Titanium peroxide nanoparticles enhanced cytotoxic effects of X-ray irradiation against pancreatic cancer model through reactive oxygen species generation in vitro and in vivo.
Titanium peroxide nanoparticles enhanced cytotoxic effects of X-ray irradiation against pancreatic cancer model through reactive oxygen species generation in vitro and in vivo.
复制标题
过氧化钛纳米粒子通过体外和体内活性氧生成增强 X 射线照射对胰腺癌模型的细胞毒性作用
DOI：
10.1186/s13014-016-0666-y
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发表时间：
2016-07-07
期刊：
影响因子：
--
通讯作者：
Kondo A
中科院分区：
文献类型：
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作者：
Nakayama M;Sasaki R;Ogino C;Tanaka T;Morita K;Umetsu M;Ohara S;Tan Z;Nishimura Y;Akasaka H;Sato K;Numako C;Takami S;Kondo A
纳米粒子的生物学应用正在迅速增加，这为提高放射治疗的疗效带来了新的可能性。在这里，我们合成了过氧化钛纳米粒子（TiOxNPs），并研究了它们作为新型药物的功效，可以有效增强放射治疗胰腺癌的效果。以锐钛矿型二氧化钛纳米颗粒（TiO2NPs）为原料合成了TiOxNPs和聚丙烯酸改性TiOxNPs（PAA-TiOxNPs）。使用透射电子显微镜和动态光散射评估 PAA-TiOxNP 的尺寸和形态。使用 X 射线吸收分析了有和没有 X 射线照射的 TiO2NP 和 PAA-TiOxNP 的晶体结构。 TiOxNPs 和 PAA-TiOxNPs 响应 X 射线照射产生活性氧的能力在无细胞系统中进行了评估，并通过体外流式细胞术分析进行了证实。通过体外和体内 γ-H2AX 病灶形成的免疫组织化学分析，评估有或没有 PAA-TiOxNPs 的 X 射线照射后的 DNA 损伤。通过体外集落形成测定评估细胞毒性。使用人胰腺癌MIAPaCa-2细胞制备异种移植物，并用于评估X射线照射、PAA-TiOxNPs以及两者的组合对肿瘤生长的抑制作用。 PAA-TiOxNPs 的核心结构被发现为锐钛矿型。 TiOxNPs 和 PAA-TiOxNPs 显示出响应 X 射线照射以剂量和浓度依赖性方式产生羟基自由基的独特能力，而 TiO2NPs 则不然。在最高浓度的 TiOxNPs 下，经过 30 Gy 的辐射处理后，羟基自由基的数量增加了 8.5 倍以上。 PAA-TiOxNPs 的吸收增强了 DNA 损伤，并在体外对 X 射线照射产生了更高的细胞毒性。与单独使用 PAA-TiOxNPs 或 X 射线治疗相比，PAA-TiOxNPs 和 X 射线照射的组合可诱导显着更强的肿瘤生长抑制 (p<0.05)。照射后 43 天没有观察到明显的毒性或体重减轻。 TiOxNPs 是增强辐射对胰腺癌影响的潜在药物，并通过羟基自由基的产生发挥作用；由于这种能力，它们将来可以用于胰腺癌的治疗。本文的在线版本 (doi:10.1186/s13014-016-0666-y) 包含补充材料，可供授权用户使用。
Biological applications of nanoparticles are rapidly increasing, which introduces new possibilities to improve the efficacy of radiotherapy. Here, we synthesized titanium peroxide nanoparticles (TiOxNPs) and investigated their efficacy as novel agents that can potently enhance the effects of radiation in the treatment of pancreatic cancer. TiOxNPs and polyacrylic acid-modified TiOxNPs (PAA-TiOxNPs) were synthesized from anatase-type titanium dioxide nanoparticles (TiO2NPs). The size and morphology of the PAA-TiOxNPs was evaluated using transmission electron microscopy and dynamic light scattering. The crystalline structures of the TiO2NPs and PAA-TiOxNPs with and without X-ray irradiation were analyzed using X-ray absorption. The ability of TiOxNPs and PAA-TiOxNPs to produce reactive oxygen species in response to X-ray irradiation was evaluated in a cell-free system and confirmed by flow cytometric analysis in vitro. DNA damage after X-ray exposure with or without PAA-TiOxNPs was assessed by immunohistochemical analysis of γ-H2AX foci formation in vitro and in vivo. Cytotoxicity was evaluated by a colony forming assay in vitro. Xenografts were prepared using human pancreatic cancer MIAPaCa-2 cells and used to evaluate the inhibition of tumor growth caused by X-ray exposure, PAA-TiOxNPs, and the combination of the two. The core structures of the PAA-TiOxNPs were found to be of the anatase type. The TiOxNPs and PAA-TiOxNPs showed a distinct ability to produce hydroxyl radicals in response to X-ray irradiation in a dose- and concentration-dependent manner, whereas the TiO2NPs did not. At the highest concentration of TiOxNPs, the amount of hydroxyl radicals increased by >8.5-fold following treatment with 30 Gy of radiation. The absorption of PAA-TiOxNPs enhanced DNA damage and resulted in higher cytotoxicity in response to X-ray irradiation in vitro. The combination of the PAA-TiOxNPs and X-ray irradiation induced significantly stronger tumor growth inhibition compared to treatment with either PAA-TiOxNPs or X-ray alone (p < 0.05). No apparent toxicity or weight loss was observed for 43 days after irradiation. TiOxNPs are potential agents for enhancing the effects of radiation on pancreatic cancer and act via hydroxyl radical production; owing to this ability, they can be used for pancreatic cancer therapy in the future. The online version of this article (doi:10.1186/s13014-016-0666-y) contains supplementary material, which is available to authorized users.