Biodistribution and subcellular localization of an unnatural boron-containing amino acid (cis-ABCPC) by imaging secondary ion mass spectrometry for neutron capture therapy of melanomas and gliomas.
Biodistribution and subcellular localization of an unnatural boron-containing amino acid (cis-ABCPC) by imaging secondary ion mass spectrometry for neutron capture therapy of melanomas and gliomas.
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DOI：
10.1371/journal.pone.0075377
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kabalka GW
中科院分区：
文献类型：
--
作者：
Chandra S;Barth RF;Haider SA;Yang W;Huo T;Shaikh AL;Kabalka GW
开发新的硼输送剂是提高硼中子俘获治疗有效性的优先事项。在本研究中，1-氨基-3-硼基-环戊烷羧酸（顺-ABCPC）作为其L-和D-对映异构体的混合物进行了体内评价使用B16黑色素瘤模型的人肿瘤和F98大鼠胶质瘤作为模型的人胶质瘤。基于二次离子质谱（西姆斯）的成像仪器，CAMECA IMS 3F西姆斯离子显微镜，用于在500 nm空间分辨率下对硼进行定量成像。在黑色素瘤模型中的体内和体外研究都表明，硼定位于细胞质和细胞核中，具有一些细胞间变异性。B16细胞中顺式ABCPC的摄取是时间依赖性的，4小时后细胞核和营养培养基之间的硼分配比为7.5：1。孵化此外，顺式ABCPC在细胞周期的所有阶段（包括S期）向细胞递送硼。使用F98大鼠神经胶质瘤模型的体内西姆斯研究揭示了主要肿瘤块和正常脑组织之间的8：1硼分配比，浸润肿瘤细胞和邻近正常脑之间的比率为5：1。由于顺式ABCPC是水溶性的，并且可以通过L型氨基酸转运蛋白（LAT）穿过血脑屏障，因此由于高级别胶质瘤中LAT的上调，它可能优先在正常脑中的浸润肿瘤细胞中积累。一旦被困在肿瘤细胞内，cis-ABCPC就不能被代谢，并且保持在游离池中或与细胞基质组分结合。与p-boronophenylalanine的动物和临床研究中报道的那些相比，主要肿瘤块和浸润肿瘤细胞的硼摄取的显著改善强烈表明，顺式ABCPC有潜力成为用于神经胶质瘤和黑色素瘤的中子捕获治疗的新型硼递送剂。
The development of new boron-delivery agents is a high priority for improving the effectiveness of boron neutron capture therapy. In the present study, 1-amino-3-borono-cyclopentanecarboxylic acid (cis-ABCPC) as a mixture of its L- and D- enantiomers was evaluated in vivo using the B16 melanoma model for the human tumor and the F98 rat glioma as a model for human gliomas. A secondary ion mass spectrometry (SIMS) based imaging instrument, CAMECA IMS 3F SIMS Ion Microscope, was used for quantitative imaging of boron at 500 nm spatial resolution. Both in vivo and in vitro studies in melanoma models demonstrated that boron was localized in the cytoplasm and nuclei with some cell-to-cell variability. Uptake of cis-ABCPC in B16 cells was time dependent with a 7.5:1 partitioning ratio of boron between cell nuclei and the nutrient medium after 4 hrs. incubation. Furthermore, cis-ABCPC delivered boron to cells in all phases of the cell cycle, including S-phase. In vivo SIMS studies using the F98 rat glioma model revealed an 8:1 boron partitioning ratio between the main tumor mass and normal brain tissue with a 5:1 ratio between infiltrating tumor cells and contiguous normal brain. Since cis-ABCPC is water soluble and can cross the blood-brain-barrier via the L-type amino acid transporters (LAT), it may accumulate preferentially in infiltrating tumor cells in normal brain due to up-regulation of LAT in high grade gliomas. Once trapped inside the tumor cell, cis-ABCPC cannot be metabolized and remains either in a free pool or bound to cell matrix components. The significant improvement in boron uptake by both the main tumor mass and infiltrating tumor cells compared to those reported in animal and clinical studies of p-boronophenylalanine strongly suggest that cis-ABCPC has the potential to become a novel new boron delivery agent for neutron capture therapy of gliomas and melanomas.
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影响因子：
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