Gene-Product Auto-Targeting to Tumor Vessels

在发展肿瘤靶向基因传递方面已经做了很大的努力，但还没有引起注意。 靶向从转基因基因转录和翻译的治疗性基因产品 将正常组织转化为肿瘤。靶向肿瘤基因产物对系统基因非常重要 因为只有一部分基因通过使用最多的 成功的系统性肿瘤靶向基因传递技术。靶向肿瘤中的基因产物也是 对于瘤内基因传递很重要，因为最常用的治疗性基因，如TRAIL 产生分泌到血液循环中的、对正常细胞有害的可溶性蛋白质。 此外，一些基因产物，如IL-12，在与肿瘤共定位时更有效， 与全身定位的比较(Li，S.，JNCI，2002；Li，S.，Mol Treatment，2005)。在此应用程序中， 申请者将选择有效的肿瘤血管靶向多肽来靶向或锚定治疗基因 从注射的基因转录并翻译成肿瘤的产物。具体来说，肿瘤血管- 编码所选肿瘤血管锚定小肽的锚定IL-12基因和IL-12将是 通过电脉冲产生并将其注入肿瘤中以获得肿瘤靶向基因 递送和肿瘤靶向基因产品自动递送。假设是增加的IL-12 肿瘤血管锚定的IL-12在肿瘤中的蓄积及血清中IL-12循环的减少 电基因治疗将极大地降低全身毒性，促进肿瘤根除。为了测试这一点 假设，我们将1)选择最有效的多肽来锚定转录的基因产物 并使用我们的高通量体内筛选系统将注入的基因翻译到肿瘤中；2) 肿瘤血管锚定IL-12电基因治疗的疗效观察 免疫活性荷瘤小鼠和自发荷瘤猫科动物的肿瘤；3)检测 IL-12抑制肿瘤血管生成及肿瘤血管锚定的新机制 增强对肿瘤血管生成的抑制作用。我们提议的实验具有很高的概率 因为我们有一个很好的模型系统，可以获得自发性肿瘤- 携带大型动物，以及完成任务所需的所有资源。

Great effort has been made in developing tumor-targeted gene delivery, but no attention has been given to targeting the therapeutic gene products that are transcribed and translated from genes transfected in normal tissues into tumors. Targeting gene product in tumors is very important for systemic gene delivery because only a portion of genes are successfully delivered into tumors by using the most successful systemic tumor-targeted gene delivery technology. Targeting gene product in tumors is also important for intratumoral gene delivery because the most commonly used therapeutic genes like TRAIL yield soluble proteins that are secreted into the blood circulation and are harmful to normal cells. Moreover, some gene products such as IL-12 are more effective when co-localized with tumors, compared to systemic localization (Li,S., JNCI, 2002; Li, S., Mol Therapy, 2005). In this application, the applicant will select the effective tumor vessel-targeted peptides to target or anchor the therapeutic gene product transcribed and translated from the injected gene into tumors. Specifically, tumor vessel- anchored IL-12 gene encoding the selected tumor vessel-anchored mini-peptide and IL-12 will be generated and will be administered into tumors via electric pulses to achieve the tumor-targeted gene delivery and the tumor-targeted gene-product auto-delivery. The hypothesis is that the increased IL-12 accumulation in tumor and reduction of IL-12 circulation in serum by using tumor vessel-anchored IL-12 electrogenetherapy will greatly reduce systemic toxicity and enhance tumor eradication. To test this hypothesis, we will 1) select the most effective peptides for anchoring gene product that are transcribed and translated from the injected gene into tumors using our high throughput in vivo screening system; 2) Determine the therapeutic efficacy of tumor vessel-anchoring IL-12 electrogenetherapy for treating tumors in immunocompetent tumor-bearing mice and spontaneous tumor bearing felines; and 3) test a novel mechanism by which IL-12 inhibits tumor angiogenesis and by shich tumor vessel-anchoredIL-12 enhances the inhibition of tumor angiogenesis. The experiments that we propose have a high probality of success because we have an excellent model system in place, the access to spontaneous tumor- bearing large animals, and all the resources necessary to complete the task.