Therapeutic targeting of polo-like kinase 1 using RNA-interfering nanoparticles (iNOPs) for the treatment of non-small cell lung cancer

Oncotarget. 2015 May 20;6(14):12020-34. doi: 10.18632/oncotarget.2664.

Abstract

Non-small cell lung cancer (NSCLC) remains the most common cause of cancer death worldwide due its resistance to chemotherapy and aggressive tumor growth. Polo-like kinase 1 (PLK1) is a serine-threonine protein kinase which is overexpressed in cancer cells, and plays a major role in regulating tumor growth. A number of PLK1 inhibitors are in clinical trial; however, poor tumor bioavailability and off-target effects limit their efficacy. Short-interfering-RNA (siRNA) holds promise as a class of therapeutics, which can selectively silence disease-causing genes. However, siRNA cannot enter cells without a delivery vehicle. Herein, we investigated whether RNAi-interfering nanoparticles could deliver siRNA to NSCLC cells and silence PLK1 expression in vitro and in vivo. iNOP-7 was non-toxic, and delivered siRNA with high efficiency to NSCLC cells. iNOP-7-PLK1 siRNA silenced PLK1 expression and reduced NSCLC growth in vitro. Notably, iNOP-7 delivered siRNA to orthotopic lung tumors in mice, and administration of iNOP-7-PLK1 siRNA reduced lung tumor burden. These novel data show that iNOP-7 can deliver siRNA against PLK1 to NSCLC cells, and decrease cell proliferation both in vitro and in vivo. iNOP-7-PLK1 siRNA may provide a novel therapeutic strategy for the treatment of NSCLC as well as other cancers which aberrantly express this gene.

Keywords: Polo-like kinase 1; interfering nanoparticles; non-small cell lung cancer; orthotopic non-small cell lung cancer mouse model; siRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / therapy*
  • Cell Cycle Proteins / genetics*
  • Cell Proliferation
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / therapy*
  • Mice
  • Nanoparticles
  • Protein-Serine-Threonine Kinases / genetics*
  • Proto-Oncogene Proteins / genetics*
  • RNA Interference / immunology*
  • RNA, Small Interfering / genetics*
  • Transfection

Substances

  • Cell Cycle Proteins
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1