IF7-Conjugated Nanoparticles Target Annexin 1 of Tumor Vasculature against P-gp Mediated Multidrug Resistance
IF7-Conjugated Nanoparticles Target Annexin 1 of Tumor Vasculature against P-gp Mediated Multidrug Resistance
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IF7 缀合纳米颗粒靶向肿瘤脉管系统的膜联蛋白 1，对抗 P-gp 介导的多药耐药性
DOI：
10.1021/acs.bioconjchem.5b00283
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发表时间：
2015-08-01
影响因子：
4.7
通讯作者：
Chen, Hong-Zhuan
中科院分区：
文献类型：
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作者：
Yu, De-Hong;Liu, Ya-Rong;Chen, Hong-Zhuan
多药耐药是临床化疗失败的主要原因。利用纳米药物进行抗血管生成癌症治疗，可以将抗血管生成药物靶向递送至肿瘤内皮细胞，这可能有助于治疗多药耐药癌症的创新策略。在这项研究中，我们开发了一种新的纳米给药系统（nano-DDS），提高了对多药耐药人乳腺癌MCF-7/ADR细胞的抗血管生成功效。在此，IF 7配体是被设计为以高亲和力和特异性结合膜联蛋白1（Anxa 1）的肽，膜联蛋白1是肿瘤脉管系统表面的高度特异性标志物。含有紫杉醇的IF 7缀合的Anxa 1靶向纳米颗粒（IF 7-PTX-NP）允许受控的药物释放，并在体内显示出有利的延长循环。IF 7-PTX-NP通过IF 7-Anxa 1相互作用被人脐静脉内皮细胞（HUVEC）显著内化，并且相对于Taxol和PTX-NP，这促进了摄取增强了抑制HUVEC增殖、迁移和在基质胶塞中管形成的预期抗血管生成活性。随着IF 7-PTX-NP靶向肿瘤血管，更多的纳米颗粒在MCF-7/ADR肿瘤中积累，更重要的是，诱导肿瘤血管内皮细胞的显著凋亡和肿瘤组织的坏死。配制在IF 7-PTX-NP中的低剂量紫杉醇（lmg/kg）显示出显著的抗癌功效，延迟MCF-7/ADR肿瘤的生长。仅使用8倍剂量的紫杉醇（8 mg/kg）作为Taxol + XR 9576（一种强效P-gp抑制剂）获得相同的疗效。IF 7-PTX-NP的抗癌功效与改善的抗血管生成作用强烈相关，这明显表现为肿瘤微血管密度的显著降低和凋亡肿瘤细胞的显著增加，对小鼠没有明显的毒性。这种靶向肿瘤新生血管的纳米DDS为治疗多药耐药癌症提供了一种有前途的策略。
Multidrug resistance is the main cause of clinical chemotherapeutic failure. Antiangiogenic cancer therapy with nanomedicine that allows the targeted delivery of antiangiogenic agents to tumor endothelial cells may contribute to innovative strategies for treating multidrug-resistant cancers. In this study, we developed a new nanodrug delivery system (nano-DDS), with improved antiangiogenic efficacy against multidrug resistant human breast cancer MCF-7/ADR cells. Here, the IF7 ligand was a peptide designed to bind the annexin 1 (Anxa 1), a highly specific marker of the tumor vasculature surface, with high affinity and specificity. IF7-conjugated Anxa 1-targeting nanoparticles containing paclitaxel (IF7-PTX-NP) allowed controlled drug release and displayed favorable prolonged circulation in vivo. IF7-PTX-NP was significantly internalized by human umbilical vein endothelial cells (HUVEC) through the IF7-Anxa 1 interaction, and this facilitated uptake enhanced the expected antiangiogenic activity of inhibiting HUVEC proliferation, migration, and tube formation in a Matrigel plug relative to those of Taxol and PTX-NP. As IF7-PTX-NP targeted the tumor vessels, more nanopartides accumulated in MCF-7/ADR tumors, and more importantly, induced significant apoptosis of the tumor vascular endothelial cells and necrosis of the tumor tissues. Low dose paclitaxel (1 mg/kg) formulated in IF7-PTX-NP showed significant anticancer efficacy, delaying the growth of MCF-7/ADR tumors. The same efficacy was only obtained with an 8-fold dose of paclitaxel (8 mg/kg) as Taxol plus XR9576, a potent P-gp inhibitor. The anticancer efficacy of IF7-PTX-NP was strongly associated with the improved antiangiogenic effect, evident as a dramatic reduction in the tumor microvessel density and pronounced increase in apoptotic tumor cells, with no obvious toxicity to the mice. This nano-DDS, which targets the tumor neovasculature, offers a promising strategy for the treatment of multidrug-resistant cancer.