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

Abstract

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.

• Authors: Nathan A Koonce, Charles M Quick, Matthew E Hardee, Azemat Jamshidi-Parsian, Judith A Dent, Giulio F Paciotti, Dmitry Nedosekin, Ruud P M Dings, Robert J Griffin
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 93 Issue 3 Pg. 588-96 (Nov 01 2015) ISSN: 1879-355X [Electronic] United States
• PMID: 26461001 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

• Animals
• Blood Vessels (drug effects, radiation effects)
• Carcinoma, Squamous Cell (blood supply, pathology, 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, pathology, therapy)
• Mammary Neoplasms, Experimental (blood supply, pathology, therapy)
• Mice
• Mice, Inbred BALB C
• Nanoparticles (therapeutic use)
• Polyethylene Glycols (therapeutic use)
• Pressure
• Radiotherapy Dosage
• Random Allocation
• Tumor Necrosis Factor-alpha (therapeutic use)