Combination of gold nanoparticle-conjugated TNF-α and radiation therapy results in a synergistic anti-tumor response in murine carcinoma models
Menée sur des modèles murins de carcinome mammaire ou de carcinome épidermoïde de la tête et du cou, cette étude met en évidence l'effet synergique d'une radiothérapie et du TNF-alpha conjugué à une nanoparticule d'or
Introduction : Although remarkable preclinical antitumor effects have been shown for tumor necrosis factor-
α (TNF) alone and in combination with radiation, clinical use is hindered by systemic dose-limiting toxicities. Here, we investigated the physiological and anti-tumor effects of radiotherapy combined with the novel nanomedicine CYT-6091, a 27-nm average diameter polyethylene glycol-TNF coated gold nanoparticle which passed through Phase I trials recently. Methods
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Physiological and anti-tumor effects of single and fractionated radiation in combination with CYT-6091 were studied in the murine 4T1 breast carcinoma and SCCVII head and neck tumor squamous cell carcinoma models. Results
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In the 4T1 murine breast tumor model we observed a significant reduction in tumor interstitial fluid pressure (IFP) 24h after CYT-6091 alone and combined with a radiation dose of 12 Gy (p<0.05 vs control), whereas radiation alone (12Gy) had negligible effect on IFP. In the SCCVII head and neck tumor model, the baseline IFP was not markedly elevated and there was little additional change in IFP post single dose radiation or combined therapy (p>0.05 vs control) despite extensive observed vascular damage. 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 to all other groups (p<0.05). Finally, we observed a >2-fold delay in tumor growth when CYT-6091 was combined with a single 20 Gy irradiation- notably irrespective of treatment sequence. Moreover, when hypofractionated radiation (12 Gy x 3) was applied in combination with CYT-6091 treatment, a >5-fold growth delay was observed in the combined treatment group of both tumor models and determined to be synergistic. Conclusions
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Our results demonstrate that gold-labeled TNF nanoparticles in combination with single or fractionated high-dose radiation therapy is effective in reducing interstitial fluid pressure and tumor growth and shows promise for clinical translation.