Enhanced Glioblastoma Targeting Ability of Carfilzomib Enabled by a (D)A7R-Modified Lipid Nanodisk
Enhanced Glioblastoma Targeting Ability of Carfilzomib Enabled by a (D)A7R-Modified Lipid Nanodisk
复制标题
(D)A7R 修饰的脂质纳米盘增强了卡非佐米的胶质母细胞瘤靶向能力
DOI：
10.1021/acs.molpharmaceut.8b00270
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发表时间：
2018
影响因子：
4.9
通讯作者：
Lu Weiyue
中科院分区：
文献类型：
--
作者：
Zhang Mingfei;Lu Linwei;Ying Man;Ruan Huitong;Wang Xiaoyi;Wang Huan;Chai Zhilan;Wang Songli;Zhan Changyou;Pan Jun;Lu Weiyue
肿瘤的稳健增殖依赖于丰富的新生血管系统的营养供应。因此，肿瘤靶向治疗的基本策略不仅包括杀死常规癌细胞，还应包括阻断肿瘤新生血管。D肽DA 7 R可与血管内皮生长因子受体2（VEGFR 2）和神经纤毛蛋白1（NRP-1）特异性结合，实现多靶点识别。因此，本研究的主要目的是构建一种多功能肽DA 7 R修饰的卡非佐米脂质纳米片（DA 7 R-ND/CFZ），并评价其体内外抗胶质母细胞瘤的疗效。结果表明，DA 7 R肽结合脂质纳米盘能被U87 MG细胞和HUVECs特异性摄取。此外，DA 7 R-ND在体外肿瘤球体模型上表现出比未修饰的制剂更强的渗透性，并且在皮下和颅内荷瘤裸鼠模型上表现出更多的体内肿瘤区域蓄积。当负载蛋白酶体抑制剂卡非佐米时，DA 7 R修饰的纳米盘在体外和体内均能显著抑制肿瘤增殖，延长荷颅内肿瘤裸鼠的生存时间，并抑制新生血管形成，其效力高于未修饰的纳米盘。本研究证实了七肽DA 7 R偶联纳米盘是一种很有前途的胶质母细胞瘤靶向治疗纳米载体。
The robust proliferation of tumors relies on a rich neovasculature for nutrient supplies. Therefore, a basic strategy of tumor targeting therapy should include not only killing regular cancer cells but also blocking tumor neovasculature. D-peptideDA7R, which was previously reported to specifically bind vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1), could achieve the goal of multitarget recognition. Accordingly, the main purposes of this work were to establish a carfilzomib-loaded lipid nanodisk modified with multifunctional peptideDA7R (DA7R-ND/CFZ) and to evaluate its anti-glioblastoma efficacy in vitro and in vivo. It is testified that theDA7R peptide-conjugated lipid nanodisk can be specifically taken up by U87MG cells and HUVECs. Furthermore,DA7R-ND demonstrated a more enhanced penetration than that of the nonmodified formulation on the tumor spheroid model in vitro and more tumor region accumulation in vivo on the subcutaneous and intracranial tumor-bearing nude mice model.DA7R-ND was shown to co-localize with tumor neovasculature in vivo. When loaded with proteasome inhibitor carfilzomib, theDA7R-decorated nanodisk could remarkably suppress tumor proliferation, extend survival time of nude mice bearing an intracranial tumor, and inhibit neovasculature formation with an efficacy higher than that of the nonmodified nanodisk in vitro and in vivo. The present study verified that the heptapeptideDA7R-conjugated nanodisk is a promising nanocarrier for glioblastoma targeting therapy.