Centre de Résonance Magnétique des Systèmes Biologiques, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5536, Université Bordeaux Segalen, 33076 Bordeaux, France;
Nano-H SAS, 38070 Saint Quentin-Fallavier, France;Institut National de la Santé et de la Recherche Médicale Unité 823 andUniversité Joseph Fourier, Institut Albert Bonniot, 38706 Grenoble, France; and.
Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):9247-52. doi: 10.1073/pnas.1402196111. Epub 2014 Jun 9.
One of the main reasons for the dismal prognosis of lung cancer is related to the late diagnosis of this pathology. In this work, we evaluated the potential of optimized lung MRI techniques and nebulized ultrasmall multimodal gadolinium-based contrast agents [ultrasmall rigid platforms (USRPs)] as a completely noninvasive approach for non-small-cell lung cancer (NSCLC) in vivo detection. A mouse model of NSCLC expressing the luciferase gene was developed. Ultrashort echo-time free-breathing MRI acquisitions were performed before and after i.v. or intrapulmonary administration of the nanoparticles to identify and segment the tumor. After orotracheal or i.v. administration of USRPs, an excellent colocalization of the position the tumor with MRI, bioluminescence and fluorescence reflectance imaging, and histology was observed in all mice. Significantly higher signal enhancements and contrast-to-noise ratios were observed with orotracheal administration using lower doses, reducing the toxicity issues and the interobserver variability in tumor detection. The observations suggested the existence of an unknown original mechanism (different from the enhanced permeability and retention effect) responsible for this phenomenon. MRI and USRPs were shown to be powerful imaging tools able to detect, quantify, and longitudinally monitor the development of submillimetric NSCLCs. The absence of ionizing radiation and high resolution MRI, along with the complete noninvasiveness and good reproducibility of the proposed protocol, make this technique potentially translatable to humans. To our knowledge this is the first time that the advantages of an orotracheal administration route are demonstrated for the investigation of the pathomorphological changes due to NSCLCs.
肺癌预后不佳的主要原因之一与该病理学的晚期诊断有关。在这项工作中，我们评估了优化的肺部 MRI 技术和雾化超小多模态镧系基造影剂（超小刚性平台（USRP））作为一种完全非侵入性方法在体内检测非小细胞肺癌（NSCLC）的潜力。建立了表达荧光素酶基因的 NSCLC 小鼠模型。在静脉内或肺内给予纳米颗粒前后进行超短回波时间自由呼吸 MRI 采集，以识别和分割肿瘤。经气管内或静脉内给予 USRP 后，所有小鼠的肿瘤位置与 MRI、生物发光和荧光反射成像以及组织学均具有极好的共定位。与静脉内给药相比，气管内给药使用较低剂量可观察到信号增强和信噪比显著提高，从而降低了毒性问题和肿瘤检测的观察者间变异性。观察结果表明存在一种未知的原始机制（与增强的通透性和保留效应不同）负责这种现象。MRI 和 USRP 被证明是强大的成像工具，能够检测、定量和纵向监测亚毫米 NSCLC 的发展。由于不存在电离辐射和高分辨率 MRI，以及所提出方案的完全非侵入性和良好的可重复性，因此该技术具有潜在的转化为人类的能力。据我们所知，这是第一次证明经气管内给药途径的优势可用于研究由于 NSCLC 引起的形态病理变化。
