State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, China.
Department of Materials Science and Engineering, Stanford University, Stanford, CA, 94305, USA.
Biomaterials. 2017 Oct;141:86-95. doi: 10.1016/j.biomaterials.2017.06.035. Epub 2017 Jun 23.
The strong dependence on oxygen level, low ultraviolet/visible (UV/vis) light penetration depth and the extremely short lifetime of reactive oxygen species (ROS) are the major challenges of photodynamic therapy (PDT) for tumors. Fenton reaction can produce abundant ROS such as reactive hydroxyl radicals (OH) with significantly higher oxidation performance than singlet oxygen (O), which, however, has been rarely used in biomedical fields due to strict reaction conditions (favorably in pH range of 3-4, mostly under UV/vis light catalysis). Herein we propose and demonstrate a photochemotherapy (PCT) strategy of cancer therapy using near-infrared (NIR)-assisted tumor-specific Fenton reactions. NIR light-upconverted UV/vis light by upconversion nanoparticles (UCNPs) catalyze the intra-mitochondrial Fenton reaction between the delivered Fe and HO species over-expressed in cancer cell's mitochondria to in-situ kill the cancer cells. The intra-mitochondrial ROS generation of enabled by directly targeting the mitochondrial DNA (mtDNA) helix minimized the distance between the ROS and mtDNA molecules, thus the present PCT strategy showed much enhanced and tumor-specific therapeutic efficacy, as demonstrated by the intratumoral-accelerated OH burst and elevated cytotoxicity. Following the direct intratumoral injection, the PCT revealed marked tumor regression effect in vivo. This constructed PCT-agent is the first paradigm of NIR-upconversion catalyzed intra-mitochondrial Fenton reaction in response to tumoral microenvironment, establishing a novel photochemotherapy strategy for efficient cancer therapy.
氧依赖性强、紫外/可见光（UV/vis）穿透深度低以及活性氧（ROS）的寿命极短，这些都是肿瘤光动力疗法（PDT）的主要挑战。芬顿反应可以产生大量的 ROS，如具有比单线态氧（O）更高氧化性能的活性羟基自由基（OH），但由于严格的反应条件（在 pH 值为 3-4 的范围内有利，主要在 UV/vis 光催化下），它在生物医学领域的应用很少。在此，我们提出并证明了一种使用近红外（NIR）辅助肿瘤特异性芬顿反应的光化疗（PCT）策略来治疗癌症。上转换纳米粒子（UCNPs）将近红外光上转换为 UV/vis 光，从而在癌细胞线粒体中催化递送入的 Fe 和过表达的 HO 之间的内线粒体芬顿反应，就地杀死癌细胞。通过直接靶向线粒体 DNA（mtDNA）螺旋产生的内线粒体 ROS 生成，最小化了 ROS 和 mtDNA 分子之间的距离，因此，所提出的 PCT 策略表现出了显著增强的肿瘤特异性治疗效果，如肿瘤内 OH 爆发加速和细胞毒性升高所证明的那样。在直接瘤内注射后，PCT 在体内显示出明显的肿瘤消退效果。这种构建的 PCT 试剂是首例对肿瘤微环境做出响应的 NIR 上转换催化内线粒体芬顿反应，为高效癌症治疗建立了一种新的光化疗策略。
