Targeted Treatment of Metastatic Breast Cancer by PLK1 siRNA Delivered by an Antioxidant Nanoparticle Platform

Abstract

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.

The Emerging Role of Polo-Like Kinase 1 in Epithelial-Mesenchymal Transition and Tumor Metastasis

“…In addition, PLK1 inhibition could potentially be a promising strategy to prevent prostate cancer dissemination. Consistent with this notion, a recent study reported that PLK1 depletion, mediated by PLK1 siRNA delivered by an antioxidant nanoparticle platform, inhibits lung metastasis and prolongs overall survival in a mouse model of breast cancer metastasis [ 118 ]. PLK1 inhibition by a small molecule inhibitor hindered brain metastases and prolonged survival in a mouse model of breast cancer brain metastasis [ 119 ].…”

Cytoplasmic M‑CSF facilitates apoptosis resistance by inhibiting the HIF‑1α/BNIP3/Bax signalling pathway in MCF‑7 cells

“…Globally, breast cancer accounted for the highest number of new cancer cases in 2015 (22). Nearly 30% of newly diagnosed patients with early stage breast cancer develop a distant metastasis despite receiving therapy (23). Current therapy options for breast cancer include surgery, hormonal therapy, immunotherapy, chemotherapy, radiation therapy, or a combination of these treatments (24).…”

Rekindling RNAi Therapy: Materials Design Requirements for In Vivo siRNA Delivery

“…Monoclonal antibodies are those generated from a single cell lineage that bind to a single epitope on their target (as opposed to polyclonal antibodies that are generated by a range of B cells that bind to multiple epitopes on their target). The most commonly used mAb for targeted delivery of siRNA is Trastuzumab, an IgG1 mAb against human epidermal growth factor 2 (HER2) for selective targeting of breast cancer . Another common antibody, useful for targeting the wider epidermal growth factor receptor (EGFR) family is Cetuximab .…”