Combination of Gold Nanoparticle-Conjugated Tumor Necrosis Factor-α and Radiation Therapy Results in a Synergistic Antitumor Response in Murine Carcinoma Models

Int J Radiat Oncol Biol Phys. 2015 Nov 1;93(3):588-96. doi: 10.1016/j.ijrobp.2015.07.2275. Epub 2015 Jul 26.


Purpose: 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 and materials: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Vessels / drug effects
  • Blood Vessels / radiation effects
  • Carcinoma, Squamous Cell / blood supply
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / therapy*
  • Cell Count
  • Cell Hypoxia
  • Combined Modality Therapy / methods
  • Disease Models, Animal
  • Drug Evaluation, Preclinical / methods
  • Extracellular Fluid / radiation effects
  • Female
  • Gold / therapeutic use*
  • Head and Neck Neoplasms / blood supply
  • Head and Neck Neoplasms / pathology
  • Head and Neck Neoplasms / therapy*
  • Mammary Neoplasms, Experimental / blood supply
  • Mammary Neoplasms, Experimental / pathology
  • Mammary Neoplasms, Experimental / therapy*
  • Mice
  • Mice, Inbred BALB C
  • Nanoparticles / therapeutic use*
  • Polyethylene Glycols / therapeutic use*
  • Pressure
  • Radiotherapy Dosage
  • Random Allocation
  • Tumor Necrosis Factor-alpha / therapeutic use*


  • CYT-6091
  • Tumor Necrosis Factor-alpha
  • Polyethylene Glycols
  • Gold