Shukla Supriya, Wu Gong, Chatterjee Madhumita, Yang Weilian, Sekido Masaru, Diop Lamine A, Müller Rainer, Sudimack Jennifer J, Lee Robert J, Barth Rolf F, Tjarks Werner
College of Pharmacy, Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA.
Bioconjug Chem. 2003 Jan-Feb;14(1):158-67. doi: 10.1021/bc025586o.
Successful treatment of cancer by boron neutron capture therapy (BNCT) requires the selective delivery of (10)B 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 (10)B 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 approximately 15 decaborate clusters and approximately 1 PEG(2000) unit with folic acid attached to the distal end, the other containing approximately 13 decaborate clusters, approximately 1 PEG(2000) unit, and approximately 1 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.
通过硼中子俘获疗法（BNCT）成功治疗癌症需要将硼 - 10（¹⁰B）选择性地递送至肿瘤内的组成细胞。叶酸受体在多种人类肿瘤中表达增强，有可能作为BNCT的分子靶点。在本研究中，我们研究了使用含第三代聚酰胺 - 胺树枝状大分子的硼化聚乙二醇（PEG）叶酸缀合物靶向癌细胞上叶酸受体的可能性，通过减少网状内皮系统对这些缀合物的摄取来获得BNCT所需的硼 - 10浓度。首先，我们将12 - 15个十硼酸盐簇共价连接到第三代聚酰胺 - 胺树枝状大分子上。然后将不同数量、不同链长的PEG单元连接到这些硼化树枝状大分子上以减少肝脏摄取。在所有制备的组合中，带有1 - 1.5个PEG(2000)单元的硼化树枝状大分子在C57BL / 6小鼠中表现出最低的肝脏摄取（7.2 - 7.7％注射剂量（ID）/克肝脏）。因此，制备了两种靶向叶酸受体的硼化第三代聚酰胺 - 胺树枝状大分子，一种含有约15个十硼酸盐簇和约1个PEG(2000)单元，叶酸连接在末端；另一种含有约13个十硼酸盐簇、约1个PEG(2000)单元和约1个PEG(800)单元，叶酸连接在末端。使用叶酸受体（+）KB细胞的体外研究表明，后一种缀合物具有受体依赖性摄取。用这种缀合物在携带叶酸受体（+）小鼠24JK - FBP肉瘤的C57BL / 6小鼠中进行的生物分布研究导致肿瘤选择性摄取（6.0％ID /克肿瘤），但肝脏（38.8％ID /克）和肾脏（62.8％ID /克）摄取也很高，表明连接第二个PEG单元和/或叶酸可能会对这种缀合物的药效学产生不利影响。
