Improved Antiglioblastoma Activity and BBB Permeability by Conjugation of Paclitaxel to a Cell-Penetrative MMP-2-Cleavable Peptide

组会讲课人员：李敏

Improved Antiglioblastoma Activity and BBB Permeability by Conjugation of Paclitaxel to a Cell-Penetrative MMP-2-Cleavable Peptide

通过紫杉醇与细胞穿透性MMP-2可切割肽的偶联来改善抗胶质母细胞瘤活性和BBB通透性

主讲人：李敏

Advanced Science | December 2020 | Volume 8 | Issue 3 | 2001960 | DOI:10.1002/advs.202001960

Abstract：

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.

摘要：

为了解决神经胶质母细胞瘤(GBM)治疗中受体杂乱和血脑屏障(BBB)通透性差的问题，基于多肽-药物偶联策略，开发了一种新型的双功能纳米复合给药系统。本研究设计并筛选出与其亲和力最强的SynB3-PVGLIG-PTX，并经基质金属蛋白酶-2(MMP-2)筛选。将MMP-2敏感多肽(PVGLIG)和细胞穿透肽(SynB3)结合形成双功能多肽。此外，SynB3-PVGLIG-PTX作为一种药物-多肽纳米复合物，具有很高的形成聚集体的潜力，具有良好的溶解性，可以通过切割MMP-2来释放紫杉醇(PTX)。从功能的角度来看，SynB3-PVGLIG-PTX在有MMP-2存在的情况下，可以特异性地抑制体外培养的GBM细胞的增殖、迁移和侵袭，而在MMP-2 siRNA转染组中则相反。体内进一步研究表明，与PTX和替莫唑胺相比，SynB3-PVGLIG-PTX容易进入U87 MG裸鼠移植瘤的脑内，并能通过控制释放PTX而对GBM产生更好的抑制作用。因此，由于SynB3-PVGLIG-PTX的特异性和血脑屏障的通透性，可以作为一种新型的载药系统来治疗GBM。