Oncolytic vaccinia virus expressing the human somatostatin receptor SSTR2:: Molecular imaging after systemic delivery using 111In-Pentetreotide
Oncolytic vaccinia virus expressing the human somatostatin receptor SSTR2:: Molecular imaging after systemic delivery using 111In-Pentetreotide
复制标题
DOI：
10.1016/j.ymthe.2004.06.158
复制
发表时间：
2004-09-01
影响因子：
12.4
通讯作者：
Bartlett, DL
中科院分区：
文献类型：
--
作者：
McCart, JA;Mehta, N;Bartlett, DL
溶瘤痘苗病毒（VV）具有肿瘤特异性、高水平的转基因表达和抗肿瘤作用。随着基因治疗载体进入临床试验，无创性地可视化载体生物分布的能力将是必要的，因此，创造一种既能治疗肿瘤又能在全身输送后进行无创成像的VV是一个令人兴奋的概念。为了便于成像，我们构建了表达人生长抑素受体2型（SSTR2）的VV。用表达sstr2的VV或对照感染的细胞与生长抑素类似物in -111-戊特肽孵育，并添加或不添加过量的非放射性标记戊特肽。sstr2感染的细胞结合in -111-戊treotide的效率比对照病毒感染的细胞高6倍，这种结合被非放射性标记的戊treotide特异性阻断。将皮下移植的小鼠结肠CA裸鼠腹腔注射表达sstr2的VV或对照VV。6天后，给小鼠注射in -111-戊肽并成像。小鼠被处死，收集器官并在伽马计数器中计数。测定肿瘤和正常组织的放射性吸收（每克注射剂量百分比）和肿瘤与正常组织的比值。与接受对照病毒的动物肿瘤相比，感染表达sstr2的VV的肿瘤积累的放射性浓度明显更高。注射VV后6天，sstr2感染的肿瘤在成像上可见，并且在病毒注射后重复注射in -111-戊特肽可显示长达3周。这种报告基因成像策略可能是一种非常有效的方法，可以可视化载体的分布、表达和持续时间，并增强VV作为一种新的抗癌治疗方法的潜力。
Oncolytic vaccinia viruses (VV) have demonstrated tumor specificity, high levels of transgene expression, and anti-tumor effects. The ability to visualize vector biodistribution noninvasively will be necessary as gene therapy vectors come to clinical trials, and the creation of a VV that can both treat tumors and permit noninvasive imaging after systemic delivery is therefore an exciting concept. To facilitate imaging, a VV expressing the human somatostatin receptor type 2 (SSTR2) was created. Cells infected with the SSTR2-expressing VV or controls were incubated with the somatostatin analog In-111-pentetreotide with or without an excess of nonradiolabeled pentetreotide. The SSTR2-infected cells bound In-111-pentetreotide sixfold more efficiently than control virus-infected cells and this binding was specifically blocked by nonradiolabeled pentetreotide. Nude mice bearing subcutaneous murine colon CA xenografts were injected intra peritoneally with the SSTR2-expressing VV or control VV. After 6 days, mice were injected with In-111-pentetreotide and imaged. Mice were sacrificed and organs collected and counted in a gamma counter. The uptake of radioactivity in tumors and normal tissues (percentage injected dose per gram) and tumor-to-normal tissue ratios were determined. Tumors infected with the SSTR2-expressing VV accumulated significantly higher concentrations of radioactivity compared to tumors in animals receiving the control virus. SSTR2-infected tumors were visible on imaging 6 days after VV injection and could be visualized for up to 3 weeks post-viral injection using repeat injections of In-111-pentetreotide. This reporter gene imaging strategy could be a very effective method to visualize vector distribution, expression, and persistence over time and enhances the potential of VV as a novel anti-cancer therapeutic.