Peptide-conjugated biodegradable nanoparticles as a carrier to target paclitaxel to tumor neovasculature
Peptide-conjugated biodegradable nanoparticles as a carrier to target paclitaxel to tumor neovasculature
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肽缀合的可生物降解纳米颗粒作为载体将紫杉醇靶向肿瘤新血管系统
DOI：
10.1016/j.biomaterials.2009.11.047
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发表时间：
2010-03-01
期刊：
影响因子：
14
通讯作者：
Chen, Hong-Zhuan
中科院分区：
文献类型：
--
作者：
Yu, De-Hong;Lu, Qin;Chen, Hong-Zhuan
抗血管生成癌症治疗可以通过将抗血管生成药物靶向递送至肿瘤新血管系统的内皮细胞来实现。在本研究中，我们开发了一种药物递送系统（DIDS），即与 K237-(HTMYYHHYQHHL) 肽缀合的纳米颗粒，用于肿瘤新血管系统靶向药物递送。紫杉醇是一种具有有效抗血管生成活性的化疗药物，被用作原型药物。我们通过开环聚合合成了醛聚乙二醇-聚丙交酯（醛-PEG-PLA）嵌段共聚物。使用 O/W 乳液和蒸发技术制备负载紫杉醇的纳米颗粒 (PTX-NP)。 K237配体是一种肽，能够以高亲和力和特异性与肿瘤新生血管内皮细胞表面主要表达的KDR受体结合，并抑制VEGF-KDR血管生成信号通路，利用N端聚乙二醇化技术将K237配体与PEG链的醛基缀合。 K237缀合紫杉醇负载纳米颗粒(K237-PTX-NP)的流体动力学直径为150 nm。纳米粒子表面上的K237密度为474，与K237肽连接的两个相邻PEG链之间的平均距离为12nm。 K237 缀合的纳米颗粒可以通过 K237-KDR 相互作用被人脐静脉内皮细胞 (HUVEC) 显着内化，与用商业制剂紫杉醇 (R) 和 PTX-NP 处理的细胞相比，这种促进的摄取导致 HUVEC 增殖、迁移和管形成显示出预期的抗血管生成活性增强。 K237-PTX-NP的长循环特性和K237配体保证了快速、长期、准确的体内肿瘤新生血管靶向，随后植入雌性BLAB/c裸鼠的MDA-MB-231乳腺肿瘤中肿瘤新生血管内皮细胞显着凋亡和肿瘤组织坏死。这种纳米颗粒DDS为紫杉醇化疗应用提供了新的策略，它还可以用于携带其他具有抗血管生成活性的化疗药物、基因和蛋白质，用于抗血管生成癌症治疗。 (C) 2009 Elsevier Ltd. 保留所有权利。
Antiangiogenic cancer therapy can be achieved through the targeted delivery of antiangiogenic agents to the endothelial cells of tumor neovasculature. In the present study, we developed a drug delivery system (DIDS), nanoparticles conjugated with K237-(HTMYYHHYQHHL) peptides for tumor neovasculature targeting drug delivery. Paclitaxel, a chemotherapeutic agent with potent antiangiogenic activity, was used as a prototype drug. We synthesized the aldehyde poly(ethylene glycol)-poly(lactide) (aldehyde-PEG-PLA) block copolymer by ring opening polymerization. The nanoparticles loading paclitaxel (PTX-NP) were fabricated using the O/W emulsion and evaporation technique. K237 ligand, a peptide that can bind to the KDR receptors predominantly expressed on the surface of tumor neovasculature endothelial cells with high affinity and specificity and inhibit the VEGF-KDR angiogenic signal pathway, was conjugated to the aldehyde group of PEG chain using the N-terminal PEGylation technique. The K237 conjugated paclitaxel-loaded nanoparticles (K237-PTX-NP) had a hydrodynamic diameter of 150 nm. The K237 density on nanoparticle surface was 474 and the mean distance between two neighboring PEG chains linked to K237 peptide was 12 nm. The K237 conjugated nanoparticles could be significantly internalized by human umbilical vein endothelial cells (HUVEC) through the K237-KDR interaction, and this facilitated uptake led to the expected enhanced antiangiogenic activity shown by HUVEC proliferation, migration and tube formation compared to cells treated with the commercial formulation Taxol (R) and PTX-NP. The long-circulating property and the K237 ligand of K237-PTX-NP warranted rapid, long-term, and accurate in vivo tumor neovasculature targeting, and thereafter the significant apoptosis of tumor neovasculature endothelial cells and necrosis of tumor tissues of MDA-MB-231 breast tumors implanted in female BLAB/c nude mice. This nanoparticulate DDS offers a new strategy for paclitaxel chemotherapy application and it could also be used to carry other chemotherapeutic drugs, genes, and proteins with antiangiogenic activity for antiangiogenic cancer therapy. (C) 2009 Elsevier Ltd. All rights reserved.