Herpes simplex virus thymidine kinase-mediated suicide gene therapy using nano/microbubbles and ultrasound
Herpes simplex virus thymidine kinase-mediated suicide gene therapy using nano/microbubbles and ultrasound
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DOI：
10.1016/j.ultrasmedbio.2007.09.004
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发表时间：
2008-03-01
影响因子：
2.9
通讯作者：
Kodama, Tetsuya
中科院分区：
文献类型：
--
作者：
Aoi, Atsuko;Watanabe, Yukiko;Kodama, Tetsuya
一种使用超声(US)和纳米/微泡(NBS)的物理方法可以将外源分子无创地输送到特定的靶点。在这项研究中，我们评估了这项技术在使用前药激活疗法进行癌症基因治疗中的应用。用低强度脉冲超声(1 MHz，1.3W/cm(2))和NBS体外转导单纯疱疹病毒胸苷激酶(HSVtk)基因，进行基因转移。在转导细胞中加入更昔洛韦(GCV)可导致HSVtk/GCV依赖的细胞死亡。这项技术随后在体内进行了评估，使用了皮下肿瘤(1 MHz；3.0W/cm(2))的小鼠。通过荧光素酶活性检测，肿瘤的基因转移是暂时的，在转导后24小时达到表达高峰，48小时后表达下降，表明US/NB介导的基因转移是瞬时的。使用两种不同的实验治疗方案，通过US/NB介导的HSVtk基因转移在肿瘤内重复传递基因，然后反复给予GCV，评估了该方法的治疗潜力。在这两种情况下，观察到肿瘤大小急剧缩小了4倍。综上所述，这些数据显示了US/NB作为一种新的物理基因输送方法用于癌症基因治疗的潜力。
A physical method using ultrasound (US) and nano/microbubbles (NBs) can deliver exogenous molecules noninvasively into a specific target site. In this study, we evaluated the application of this technology to cancer gene therapy using prodrug activation therapy. Low-intensity pulsed ultrasound (1 MHz; 1.3 W/cm(2)) and NBs were used to transduce the herpes simplex thymidine kinase (HSVtk) gene in vitro, leading to gene transfer. The addition of ganciclovir (GCV) to the transduced cells led to HSVtk/GCV-dependent cell death mediated by apoptosis. This technology was then assessed in vivo, using mice bearing subcutaneous tumors (1 MHz; 3.0 W/cm(2)). Gene transfer to the tumor, measured by luciferase activity, was transient, with a peak of expression 24 h after transduction, and decreased at 48 h, demonstrating the transient nature of US/NB-mediated gene transfer. The therapeutic potential of this approach was evaluated through repeated intratumoral gene delivery using US/NB-mediated transfer of the HSVtk gene, followed by recurrent administration of GCV, using two different experimental treatment protocols. In both cases, dramatic reductions of the tumor size by a factor of four were observed. Altogether, these data demonstrate the potential of US/NB as a new physical gene delivery method for cancer gene therapy.