期刊论文详细信息
Journal of Nuclear Medicine
Systemic Image-Guided Liver Cancer Radiovirotherapy Using Dendrimer-Coated Adenovirus Encoding the Sodium Iodide Symporter as Theranostic Gene
Burkhard Göke1  Reingard Senekowitsch-Schmidtke1  Manfred Ogris1  Ernst Wagner1  Per S. Holm1  Markus Schwaiger1  Christine Spitzweg1  Nathalie Schwenk1  Alexandra Vetter1  Geoffrey K. Grünwald1  Christian Zach1  Michael J. Willhauck1  Kathrin Klutz1 
关键词: adenovirus serotype 5;    PAMAM dendrimer;    sodium iodide symporter (NIS);    radiovirotherapy;    gene therapy;   
DOI  :  10.2967/jnumed.112.115493
学科分类:医学(综合)
来源: Society of Nuclear Medicine
PDF
【 摘 要 】

Currently, major limitations for the clinical application of adenovirus-mediated gene therapy are high prevalence of neutralizing antibodies, widespread expression of the coxsackie-adenovirus receptor (CAR), and adenovirus sequestration by the liver. In the current study, we used the sodium iodide symporter (NIS) as a theranostic gene to investigate whether coating of adenovirus with synthetic dendrimers could be useful to overcome these hurdles in order to develop adenoviral vectors for combination of systemic oncolytic virotherapy and NIS-mediated radiotherapy. Methods: We coated replication-deficient (Ad5-CMV/NIS) (CMV is cytomegalovirus) and replication-selective (Ad5-E1/AFP-E3/NIS) adenovirus serotype 5 carrying the hNIS gene with poly(amidoamine) dendrimers generation 5 (PAMAM-G5) in order to investigate transduction efficacy and altered tropism of these coated virus particles by 123I scintigraphy and to evaluate their therapeutic potential for systemic radiovirotherapy in a liver cancer xenograft mouse model. Results: After dendrimer coating, Ad5-CMV/NIS demonstrated partial protection from neutralizing antibodies and enhanced transduction efficacy in CAR-negative cells in vitro. In vivo 123I scintigraphy of nude mice revealed significantly reduced levels of hepatic transgene expression after intravenous injection of dendrimer-coated Ad5-CMV/NIS (dcAd5-CMV/NIS). Evasion from liver accumulation resulted in significantly reduced liver toxicity and increased transduction efficiency of dcAd5-CMV/NIS in hepatoma xenografts. After PAMAM-G5 coating of the replication-selective Ad5-E1/AFP-E3/NIS, a significantly enhanced oncolytic effect was observed after intravenous application (virotherapy) that was further increased by additional treatment with a therapeutic dose of 131I (radiovirotherapy) and was associated with markedly improved survival. Conclusion: These results demonstrate efficient liver detargeting and tumor retargeting of adenoviral vectors after coating with synthetic dendrimers, thereby representing a promising innovative strategy for systemic NIS gene therapy. Moreover, our studybased on the function of NIS as a theranostic gene allowing the noninvasive imaging of NIS expression by 123I scintigraphyprovides detailed characterization of in vivo vector biodistribution and localization, level, and duration of transgene expression, essential prerequisites for exact planning and monitoring of clinical gene therapy trials that aim to individualize the NIS gene therapy concept.

【 授权许可】

Unknown   

【 预 览 】
附件列表
Files Size Format View
RO201912010198880ZK.pdf 1215KB PDF download
  文献评价指标  
  下载次数:8次 浏览次数:8次