Boron delivery for boron neutron capture therapy targeting a cancer-upregulated oligopeptide transporter
Boron delivery for boron neutron capture therapy targeting a cancer-upregulated oligopeptide transporter
复制标题
DOI：
10.1016/j.jphs.2019.01.012
复制
发表时间：
2019-03-01
影响因子：
3.5
通讯作者：
Kanai, Yoshikatsu
中科院分区：
文献类型：
--
作者：
Miyabe, Junji;Ohgaki, Ryuichi;Kanai, Yoshikatsu
硼中子俘获治疗(BNCT)是一种利用B-10的中子俘获和核裂变反应进入肿瘤细胞的放射治疗方法。BNCT中最常用的硼剂p-硼-L-苯丙氨酸(BPA)是通过肿瘤细胞上调的氨基酸转运蛋白在肿瘤中蓄积的。在这里，我们利用BPA和酪氨酸二肽(BPA-Tyr和Tyr-BPA)，提出了一种新的策略，通过在各种癌症中上调的寡肽转运蛋白PEPT1将硼选择性地输送到肿瘤细胞中。动力学分析表明，BPA-Tyr和Tyr-BPA是由寡肽转运体PEPT1和PEPT2转运的。肿瘤细胞内固有的寡肽转运活性与PEPT1蛋白表达水平明显相关，但与PEPT2蛋白表达水平无关，提示PEPT1至少在肿瘤细胞系中是主要的寡肽转运载体。此外，利用BPA-Tyr和Tyr-BPA，通过PEPT1介导的机制，成功地将硼转移到表达PEPT1的胰腺癌细胞ASPC-1中。静脉注射BPA-Tyr给荷ASPC-1异种移植瘤的小鼠，可导致肿瘤内显著的硼蓄积。认为寡肽转运体，尤其是PEPT1，有望成为BNCT中硼转运的分子靶点。含有双酚A的二肽将有可能开发出针对PEPT1的新型硼载体。(C)2019年提交人。由爱思唯尔B.V.代表日本药理学会制作和主办。这是CC BY-NC-ND License(http://creativecommons.org/licenses/by-nc-nd/4.0/).下的一篇开放获取文章
Boron neutron capture therapy (BNCT) is a radiotherapy utilizing the neutron capture and nuclear fission reaction of B-10 taken up into tumor cells. The most commonly used boron agent in BNCT, p-borono-L-phenylalanine (BPA), is accumulated in tumors by amino acid transporters upregulated in tumor cells. Here, by using dipeptides of BPA and tyrosine (BPA-Tyr and Tyr-BPA), we propose a novel strategy of selective boron delivery into tumor cells via oligopeptide transporter PEPT1 upregulated in various cancers. Kinetic analyses indicated that BPA-Tyr and Tyr-BPA are transported by oligopeptide transporters, PEPT1 and PEPT2. The intrinsic oligopeptide transport activity in tumor cells clearly correlated with PEPT1 protein expression level but not with PEPT2, suggesting that PEPT1 is the predominant oligopeptide transporter at least in tumor cell lines. Furthermore, using BPA-Tyr and Tyr-BPA, boron was successfully delivered into PEPT1-expressing pancreatic cancer AsPC-1 cells via a PEPT1-mediated mechanism. Intravenous administration of BPA-Tyr into the mice bearing AsPC-1 xenograft tumors resulted in significant boron accumulation in the tumors. It is proposed that the oligopeptide transporters, especially PEPT1, are promising candidates for molecular targets of boron delivery in BNCT. The BPA-containing dipeptides would have a potential for the development of novel boron carriers targeting PEPT1. (c) 2019 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).