯作者：
Langel U
DOI：
10.1152/ajpheart.00909.2013
发表时间：
2014-03-01
影响因子：
4.8
作者：
Hughes, Bryan G.;Fan, Xiaohu;Schulz, Richard
通讯作者：
Schulz, Richard
负载紫杉醇的脂质体装饰有多功能串联肽，用于神经胶质瘤靶向。
影响因子：
14
作者：
Liu, Yayuan;Ran, Rui;He, Qin
通讯作者：
He, Qin
影响因子：
--
作者：
Rampogu S;Rampogu Lemuel M
通讯作者：
Rampogu Lemuel M