摘要
肿瘤血管生成涉及许多信号通路,这为抑制肿瘤生长和转移提供了潜在的治疗靶点。由于血管内皮生长因子在血管生成和肿瘤发展过程中的重要作用,血管内皮生长因子序列特异性的小分子干扰核糖核酸(siRNA)用于抗血管生成的肿瘤治疗正在发展中。在本文中,通过连接两个受体特异性的多肽(Angiopep 和 tLyP-1)而设计了双重修饰的脂质体(At-Lp),Angiopep 和 tLyP-1分别专门以脑肿瘤靶点的低密度脂蛋白受体(LRP)和肿瘤穿透的神经纤毛蛋白质-1受体(NRP-1)作为靶点。通过体外实验和U87 MG 肿瘤的原位移植瘤模型的实验对At-Lp修饰的血管内皮生长因子siRNA的基因转染、基因沉默和抗肿瘤作用进行了评价。与没有进行修饰和进行了单次修饰的脂质体相比,At-Lp显著增强了细胞摄取(2倍)和血管内皮生长因子在U87 MG胶质母细胞瘤细胞中的下调表达。At-Lp通过增强渗透性、保留效应和受体介导内吞作用内摄入肿瘤细胞,随后,通过一个有效的内涵体逃脱将siRNA负载于细胞质。At-Lp在抑制肿瘤生长、抗血管生成、血管内皮生长因子的表达及在接种了U87 MG胶质母细胞瘤的裸鼠体内运用后并不激活系统毒性和先天免疫反应的细胞凋亡作用方面显示了极好的优越性。这些结果表明联合两种受体特异性的多肽修饰的脂质体在癌症抗血管生成治疗方面的siRNA的有效的靶向传递是一个很有前途的平台。
关键词: Angiopep
Current Gene Therapy
Title:Dual Receptor-Specific Peptides Modified Liposomes as VEGF siRNA Vector for Tumor-Targeting Therapy
Volume: 14 Issue: 4
Author(s): Zhenzhen Yang, Bai Xiang, Dawen Dong, Zhanzhang Wang, Jingquan Li and Xianrong Qi
Affiliation:
关键词: Angiopep
摘要: Tumor angiogenesis involves multiple signaling pathways that provide potential therapeutic targets to inhibit tumor growth and metastasis. Regarding the significant role of vascular endothelial growth factor (VEGF) in angiogenesis and tumor progression, VEGF sequence-specific small interfering RNA (siRNA) for anti-angiogenic tumor therapy are under development. In the present study, dual-modified liposomes (At-Lp) was designed by attaching two receptorspecific peptides, Angiopep and tLyP-1, which specifically targeting low-density lipoprotein receptor (LRP) for brain tumor targeting and neuropilin-1 receptor (NRP-1) for tumor penetration, respectively. Gene transfection and silencing, and antitumor effect of the At-Lp loaded with VEGF siRNA were evaluated in vitro and in orthotopic xenograft models of U87 MG tumor. The At-Lp significantly enhanced cellular uptake (2-fold) and down-regulated expression of VEGF in U87 MG glioblastoma cells compared with non-modified and single-modified liposomes. The internalization of the At-Lp into tumor cells was taken via the enhanced permeability and retention effect and receptor-mediated endocytosis, followed by an effective endosomal escape of loaded siRNA into the cytoplasm. The At-Lp showed great superiority in inhibition of tumor growth, anti-angiogenesis, expression of VEGF and apoptosis effect after in vivo application against nude mice bearing U87 MG glioblastoma without activation of system-associated toxicity and the innate immune response. These results demonstrated that the combination of two receptor-specific peptides-mediated liposomes presented a promising platform for effective targeting delivery of siRNA for cancer anti-angiogenic therapy.
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Yang Zhenzhen, Xiang Bai, Dong Dawen, Wang Zhanzhang, Li Jingquan and Qi Xianrong, Dual Receptor-Specific Peptides Modified Liposomes as VEGF siRNA Vector for Tumor-Targeting Therapy, Current Gene Therapy 2014; 14 (4) . https://dx.doi.org/10.2174/1566523214666140612151726
DOI https://dx.doi.org/10.2174/1566523214666140612151726 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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