Department of Chemical Biology, CSIR-Indian Institute of Chemical Technology , Uppal Road, Hyderabad 500007, India.
Academy of Scientific & Innovative Research (AcSIR) , 2 Rafi Marg, New Delhi, India.
Mol Pharm. 2017 Nov 6;14(11):3834-3847. doi: 10.1021/acs.molpharmaceut.7b00569. Epub 2017 Oct 10.
Despite significant progress in neurosurgery and radiation therapy during the past decade, overall survivability (OS) of glioblastoma patients continues to be less than 2 years. The scope of systemic chemotherapy is greatly limited by poor drug transport across the blood brain barrier (BBB) and, thereby, suboptimal drug accumulation in glioma tissue. To this end, use of large amino acid transporter-1 (LAT1) overexpressed both on brain capillary endothelial cells (BCECs) and glioma cells has begun. Prior reports on the use of LAT1 mediated delivery of model drugs showed their brain accumulations. However, in depth in vivo glioblastoma regression studies aimed at examining the therapeutic potential of LAT1 mediated delivery of potent chemotherapeutics to brain tumor tissues have not yet been undertaken. Herein, we report on the development of a nanometric (100-135 nm) promising LAT1 selective liposomal drug carrier prepared from a novel l-3,4-dihydroxyphenylalanine (l-DOPA) functionalized amphiphile (Amphi-DOPA). In vitro studies using Rh-PE labeled liposomes of Amphi-DOPA both in untreated glioma (GL261) cells and in GL261cells preincubated with LAT1 antibody revealed LAT1 mediated cellular uptake. Intravenously administered NIR-dye labeled liposomes of Amphi-DOPA in glioblastoma-bearing mice showed preferential accumulation of the dye in brain tissue. Notably iv administration of WP1066-loaded liposomes of Amphi-DOPA enhanced the overall survivability of C57BL/6J mice bearing orthotopically established mouse glioblastoma by ∼60% compared to that for the untreated mouse group. Furthermore, we show that the OS of established glioblastoma-bearing mice can be significantly enhanced (by >300% compared to that for the untreated mouse group) when the presently described LAT1 mediated targeted chemotherapy with WP1066-loaded liposomes of Amphi-DOPA is combined with in vivo DC-targeted DNA vaccination using a survivin (a glioblastoma antigen) encoded DNA vaccine. The present findings open a new door for LAT1 mediated systemic chemotherapy of glioblastoma.
尽管在过去十年中神经外科和放射治疗取得了重大进展，但胶质母细胞瘤患者的总体生存率（OS）仍不到 2 年。全身化疗的范围受到血脑屏障（BBB）通透性差的极大限制，从而导致药物在胶质瘤组织中的积累不足。为此，开始使用在脑毛细血管内皮细胞（BCEC）和神经胶质瘤细胞上过度表达的大型氨基酸转运蛋白-1（LAT1）。先前关于使用 LAT1 介导的模型药物传递的报告显示了它们在大脑中的积累。然而，针对 LAT1 介导的将有效的化学疗法递送至脑肿瘤组织的治疗潜力的深入体内胶质母细胞瘤消退研究尚未进行。在此，我们报告了一种纳米级（100-135nm）有前途的 LAT1 选择性脂质体药物载体的开发，该载体由新型 l-3,4-二羟基苯丙氨酸（l-DOPA）功能化的两亲物（Amphi-DOPA）制备。在未经处理的神经胶质瘤（GL261）细胞和预先用 LAT1 抗体孵育的 GL261 细胞中使用 Rh-PE 标记的 Amphi-DOPA 脂质体的体外研究表明，LAT1 介导的细胞摄取。在荷胶质母细胞瘤小鼠中静脉内给予 NIR 染料标记的 Amphi-DOPA 脂质体显示出染料在脑组织中的优先积累。值得注意的是，与未处理的小鼠组相比，载 WP1066 的 Amphi-DOPA 脂质体的静脉内给药增强了荷原位建立的小鼠胶质母细胞瘤的 C57BL/6J 小鼠的总体生存率约 60％。此外，我们表明，与未处理的小鼠组相比，当用载 WP1066 的 Amphi-DOPA 脂质体进行目前描述的 LAT1 介导的靶向化疗与使用编码生存素（一种胶质母细胞瘤抗原）的 DNA 疫苗进行体内树突状细胞靶向 DNA 疫苗接种相结合时，可以显著提高已建立的胶质母细胞瘤荷瘤小鼠的 OS（与未处理的小鼠组相比增加超过 300％）。目前的发现为胶质母细胞瘤的 LAT1 介导的系统化疗开辟了新的途径。
