Boronated epidermal growth factor as a potential targeting agent for boron neutron capture therapy of brain tumors
Boronated epidermal growth factor as a potential targeting agent for boron neutron capture therapy of brain tumors
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DOI：
10.1021/bc950077q
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发表时间：
1996-01-01
影响因子：
4.7
通讯作者：
Carlsson, J
中科院分区：
文献类型：
--
作者：
Capala, J;Barth, RF;Carlsson, J
为了使硼中子俘获疗法 (BNCT) 取得成功，必须将大量（类似于 10(9)）B-10 原子递送至每个癌细胞，以维持致命的 B-10(n, α)Li-7 反应。大多数高级神经胶质瘤表达扩增的表皮生长因子受体 (EGFR) 基因，并且在细胞表面发现 EGFR 数量增加。如果足够多的 B-10 原子可以附着在 EGF 上，所得的生物结合物可能有助于靶向脑肿瘤。为了实现这一目标，我们使用异氰酸酯多面体硼烷 Na(CH3)(3)NB10H8NCO 对第四代星爆树枝状聚合物 (SD) 进行硼化。为了进行缀合，使用 N-琥珀酰亚胺基 3-(2-吡啶基二硫代)丙酸酯 (SPDP) 将反应性硫醇基团引入硼化 SD，并使用间马来酰亚胺苯甲酰基-N-羟基磺基琥珀酰亚胺酯 (sMBS) 衍生化 EGF。随后衍生的 ESD 的硫醇基团与衍生的 EGF 的马来酰亚胺基团反应产生稳定的 ESD-EGF 生物缀合物，每个 EGF 分子含有大约 960 个硼原子。电子光谱成像发现，ESD-EGF最初与细胞表面膜结合，然后被内吞，导致硼在溶酶体中积累。这些生物缀合物的良好体外特性表明它们可能可用于体内靶向 EGFR 阳性脑肿瘤。
In order for boron neutron capture therapy (BNCT) to be successful, a large number (similar to 10(9)) of B-10 atoms must be delivered to each cancer cell in order to sustain a lethal B-10(n, alpha)Li-7 reaction. The majority of high grade gliomas express an amplified epidermal growth factor receptor (EGFR) gene, and increased numbers of EGFR are found on the cell surface. If a sufficiently large number of B-10 atoms could be attached to EGF, the resulting bioconjugates might be useful for targeting brain tumors. In order to accomplish this, we have boronated a fourth-generation starburst dendrimer (SD) using an isocyanato polyhedral borane, Na(CH3)(3)NB10H8NCO. For conjugation, reactive thiol groups were introduced into the boronated SD using N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP), and EGF was derivatized with m-maleimidobenzoyl-N-hydroxysulfosuccinimide ester (sMBS). Subsequent reaction of thiol groups of derivatized ESD with maleimide groups of derivatized EGF produced stable ESD-EGF bioconjugates containing similar to 960 atoms of boron per molecule of EGF. As determined by electron spectroscopic imaging, the ESD-EGF initially was bound to the cell surface membrane and then was endocytosed, which resulted in accumulation of boron in lysosomes. The favorable in vitro properties of these bioconjugates suggest that they may be useful for the in vivo targeting of EGFR positive brain tumors.