Systemic dissemination of viral vectors during intratumoral injection.
Systemic dissemination of viral vectors during intratumoral injection.
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发表时间：
2003-11
影响因子：
5.7
通讯作者：
Yong Wang;Jim Hu;A. Krol;Yongping Li;Chuan-Yuan Li;F. Yuan
中科院分区：
文献类型：
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作者：
Yong Wang;Jim Hu;A. Krol;Yongping Li;Chuan-Yuan Li;F. Yuan
瘤内注射是一种常规的局部病毒基因传递方法，可改善病毒载体在肿瘤组织中的间质转运，降低全身毒性。然而，如果转基因产品具有剧毒，那么转基因产品在正常器官中的浓度，如在肝脏中，仍可能超过正常组织的耐受性。正常组织中的浓度升高很可能是由肿瘤病毒载体的传播引起的。因此，我们研究了瘤内注射小鼠白介素12、荧光素酶、增强型绿色荧光蛋白或β-半乳糖苷酶的腺病毒载体后，转基因在小鼠肝脏、血清和小鼠乳腺癌(4T1)中的表达。我们还在Krogh圆柱体模型的基础上，对肿瘤内注射后病毒在肿瘤中的传输进行了数值模拟。我们的实验数据和数值模拟表明，病毒在小鼠体内的传播是显著的，并且主要发生在瘤内注射期间。为了减少病毒传播，我们将这些载体与粘性海藻酸盐溶液混合，并将混合物注射到肿瘤中。我们的数据显示，藻酸盐溶液可以显着减少病毒传播，同时对肿瘤中的转基因表达和白细胞介素12诱导的肿瘤生长延迟影响很小。这些数据表明，在癌症的局部病毒基因治疗中，病毒传播是一个潜在的问题，海藻酸盐溶液可以显著减少病毒传播，而不会影响基因治疗的效果。
Intratumoral injection is a routine method for local viral gene delivery that may improve interstitial transport of viral vectors in tumor tissues and reduce systemic toxicity. However, the concentration of transgene products in normal organs, such as in the liver, may still exceed normal tissue tolerance if the products are highly toxic. The elevated concentration in normal tissues is likely to be caused by the dissemination of viral vectors from the tumor. Therefore, we investigated transgene expression in the liver, the serum, and a mouse mammary carcinoma (4T1) in mice after intratumoral injection of adenoviral vectors for mouse interleukin-12, luciferase, enhanced green fluorescence protein, or beta-galactosidase. We also performed numerical simulations of virus transport in tumors after intratumoral injection, based on the Krogh cylinder model. Our experimental data and numerical simulations demonstrated that virus dissemination was significant in mice and it occurred mainly during the intratumoral injection. To reduce virus dissemination, we mixed these vectors with a viscous alginate solution and injected the mixture into the tumors. Our data showed that the alginate solution could significantly reduce virus dissemination while having minimal effects on transgene expression in tumors and on interleukin-12-induced tumor growth delay. These data suggest that virus dissemination is a potential problem in local viral gene therapy of cancer and that the dissemination could be significantly reduced by the alginate solution without compromising the efficacy of gene therapy.