CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics and National Center for Nanoscience Technology of China, Chinese Academy of Sciences , Beijing 100049, People's Republic of China.
College of Chemistry and Environment Protection Engineering, Southwest Minzu University , Chengdu 610041, People's Republic of China.
ACS Nano. 2017 Jul 25;11(7):7164-7176. doi: 10.1021/acsnano.7b03037. Epub 2017 Jun 26.
Radioresistance is one of the undesirable impediments in hypoxic tumors, which sharply diminishes the therapeutic effectiveness of radiotherapy and eventually results in the failure of their treatments. An attractive strategy for attenuating radioresistance is developing an ideal radiosensitization system with appreciable radiosensitization capacity to attenuate tumor hypoxia and reinforce radiotherapy response in hypoxic tumors. Therefore, we describe the development of Gd-containing polyoxometalates-conjugated chitosan (GdW@CS nanosphere) as a radiosensitization system for simultaneous extrinsic and intrinsic radiosensitization, by generating an overabundance of cytotoxic reactive oxygen species (ROS) using high-energy X-ray stimulation and mediating the hypoxia-inducible factor-1a (HIF-1a) siRNA to down-regulate HIF-1α expression and suppress broken double-stranded DNA self-healing. Most importantly, the GdW@CS nanospheres have the capacity to promote the exhaustion of intracellular glutathione (reduced GSH) by synergy W-triggered GSH oxidation for sufficient ROS generation, thereby facilitating the therapeutic efficiency of radiotherapy. As a result, the as-synthesized GdW@CS nanosphere can overcome radioresistance of hypoxic tumors through a simultaneous extrinsic and intrinsic strategy to improve radiosensitivity. We have demonstrated GdW@CS nanospheres with special radiosensitization behavior, which provides a versatile approach to solve the critical radioresistance issue of hypoxic tumors.
放射抵抗性是缺氧肿瘤中一种不理想的障碍，它大大降低了放射治疗的疗效，最终导致治疗失败。减轻放射抵抗性的一种有吸引力的策略是开发一种具有可观放射增敏能力的理想放射增敏系统，以减轻肿瘤缺氧并增强缺氧肿瘤的放射治疗反应。因此，我们描述了一种含 Gd 的多金属氧酸盐-接枝壳聚糖（GdW@CS 纳米球）作为放射增敏系统的发展，通过使用高能 X 射线刺激产生过多的细胞毒性活性氧（ROS），并介导缺氧诱导因子-1a（HIF-1a）siRNA 下调 HIF-1α表达并抑制断裂的双链 DNA 自我修复，从而实现外源性和内源性放射增敏。最重要的是，GdW@CS 纳米球通过协同 W 触发的 GSH 氧化来促进细胞内谷胱甘肽（还原型 GSH）的耗竭，以产生足够的 ROS，从而提高放射治疗的疗效。因此，所合成的 GdW@CS 纳米球可以通过同时的外源性和内源性策略克服缺氧肿瘤的放射抵抗性，从而提高放射敏感性。我们已经证明了具有特殊放射增敏行为的 GdW@CS 纳米球，为解决缺氧肿瘤的关键放射抵抗性问题提供了一种通用的方法。
