Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
J Control Release. 2012 Jan 30;157(2):279-86. doi: 10.1016/j.jconrel.2011.08.014. Epub 2011 Aug 17.
EGFR serves as an important therapeutic target because of its over-expression in many cancers. In this study, we investigated a peptide-based therapy aimed at blocking intracellular protein-protein interactions during EGFR signaling and evaluated a targetable lipid carrier system that can deliver peptides to intracellular targets in human cancer cells. EEEEpYFELV (EV), a nonapeptide mimicking the Y845 site of EGFR which is responsible for STAT5b phosphorylation, was designed to block EGFR downstream signaling. EV was loaded onto LPH nanoparticles that are comprised of a membrane/core structure including a surface-grafted polyethylene glycol (PEG) used to evade the reticuloendothelial system (RES) and anisamide (AA) for targeting the sigma receptor over-expressed in H460 human lung cancer cells. EV formulated with PEGylated and targeted LPH (LPH-PEG-AA) was taken up by the tumor cells and trafficked to the cytoplasm with high efficiency. Using this approach, EV acted as a dominant negative inhibitor of STAT5b phosphorylation, arrested cell proliferation, and induced massive apoptosis. Intravenous administration of EV loaded in LPH-PEG-AA led to efficient EV peptide delivery to the tumor in a xenograft mouse model, and multiple injections inhibited tumor growth in a dose-dependent manner. Our findings offer proof-of-concept for an intracellular peptide-mediated cancer therapy that is delivered by carefully designed nanoparticles.
表皮生长因子受体（EGFR）在许多癌症中过度表达，因此成为重要的治疗靶点。在这项研究中，我们研究了一种针对 EGFR 信号传导过程中阻断细胞内蛋白-蛋白相互作用的基于肽的治疗方法，并评估了一种能够将肽递送至人癌细胞内靶标的靶向脂质载体系统。EEEEpYFELV（EV）是一种模拟 EGFR 中负责 STAT5b 磷酸化的 Y845 位点的九肽，旨在阻断 EGFR 下游信号转导。EV 被装载到 LPH 纳米颗粒上，该纳米颗粒由膜/核结构组成，包括表面接枝的聚乙二醇（PEG），用于逃避网状内皮系统（RES）和蒽酰胺（AA），用于靶向在 H460 人肺癌细胞中过度表达的 sigma 受体。用 PEG 化和靶向 LPH（LPH-PEG-AA）配制的 EV 被肿瘤细胞摄取，并高效地转运到细胞质中。通过这种方法，EV 作为 STAT5b 磷酸化的显性负抑制剂发挥作用，阻止细胞增殖并诱导大量细胞凋亡。在异种移植小鼠模型中，静脉内给予 LPH-PEG-AA 负载的 EV 可有效将 EV 肽递送至肿瘤，并且多次注射以剂量依赖性方式抑制肿瘤生长。我们的研究结果为精心设计的纳米颗粒介导的细胞内肽癌症治疗提供了概念验证。
