Selective eradication of tumor vascular pericytes by peptide-conjugated nanoparticles for antiangiogenic therapy of melanoma lung metastasis
Selective eradication of tumor vascular pericytes by peptide-conjugated nanoparticles for antiangiogenic therapy of melanoma lung metastasis
复制标题
通过肽缀合纳米颗粒选择性根除肿瘤血管周细胞，用于黑色素瘤肺转移的抗血管生成治疗
DOI：
10.1016/j.biomaterials.2013.12.027
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发表时间：
2014-03-01
期刊：
影响因子：
14
通讯作者：
Fang, Chao
中科院分区：
文献类型：
--
作者：
Guan, Ying-Yun;Luan, Xin;Fang, Chao
基于纳米颗粒给药系统（nano-DDS）的抗肿瘤血管生成治疗是近年来发展起来的一种新型抗肿瘤药物。目前的纳米DDS仅限于靶向肿瘤血管内皮细胞，但很少有人致力于靶向肿瘤血管周细胞，这也积极参与肿瘤血管生成。本研究以肿瘤血管周细胞高表达的NG 2蛋白多糖为靶点，构建了一种新型纳米紫杉醇纳米粒（TH 10-DTX-NP），用于B16 F10-luc-G5黑色素瘤实验性肺转移的治疗研究。结果表明，TH 10-DTX-NP在PBS及大鼠血浆与PBS（1：1，v/v）混合液中均实现了药物的控释，并具有良好的体内长循环特性。TH 10肽缀合通过TH 10和NG 2受体之间的相互作用促进纳米颗粒在周细胞中的内化，导致对周细胞活力和迁移的更多抑制。TH 10结合的纳米颗粒可以准确地靶向B16 F10-luc-G5肺转移瘤的血管周细胞，其中DTX诱导了明显的周细胞凋亡。TH 10-DTX-NP能显著延长小鼠的生存期，且无明显毒性，其增强的抗肿瘤作用与降低肺转移灶周细胞密度和微血管密度密切相关。本研究揭示了纳米DDS靶向肿瘤血管周细胞在抗肿瘤血管生成治疗中的潜力和意义。(C)2013爱思唯尔有限公司保留所有权利。
Antiangiogenic cancer therapy based on nanoparticulate drug delivery systems (nano-DDS) is emerging as a promising new approach besides the proved molecular-targeted antiangiogenic agents. The current nano-DDS are restricted to the targeting to tumor vascular endothelial cells, but seldom efforts have been made to target the tumor vascular pericytes which are also actively involved in tumor angiogenesis. In this study, we developed a new nano-DDS, TH10 peptide (TAASGVRSMH) conjugated nanoparticles loading docetaxel (TH10-DTX-NP) that can target the NG2 proteoglycan highly expressed in tumor vascular pericytes, for the investigation of therapeutic efficacy in the mice bearing B16F10-luc-G5 melanoma experimental lung metastasis. The results demonstrated that TH10-DTX-NP achieved controlled drug release in PBS and the mixture of rat plasma and PBS (1:1, v/v), and exhibited favorable in vivo long-circulating feature. TH10 peptide conjugation facilitated the nanoparticle internalization in pericytes via the interaction between TH10 and NG2 receptor, leading to more inhibition of pericyte viability and migration. TH10-conjugated nanoparticles could accurately target the vascular pericytes of B16F10-luc-G5 lung metastasis, where DTX-induced pronounceable pericyte apoptosis. TH10-DTX-NP significantly prolonged the mice survival with no obvious toxicity, and this enhanced antitumor effect was closely related with the decreased pericyte density and microvessel density in the lung metastases. The present research reveals the potency and significance of targeting tumor vascular pericytes using nano-DDS in antiangiogenic cancer therapy. (C) 2013 Elsevier Ltd. All rights reserved.