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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.

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

Author information

1
Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
2
Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
3
CytImmune Sciences, Rockville, Maryland.
4
Department of Otolaryngology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
5
Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas. Electronic address: RJGriffin@uams.edu.

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.

PMID:
26461001
PMCID:
PMC4934370
DOI:
10.1016/j.ijrobp.2015.07.2275
[Indexed for MEDLINE]
Free PMC Article

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