Targeting the urokinase plasminogen activator receptor with synthetic self-assembly nanoparticles.
Targeting the urokinase plasminogen activator receptor with synthetic self-assembly nanoparticles.
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DOI：
10.1021/bc8001908
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发表时间：
2009
影响因子：
4.7
通讯作者：
Ming Wang;D. Löwik;Andrew D. Miller;M. Thanou
中科院分区：
文献类型：
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作者：
Ming Wang;D. Löwik;Andrew D. Miller;M. Thanou
针对特定受体在癌症治疗的药物输送和基因治疗领域引起了越来越多的兴趣。尿激酶纤溶酶原激活剂受体（uPAR）在许多肿瘤中过度表达，特别是前列腺癌和乳腺癌。本研究的目的是设计、制备和表征一种合成的自组装纳米颗粒，该纳米颗粒在颗粒表面以一定的构象和摩尔比呈现靶向配体。在这里，我们描述了一种新型uPAR靶向配体的合成，该配体由名为U11肽的11个氨基酸序列组成，经烷基链修饰形成U11肽-脂质两亲物。通过后修饰将这种肽-脂质插入到亲本隐形脂质体的外层中，以获得U11肽靶向纳米颗粒。我们证明，当肽部分插入脂质体膜时，它们会分离成更单一的构象，使它们具有足够的生物活性，以观察特定受体介导的内吞作用（RME）以及将质粒DNA递送至uPAR阳性细胞（DU145细胞）。与表面具有乱序肽序列的纳米颗粒实现的转染相比，DU145 细胞的 U11 肽靶向纳米颗粒转染本质上要高 10 倍。U11 肽靶向纳米颗粒也被证明具有 uPAR 特异性，因为它们没有提高 uPAR 阴性细胞系 HEK293 上的转染水平。
Targeting specific receptors is attracting growing interest in the fields of drug delivery and gene therapy for cancer treatment. The urokinase plasminogen activator receptor (uPAR) is overexpressed on many tumors,particularly that of prostate and breast cancers. The aim of this study is to design, prepare, and characterize a synthetic self-assembled nanoparticle that presents targeting ligands at a certain conformation and molar ratio onthe surface of the particles. Here, we describe the synthesis of a novel uPAR targeting ligand consisting of an 11-amino-acid sequence named U11 peptide modified with an alkyl chain to form an U11 peptide-lipid amphiphile.This peptide-lipid is inserted into the outer layer of a parent stealth liposome by post-modification to derive a U11 peptide-targeted nanoparticle. We demonstrate that the peptide moieties become separated into more singular conformations as they are inserted into a liposome membrane, rendering them to be sufficiently biologically active to observe specific receptor-mediated endocytosis (RME) and delivery of plasmid DNA to uPAR positive cells (DU145 cells). The U11 peptide targeted nanoparticle transfection of DU145 cells is essentially 10-fold higher compared to transfection achieved by nanoparticles having a scrambled peptide sequence on their surface.U11 peptide targeted nanoparticles also proved to be uPAR-specific, as they did not improve transfection levels on the uPAR-negative cell line, HEK293.