Therapeutic targeting of polo-like kinase 1 using RNA-interfering nanoparticles (iNOPs) for the treatment of non-small cell lung cancer
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Joshua A. McCarroll1,2,*, Tanya Dwarte1,*, Huricha Baigude4, Jason Dang4,5, Lu Yang1, Rafael B. Erlich1,2, Kathleen Kimpton1, Joann Teo1,2, Sharon M. Sagnella1,2, Mia C. Akerfeldt1, Jie Liu3, Phoebe A. Phillips2,3, Tariq M. Rana4,5, Maria Kavallaris1,2
1Children’s Cancer Institute, Lowy Cancer Research Centre, Randwick, UNSW Australia (UNSW), NSW, Australia
2ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australian Centre for NanoMedicine, UNSW, NSW, Australia
3Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, UNSW, NSW, Australia
4Program for RNA Biology, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
5Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA, USA
*These authors have contributed equally to this work
Maria Kavallaris, e-mail: [email protected]
Tariq M. Rana, e-mail: [email protected]
Joshua A. McCarroll, e-mail: [email protected]
Keywords: Non-small cell lung cancer, Interfering nanoparticles, Polo-like kinase 1, siRNA, Orthotopic non-small cell lung cancer mouse model
Abbreviations: Non-small cell lung cancer (NSCLC), Interfering nanoparticle-7 (iNOP-7), RNA interference (RNAi), Polo-like kinase 1 (PLK1), Small-interfering RNA (siRNA)
Received: September 22, 2014 Accepted: October 27, 2014 Published: January 06, 2015
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.
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