Synthesis and biological evaluation of folate receptor-targeted boronated PAMAM dendrimers as potential agents for neutron capture therapy
Synthesis and biological evaluation of folate receptor-targeted boronated PAMAM dendrimers as potential agents for neutron capture therapy
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DOI：
10.1021/bc025586o
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发表时间：
2003-01-01
影响因子：
4.7
通讯作者：
Tjarks, W
中科院分区：
文献类型：
--
作者：
Shukla, S;Wu, G;Tjarks, W
通过硼中子俘获疗法（BNCT）成功治疗癌症需要选择性地将B-10递送到肿瘤内的组成细胞。叶酸受体的表达在多种人类肿瘤中被扩增，并可能作为BNCT的分子靶点。在本研究中，我们研究了使用含硼聚乙二醇（PEG）的叶酸缀合物靶向癌细胞上的叶酸受体的可能性，所述叶酸缀合物含有第三代聚酰胺胺树状聚合物，以通过减少网状内皮系统对这些缀合物的摄取来获得BNCT所需的B-10浓度。首先，我们将12-15个十硼酸根簇共价连接到第三代聚酰胺胺树枝状聚合物上。然后将具有不同链长的不同量的PEG单元连接到这些硼化树枝状聚合物以减少肝脏摄取。在所有制备的组合中，具有1-1.5个PEG（2000）单位的硼化树枝状聚合物在C57 BL/6小鼠中表现出最低的肝脏摄取（7.2-7.7%注射剂量（ID）/g肝脏）。因此，制备了两种叶酸受体靶向的硼化第三代聚酰胺-胺树枝状聚合物，一种含有类似于15个十硼酸簇和类似于1个PEG（2000）单元的末端连接有叶酸，另一种含有类似于13个十硼酸簇，类似于1个PEG（2000）单元，类似于1个PEG（800）单元的末端连接有叶酸。使用叶酸受体（+）KB细胞的体外研究证明了后者缀合物的受体依赖性摄取。在携带叶酸受体（+）鼠24 JK-FBP肉瘤的C57 BL/6小鼠中使用该缀合物进行的生物分布研究导致选择性肿瘤摄取（6.0% ID/g肿瘤），但也导致高肝（38.8% ID/g）和肾（62.8% ID/g）摄取，表明第二个PEG单元和/或叶酸的附着可能对该缀合物的药效学产生不利影响。
Successful treatment of cancer by boron neutron capture therapy (BNCT) requires the selective delivery of B-10 to constituent cells within a tumor. The expression of the folate receptor is amplified in a variety of human tumors and potentially might serve as a molecular target for BNCT. In the present study we have investigated the possibility of targeting the folate receptor on cancer cells using folic acid conjugates of boronated poly(ethylene glycol) (PEG) containing 3rd generation polyamidoamine dendrimers to obtain B-10 concentrations necessary for BNCT by reducing the uptake of these conjugates by the reticuloendothelial system. First we covalently attached 12-15 decaborate clusters to 3rd generation polyamidoamine dendrimers. Varying quantities of PEG units with varying chain lengths were then linked to these boronated dendrimers to reduce hepatic uptake. Among all prepared combinations, boronated dendrimers with 1-1.5 PEG(2000) units exhibited the lowest hepatic uptake in C57BL/6 mice (7.2-7.7% injected dose (ID)/g liver). Thus, two folate receptor-targeted boronated 3rd generation polyamidoamine dendrimers were prepared, one containing similar to15 decaborate clusters and similar to1 PEG(2000) unit with folic acid attached to the distal end, the other containing similar to13 decaborate clusters, similar to1 PEG(2000) unit, and similar to1 PEG(800) unit with folic acid attached to the distal end. In vitro studies using folate receptor (+) KB cells demonstrated receptor-dependent uptake of the latter conjugate. Biodistribution studies with this conjugate in C57BL/6 mice bearing folate receptor (+) murine 24JK-FBP sarcomas resulted in selective tumor uptake (6.0% ID/g tumor), but also high hepatic (38.8% ID/g) and renal (62.8% ID/g) uptake, indicating that attachment of a second PEG unit and/or folic acid may adversely affect the pharmacodynamics of this conjugate.