PLK1 and EGFR targeted nanoparticle as a radiation sensitizer for non-small cell lung cancer

Cancer Lett. 2019 Dec 28:467:9-18. doi: 10.1016/j.canlet.2019.09.014. Epub 2019 Sep 26.

Abstract

Radiation sensitizers that can selectively act on cancer cells hold great promise to patients who receive radiation therapy. We developed a novel targeted therapy and radiation sensitizer for non-small cell lung cancer (NSCLC) based on cetuximab conjugated nanoparticle that targets epidermal growth factor receptor (EGFR) and delivers small interfering RNA (siRNA) against polo-like kinase 1 (PLK1). EGFR is overexpressed in 50% of lung cancer patients and a mediator of DNA repair, while PLK1 is a key mitotic regulator whose inhibition enhances radiation sensitivity. The nanoparticle construct (C-siPLK1-NP) effectively targets EGFR + NSCLC cells and reduces PLK1 expression, leading to G2/M arrest and cell death. Furthermore, we show a synergistic combination between C-siPLK1-NP and radiation, which was confirmed in vivo in A549 flank tumors. We also demonstrate the translational potential of C-siPLK1-NP as a systemic therapeutic in an orthotopic lung tumor model, where administration of C-siPLK1-NP reduced tumor growth and led to prolonged survival. Our findings demonstrate that C-siPLK1-NP is effective as a targeted therapy and as a potent radiation sensitizer for NSCLC. Potential application to other EGFR + cancer types such as colorectal and breast cancer is also demonstrated.

Keywords: Epidermal growth factor receptor; Mesoporous silica; Polo-like kinase; Radiosensitizer; Small interfering RNA (siRNA).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • A549 Cells
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / therapy*
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cetuximab / administration & dosage*
  • Cetuximab / pharmacology
  • ErbB Receptors / antagonists & inhibitors
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / therapy*
  • Male
  • Molecular Targeted Therapy
  • Nanoparticles
  • Polo-Like Kinase 1
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • RNA, Small Interfering / administration & dosage*
  • RNA, Small Interfering / pharmacology
  • Radiation-Sensitizing Agents / administration & dosage*
  • Radiation-Sensitizing Agents / pharmacology
  • Treatment Outcome
  • Xenograft Model Antitumor Assays

Substances

  • Cell Cycle Proteins
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Radiation-Sensitizing Agents
  • EGFR protein, human
  • ErbB Receptors
  • Protein Serine-Threonine Kinases
  • Cetuximab