Targeted Treatment of Metastatic Breast Cancer by PLK1 siRNA Delivered by an Antioxidant Nanoparticle Platform.
Targeted Treatment of Metastatic Breast Cancer by PLK1 siRNA Delivered by an Antioxidant Nanoparticle Platform.
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DOI：
10.1158/1535-7163.mct-16-0644
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发表时间：
2017-04
影响因子：
5.7
通讯作者：
Yantasee W
中科院分区：
文献类型：
--
作者：
Morry J;Ngamcherdtrakul W;Gu S;Reda M;Castro DJ;Sangvanich T;Gray JW;Yantasee W
尽管进行了治疗，但在新诊断的早期乳腺癌患者中，约20-30%发生转移性乳腺癌。在此，我们报告了一种新的纳米颗粒平台，具有内在的抗转移特性，用于靶向递送Polo样激酶1 siRNA（siPLK 1）。我们首先在三阴性乳腺癌（TNBC）模型中对其进行了评估，该模型显示出高转移潜力。PLK 1在全激酶组筛选中被鉴定为TNBC细胞和肿瘤起始细胞的最佳治疗靶标。该平台由一个50 nm的介孔二氧化硅纳米颗粒（MSNP）核心组成，该核心逐层涂覆有生物可还原的交联PEI和PEG聚合物，与抗体缀合，用于选择性摄取到癌细胞中。最后装载SiRNA，并在PEG层下完全保护其免受血液酶降解。该材料具有净中性电荷和低非特异性细胞毒性。我们还首次表明，MSNP本身由于其ROS和NOX 4调节特性而抑制TNBC细胞中的癌症迁移和侵袭。在体内，siPLK 1-纳米构建体（6个剂量，0.5mg/kg）敲低了小鼠肺中存在的转移性乳腺癌细胞中约80%的人PLK 1 mRNA表达，并降低了实验转移小鼠模型的肺和其他器官中的肿瘤发生率和负荷。长期治疗显著延迟了小鼠死亡的发生，并提高了总体生存率。能够同时抑制癌症进展的增殖和转移标志的平台是独特的，并且具有很大的治疗潜力，也可以靶向TNBC以外的其他转移性癌症。
Metastatic breast cancer is developed in about 20–30% of newly diagnosed early stage breast cancer patients despite treatments. Herein, we report a novel nanoparticle platform with intrinsic anti-metastatic properties for the targeted delivery of Polo-like kinase 1 siRNA (siPLK1). We first evaluated it in a triple negative breast cancer (TNBC) model, which shows high metastatic potential. PLK1 was identified as the top therapeutic target for TNBC cells and tumor initiating cells in a kinome-wide screen. The platform consists of a 50-nm mesoporous silica nanoparticle (MSNP) core coated layer-by-layer with bioreducible cross-linked PEI and PEG polymers, conjugated with an antibody for selective uptake into cancer cells. SiRNA is loaded last and fully protected under the PEG layer from blood enzymatic degradation. The material has net neutral charge and low non-specific cytotoxicity. We have also shown for the first time that the MSNP itself inhibited cancer migration and invasion in TNBC cells owing to its ROS and NOX4 modulating properties. In vivo, siPLK1-nanoconstructs (6 doses of 0.5 mg/kg) knocked down about 80% of human PLK1 mRNA expression in metastatic breast cancer cells residing in mouse lungs, and reduced tumor incidence and burden in lungs and other organs of an experimental metastasis mouse model. Long-term treatment significantly delayed the onset of death in mice and improved the overall survival. The platform capable of simultaneously inhibiting the proliferative and metastatic hallmarks of cancer progression is unique and has great therapeutic potential to also target other metastatic cancers beyond TNBC.