title: Combination of Gold Nanoparticle-Conjugated Tumor Necrosis Factor-α and Radiation Therapy Results in a Synergistic Antitumor Response in Murine Carcinoma Models.
abstract: OBJECTIVE
  Although remarkable preclinical antitumor effects have been shown for tumor necrosis factor-α (TNF) alone and combined with radiation, its clinical use has been hindered by systemic dose-limiting toxicities. We investigated the physiological and antitumor effects of radiation therapy combined with the novel nanomedicine CYT-6091, a 27-nm average-diameter polyethylene glycol-TNF-coated gold nanoparticle, which recently passed through phase 1 trials.
  
  
  METHODS
  The physiologic and antitumor effects of single and fractionated radiation combined with CYT-6091 were studied in the murine 4T1 breast carcinoma and SCCVII head and neck tumor squamous cell carcinoma models.
  
  
  RESULTS
  In the 4T1 murine breast tumor model, we observed a significant reduction in the tumor interstitial fluid pressure (IFP) 24 hours after CYT-6091 alone and combined with a radiation dose of 12 Gy (P<.05 vs control). In contrast, radiation alone (12 Gy) had a negligible effect on the IFP. In the SCCVII head and neck tumor model, the baseline IFP was not markedly elevated, and little additional change occurred in the IFP after single-dose radiation or combined therapy (P>.05 vs control) despite extensive vascular damage observed. The IFP reduction in the 4T1 model was also associated with marked vascular damage and extravasation of red blood cells into the tumor interstitium. A sustained reduction in tumor cell density was observed in the combined therapy group compared with all other groups (P<.05). Finally, we observed a more than twofold delay in tumor growth when CYT-6091 was combined with a single 20-Gy radiation dose-notably, irrespective of the treatment sequence. Moreover, when hypofractionated radiation (12 Gy × 3) was applied with CYT-6091 treatment, a more than five-fold growth delay was observed in the combined treatment group of both tumor models and determined to be synergistic.
  
  
  CONCLUSIONS
  Our results have demonstrated that TNF-labeled gold nanoparticles combined with single or fractionated high-dose radiation therapy is effective in reducing IFP and tumor growth and shows promise for clinical translation.
authors.affiliation: Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Koonce
authors.affiliation: Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Quick
authors.affiliation: Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hardee
authors.affiliation: Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Azemat
authors.initials: A
authors.lastname: Jamshidi-Parsian
authors.affiliation: Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Dent
authors.affiliation: CytImmune Sciences, Rockville, Maryland.
authors.forename: Giulio F
authors.initials: GF
authors.lastname: Paciotti
authors.affiliation: Department of Otolaryngology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Nedosekin
authors.affiliation: Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Ruud P M
authors.initials: RP
authors.lastname: Dings
authors.affiliation: Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas. Electronic address: RJGriffin@uams.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Griffin
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D002452:Cell Count; D015687:Cell Hypoxia; D003131:Combined Modality Therapy / Q000379:methods; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D045604:Extracellular Fluid / Q000528:radiation effects; D005260:Female; D006046:Gold / Q000627:therapeutic use*; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011312:Pressure; D011879:Radiotherapy Dosage; D011897:Random Allocation; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
chemical_list: C000604550:CYT-6091; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols; D006046:Gold