Reporter gene imaging identifies intratumoral infection voids as a critical barrier to systemic oncolytic virus efficacy
Reporter gene imaging identifies intratumoral infection voids as a critical barrier to systemic oncolytic virus efficacy
复制标题
DOI：
10.1038/mto.2014.5
复制
发表时间：
2014-01-01
影响因子：
5.7
通讯作者：
Russell, Stephen J.
中科院分区：
文献类型：
--
作者：
Miller, Amber;Suksanpaisan, Lukkana;Russell, Stephen J.
系统给药的溶瘤病毒有能力通过肿瘤内感染中心的扩张和合并导致肿瘤破坏。因此，疗效取决于初始病毒输注后病毒感染细胞的密度和肿瘤内分布，目前正在开发递送方法以增强这些关键参数。然而，使用传统的免疫组织化学方法很难绘制肿瘤内感染中心的三维（3D）地图，需要对许多连续染色的肿瘤切片进行艰苦的三维重建，并且无法研究单个动物中传播感染的时间演变。因此，我们开发了一种高分辨率无创体内微单光子发射计算机断层扫描/计算机断层扫描（微spect /CT）成像系统，以确定编码甲状腺碘化钠同调体（NIS）的溶瘤病毒感染的肿瘤中甲状腺放射性示踪剂的瘤内分布。该成像系统用于对荷瘤小鼠全身给药溶瘤性水泡性口炎病毒后肿瘤内感染中心的密度、分布和进化进行纵向分析，揭示了接受相同治疗的动物肿瘤内和肿瘤间病毒颗粒的异质性传递。该研究提供了令人信服的高分辨率体内报告基因定位，作为一种方便的方法，用于肿瘤内病毒传播的连续监测，这将是解决肿瘤内传递等系统性溶瘤病毒功效的关键障碍所必需的。
Systemically administered oncolytic viruses have the ability to cause tumor destruction through the expansion and coalescence of intratumoral infectious centers. Efficacy is therefore dependent upon both the density and intratumoral distribution of virus-infected cells achieved after initial virus infusion, and delivery methods are being developed to enhance these critical parameters. However, the three-dimensional (3D) mapping of intratumoral infectious centers is difficult using conventional immunohistochemical methodology, requiring painstaking 3D reconstruction of numerous sequential stained tumor sections, with no ability to study the temporal evolution of spreading infection in a single animal. We therefore developed a system using very high-resolution noninvasive in vivo micro single-photon emitted computed tomography/computed tomography (microSPECT/CT) imaging to determine the intratumoral distribution of thyroid radiotracers in tumors infected with an oncolytic virus encoding the thyroidal sodium-iodide symporter (NIS). This imaging system was used for longitudinal analysis of the density, distribution, and evolution of intratumoral infectious centers after systemic administration of oncolytic vesicular stomatitis virus in tumor-bearing mice and revealed heterogeneous delivery of virus particles both within and between tumors in animals receiving identical therapy. This study provides compelling validation of high resolution in vivo reporter gene mapping as a convenient method for serial monitoring of intratumoral virus spread that will be necessary to address critical barriers to systemic oncolytic virus efficacy such as intratumoral delivery.