Multi-targeting Peptide-Functionalized Nanoparticles Recognized Vasculogenic Mimicry, Tumor Neovasculature, and Glioma Cells for Enhanced Anti-glioma Therapy
Multi-targeting Peptide-Functionalized Nanoparticles Recognized Vasculogenic Mimicry, Tumor Neovasculature, and Glioma Cells for Enhanced Anti-glioma Therapy
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多靶向肽功能化纳米颗粒可识别血管生成拟态、肿瘤新生血管和神经胶质瘤细胞，用于增强抗神经胶质瘤治疗
DOI：
10.1021/acsami.5b09934
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发表时间：
2015-12-23
影响因子：
9.5
通讯作者：
Chen, Jun
中科院分区：
文献类型：
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作者：
Feng, Xingye;Yao, Jianhui;Chen, Jun
胶质瘤是最具侵袭性和破坏性的肿瘤，其化疗失败可能是由于肿瘤的生理屏障，主要包括肿瘤灌注不均和血管通透性，导致化疗药物的渗透有限。此外，血管生成模拟（VM）通道对抗血管生成治疗具有高度抗性，是血管生成的补充，在胶质瘤中大量存在，并且总是与肿瘤复发有关。为了提高抗胶质瘤的治疗效果，本研究开发了一种基于peg - pla的纳米药物递送系统（纳米颗粒，NP），并用CK肽修饰其表面，该肽由人类超音hedgehog基因（SETH）靶向肽（CVNHPAFAC）和KDR靶向肽（K237）组成，通过GYG连接体，促进了VM通道、肿瘤新生血管和胶质瘤细胞的高效多靶向递送。体外细胞实验表明，CK-NP-PTX不仅对U87MG细胞和HUVEC细胞具有最强的抗增殖作用，而且与CVNHPAFAC-NP、K237-NP和未修饰的CVNHPAFAC-NP相比，CK-NP-PTX对VM通道的破坏效果最好。此外，体内和离体成像显示，CK-NP在胶质瘤部位的积累更具选择性。正如预期的那样，与CVNHPAFAC-NP-PTX和K237-NP-PTX治疗的小鼠相比，CK-NP-PTX治疗的胶质瘤小鼠的中位生存时间最长。这些发现提示，以CK肽为媒介的多靶点治疗可能为胶质母细胞瘤的治疗提供一条有希望的途径。
Chemotherapy failure of glioma, the most aggressive and devastating cancer, might be ascribed to the physiologic barriers of the tumor mainly including heterogeneous tumor perfusion and vascular permeability, which result in a limited penetration of chemotherapeutics. Besides, the vasculogenic mimicry (VM) channels, which are highly resistant to anti-angiogenic therapy and serve as a complement of angiogenesis, were abound in glioma and always associated with tumor recurrence. In order to enhance the therapy effect of anti-glioma, we developed a PEG-PLA-based nanodrug delivery system (nanoparticles, NP) in this study and modified its surface with CK peptide, which was composed of a human sonic hedgehog (SETH) targeting peptide (CVNHPAFAC) and a KDR targeting peptide (K237) through a GYG linker, for facilitating efficient VM channels, tumor neovasculature, and glioma cells multi-targeting delivery of paclitaxel. In vitro cellular assay showed that CK-NP-PTX not only exhibited the strongest antiproliferation effect on U87MG cells and HUVEC cells but also resulted in the most efficient destruction of VM channels when compared with CVNHPAFAC-NP, K237-NP, and the unmodified ones. Besides, CK-NP accumulated more selectively at the glioma site as demonstrated by in vivo and ex vivo imaging. As expected, the glioma-bearing mice treated with CK-NP-PTX achieved the longest median survival time compared to those treated with CVNHPAFAC-NP-PTX and K237-NP-PTX. These findings indicated that the multi-targeting therapy mediated by CK peptide might provide a promising way for glioblastoma therapy.