Department of Anesthesiology, College of Physicians and Surgeons, Columbia University Medical Center, 630 West 168th Street, P&S Box 46, New York, NY, 10032, USA.
Department of Neurological Surgery, Columbia University Medical Center, New York, NY, USA.
J Neurooncol. 2017 Dec;135(3):497-506. doi: 10.1007/s11060-017-2615-5. Epub 2017 Sep 5.
Computational modeling shows that intra-arterial delivery is most efficient when the delivered drugs rapidly and avidly bind to the target site. The cell-penetrating peptide trans-activator of transcription (TAT) is a candidate carrier molecule that could mediate such specificity for brain tumor chemotherapeutics. To test this hypothesis we first performed in vitro studies testing the uptake of TAT by one primary and three potentially metastatic brain cancer cell lines (9L, 4T-1, LLC, SKOV-3). Then we performed in vivo studies in a rat model where TAT was delivered either intra-arterially (IA) or intravenously (IV) to 9L brain tumors. We observed robust uptake of TAT by all tumor cell lines in vitro. Flow cytometry and confocal microscopy revealed a rapid uptake of fluorescein-labeled TAT within 5 min of exposure to the cancer cells. IA injections done under transient cerebral hypoperfusion (TCH) generated a four-fold greater tumor TAT concentration compared to conventional IV injections. We conclude that it is feasible to selectively target brain tumors with TAT-linked chemotherapy by the IA-TCH method.
计算模型表明，当递送到的药物迅速且强烈地与靶位结合时，动脉内递送是最有效的。穿透细胞的转录激活因子（TAT）是一种候选载体分子，可以为脑肿瘤化疗药物介导这种特异性。为了验证这一假设，我们首先进行了体外研究，测试了 TAT 在一种原发性和三种潜在转移性脑癌细胞系（9L、4T-1、LLC、SKOV-3）中的摄取。然后，我们在大鼠模型中进行了体内研究，其中 TAT 通过动脉内（IA）或静脉内（IV）途径递送至 9L 脑肿瘤。我们观察到 TAT 在所有肿瘤细胞系中的摄取都非常强。流式细胞术和共聚焦显微镜显示，在暴露于癌细胞 5 分钟内，荧光素标记的 TAT 迅速被摄取。在短暂性脑低灌注（TCH）下进行的 IA 注射与常规 IV 注射相比，肿瘤内 TAT 浓度增加了四倍。我们得出结论，通过 IA-TCH 方法，使用 TAT 连接的化疗药物选择性靶向脑肿瘤是可行的。
