title: Gold nanorod-sphingosine kinase siRNA nanocomplexes: a novel therapeutic tool for potent radiosensitization of head and neck cancer.
abstract: Radiation therapy (RT) is an important treatment modality used against a number of human cancers, including head and neck squamous cell carcinoma (HNSCC). However, most of these cancers have an inherent anti-apoptotic mechanism that makes them resistant to radiation therapy. This radioresistance of cancer cells necessitates the irradiation of tumor areas with extremely high doses of radiation to achieve effective therapy, resulting in damage to normal tissues and leading to several treatment related side effects. These side effects significantly impair the quality of life of treated patients, and preclude the possibility of repeat radiation treatment in patients with tumor recurrence. Our previous research has correlated the upregulation of the anti-apoptotic sphingosine kinase (SphK1) gene in HNSCC cells with their radioresistance properties. In the current study, we hypothesized that by downregulating the SphK1 gene using nanotechnology mediated gene silencing, we can render these cells more vulnerable to radiation therapy by enabling apoptosis at lower radiation doses. We have employed biocompatible gold nanorods (GNRs) as carriers of short interfering RNA (siRNA) targeting the SphK1 gene. GNRs play a critical role in protecting the siRNA molecules against physiological degradation, as well as delivering them inside target cells. Following their synthesis and characterization, these nanoplexes were applied to HNSCC cells in culture, resulting in the radiosensitization of the treated cells. Furthermore, the GNR-siRNA nanoplexes were injected intratumorally into subcutaneous HNSCC tumors grown in mice, prior to the initiation of radiation therapy in vivo. Subsequent exposure of GNR-SphK1siRNA nanoplex-treated tumors to radiation (GNR-SphK1siRNA + IRRA) resulted in over 50% tumor regression compared to control GNR-GFPsiRNA nanoplex and radiation treated tumors (GNR-GFPsiRNA + IRRA). In addition, we were able to induce this tumor regression in nanoplex treated tumors with radiation doses much lower than those commonly required in clinical RT. These experiments lay the foundation for the development of a nanotechnology-mediated gene silencing tool for more potent radiation therapy of a number of human cancers, with minimal, if any, toxic side effects.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA. masood@usc.edu
authors.forename: Rizwan
authors.initials: R
authors.lastname: Masood
authors.forename: Indrajit
authors.initials: I
authors.lastname: Roy
authors.forename: Sutao
authors.initials: S
authors.lastname: Zu
authors.forename: Christian
authors.initials: C
authors.lastname: Hochstim
authors.forename: Ken-Tye
authors.initials: KT
authors.lastname: Yong
authors.forename: Wing-Cheung
authors.initials: WC
authors.lastname: Law
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
authors.forename: Uttam K
authors.initials: UK
authors.lastname: Sinha
authors.forename: Paras N
authors.initials: PN
authors.lastname: Prasad
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics / Q000532:radiotherapy*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006046:Gold / Q000494:pharmacology*; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000235:genetics / Q000532:radiotherapy*; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D043942:Nanotubes; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D000099157:Sphingosine Kinase
chemical_list: D006046:Gold; D017853:Phosphotransferases (Alcohol Group Acceptor); D034741:RNA, Small Interfering; D011838:Radiation-Sensitizing Agents; D000099157:Sphingosine Kinase