Combination of Gold Nanoparticle-Conjugated Tumor Necrosis Factor-α and Radiation Therapy Results in a Synergistic Antitumor Response in Murine Carcinoma Models.
Combination of Gold Nanoparticle-Conjugated Tumor Necrosis Factor-α and Radiation Therapy Results in a Synergistic Antitumor Response in Murine Carcinoma Models.
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DOI：
10.1016/j.ijrobp.2015.07.2275
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发表时间：
2015-11-01
期刊：
影响因子：
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通讯作者：
Griffin RJ
中科院分区：
文献类型：
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作者：
Koonce NA;Quick CM;Hardee ME;Jamshidi-Parsian A;Dent JA;Paciotti GF;Nedosekin D;Dings RP;Griffin RJ
尽管肿瘤坏死因子-α (TNF)单独或联合放疗已显示出显著的临床前抗肿瘤作用，但全身性剂量限制性毒性阻碍了临床应用。在这里，我们研究了放疗联合新型纳米药物CYT-6091的生理和抗肿瘤作用，CYT-6091是一种平均直径为27 nm的聚乙二醇- tnf包覆金纳米颗粒，最近通过了I期试验。在小鼠4T1型乳腺癌和SCCVII型头颈部肿瘤鳞状细胞癌模型中，研究了单次和分次放射联合CYT-6091的生理和抗肿瘤作用。在4T1小鼠乳腺肿瘤模型中，我们观察到CYT-6091单独和联合12Gy辐射剂量后24h肿瘤间质液压力（IFP）显著降低（p<0.05），而单独辐射（12Gy）对IFP的影响可以忽略不计。在SCCVII头颈部肿瘤模型中，尽管观察到广泛的血管损伤，但基线IFP没有明显升高，单剂量放疗或联合治疗后IFP几乎没有额外的变化（p < 0.05 vs对照组）。4T1模型的IFP降低还与明显的血管损伤和红细胞外渗到肿瘤间质有关。与其他各组相比，联合治疗组肿瘤细胞密度持续降低（p<0.05）。最后，我们观察到，当CYT-6091与单次20 Gy照射联合使用时，肿瘤生长延迟了50倍，特别是与治疗顺序无关。此外，当低分割放疗（12 Gy × 3）联合CYT-6091治疗时，两种肿瘤模型的联合治疗组观察到生长延迟约5倍，并确定为协同作用。我们的研究结果表明，金标记的TNF纳米颗粒与单次或分次高剂量放射治疗相结合，可有效降低间质液压力和肿瘤生长，并显示出临床转化的希望。
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. 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. 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 × 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. 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.