Enhanced Human Epidermal Growth Factor Receptor 2 Degradation in Breast Cancer Cells by Lysosome-Targeting Gold Nanoconstructs.
Enhanced Human Epidermal Growth Factor Receptor 2 Degradation in Breast Cancer Cells by Lysosome-Targeting Gold Nanoconstructs.
复制标题
通过针对溶酶体靶向的金纳米结构来增强人类表皮生长因子受体2在乳腺癌细胞中的降解。
DOI：
10.1021/acsnano.5b05138
复制
发表时间：
2015-10-27
期刊：
影响因子：
17.1
通讯作者：
Odom TW
中科院分区：
文献类型：
--
作者：
Lee H;Dam DH;Ha JW;Yue J;Odom TW
本文描述了金纳米颗粒纳米结构如何增强乳腺癌细胞中溶酶体靶向适体的抗癌作用。由密集接枝在金纳米星（AuNS）上的抗HER 2适体（人表皮生长因子受体2，HApt）组成的纳米构建体首先靶向HER 2，然后通过HER 2介导的内吞作用内化。随着孵育时间的增加，纳米构建体复合物被发现在囊泡结构中，从早期内体开始到溶酶体，如通过共聚焦荧光和微分干涉对比显微镜观察到的。在靶细胞器溶酶体内，HER 2在低pH下被酶降解，导致细胞凋亡。在与癌细胞倍增时间相关的特定时间点，我们发现HER 2-HApt-AuNS复合物在溶酶体中的积累、溶酶体活性和HER 2的溶酶体降解呈正相关。HApt-AuNS增加的HER 2降解触发细胞死亡和细胞周期停滞在G 0/G1期，抑制细胞增殖。这项工作显示了如何感知的纳米粒子为基础的治疗的缺点-纳米结构无法从囊泡中逃逸，从而诱导生物反应-可以克服靶向溶酶体和利用溶酶体降解的生物标志物。
This paper describes how gold nanoparticle nanoconstructs can enhance anti-cancer effects of lysosomal targeting aptamers in breast cancer cells. Nanoconstructs consisting of anti-HER2 aptamer (human epidermal growth factor receptor 2, HApt) densely grafted on gold nanostars (AuNS) first targeted HER2 and then were internalized via HER2-mediated endocytosis. As incubation time increased, the nanoconstruct complexes were found in vesicular structures, starting from early endosomes to lysosomes as visualized by confocal fluorescence and differential interference contrast microscopy. Within the target organelle, lysosomes, HER2 was degraded by enzymes at low pH, which resulted in apoptosis. At specific time points related to the doubling time of the cancer cells, we found that accumulation of HER2-HApt-AuNS complexes in lysosomes, lysosomal activity, and lysosomal degradation of HER2 were positively correlated. Increased HER2 degradation by HApt-AuNS triggered cell death and cell cycle arrest in the G0/G1 phase inhibition of cell proliferation. This work shows how a perceived disadvantage of nanoparticle-based therapeutics—the inability of nanoconstructs to escape from vesicles and thus induce a biological response—can be overcome by both targeting lysosomes and exploiting lysosomal degradation of the biomarkers.