New therapeutic approach for brain tumors: Intranasal delivery of telomerase inhibitor GRN163
New therapeutic approach for brain tumors: Intranasal delivery of telomerase inhibitor GRN163
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DOI：
10.1215/15228517-2007-052
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发表时间：
2008-04-01
期刊：
影响因子：
15.9
通讯作者：
Deen, Dennis F.
中科院分区：
文献类型：
--
作者：
Hashizume, Rintaro;Ozawa, Tomoko;Deen, Dennis F.
血脑屏障是将抗癌药物输送到脑瘤的重要障碍，脑肿瘤治疗迫切需要绕过它的新策略。鼻腔给药提供了一种将治疗剂输送到大脑的实用、非侵入性方法，并可提供静脉注射和对流增强给药的另一种选择。我们用GRN163--一种寡核苷酸N3‘->；P5’硫代磷酰胺端粒酶抑制剂--经鼻腔治疗荷人脑内肿瘤移植瘤的大鼠。3‘-异硫氰酸荧光素标记的GRN163在6亩L交替滴入鼻腔22分钟后每隔2分钟滴入一次。FITC标记的GRN163在研究的所有时间点均存在于肿瘤细胞中，GRN163的积聚在注射后4h达到高峰。此外，GRN163鼻腔给药，连续12天，可显著延长小鼠的中位生存期，从对照组的35天延长到GRN163治疗组的75.5天。因此，GRN163鼻腔给药很容易绕过血脑屏障，表现出良好的肿瘤摄取，并抑制肿瘤生长，导致与对照组相比，治疗组大鼠的寿命延长。这种给药方法似乎有选择性地杀死肿瘤细胞，在正常脑组织中没有观察到毒性作用。这些数据支持脑肿瘤患者鼻腔给药的进一步发展。
The blood-brain barrier is a substantial obstacle for delivering anticancer agents to brain tumors, and new strategies for bypassing it are greatly needed for brain-tumor therapy. Intranasal delivery provides a practical, noninvasive method for delivering therapeutic agents to the brain and could provide an alternative to intravenous injection and convection-enhanced delivery. We treated rats bearing intracerebral human tumor xenografts intranasally with GRN163, an oligonucleotide N3'-> P5'thio-phosphoramidate telomerase inhibitor. 3'-Fuorescein isothiocyanate (FITC)-labeled GRN163 was administered intranasally every 2 min as 6 mu l drops into alternating sides of the nasal cavity over 22 min. FITC-labeled GRN163 was present in tumor cells at all time points studied, and accumulation of GRN163 peaked at 4 h after delivery. Moreover, GRN163 delivered intranasally, daily for 12 days, significantly prolonged the median survival from 35 days in the control group to 75.5 days in the GRN163-treated group. Thus, intranasal delivery of GRN163 readily bypassed the blood-brain barrier, exhibited favorable tumor uptake, and inhibited tumor growth, leading to a prolonged lifespan for treated rats compared to controls. This delivery approach appears to kill tumor cells selectively, and no toxic effects were noted in normal brain tissue. These data support further development of intranasal delivery of tumor-specific therapeutic agents for brain tumor patients.