Receptor-targeted liposomal delivery of boron-containing cholesterol mimics for boron neutron capture therapy (BNCT).
Receptor-targeted liposomal delivery of boron-containing cholesterol mimics for boron neutron capture therapy (BNCT).
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DOI：
10.1021/bc060075d
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发表时间：
2006-08
影响因子：
4.7
通讯作者：
B. Thirumamagal;Xiaobin B. Zhao;A. Bandyopadhyaya;Sureshbabu Naranyanasamy;Jayaseharan Johnsamuel;R. Tiwari;D. W. Golightly;Vimalkumar A. Patel;Brian T Jehning;M. Backer;R. Barth;Robert J. Lee;J. Backer;W. Tjarks
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作者：
B. Thirumamagal;Xiaobin B. Zhao;A. Bandyopadhyaya;Sureshbabu Naranyanasamy;Jayaseharan Johnsamuel;R. Tiwari;D. W. Golightly;Vimalkumar A. Patel;Brian T Jehning;M. Backer;R. Barth;Robert J. Lee;J. Backer;W. Tjarks
脂质体已经成为硼中子俘获疗法（BNCT）中肿瘤选择性硼递送策略的主要焦点，硼中子俘获疗法是基于硼原子和低能热中子之间的核反应的用于治疗癌症的二元方法。制备了三种新型的碳硼烷胆固醇衍生物作为脂质双层组分，用于构建BNCT的非靶向和受体靶向硼酸化脂质体。这些新的硼化胆固醇模拟物的主要结构特征是用碳硼烷簇取代胆固醇的B和C环。计算分析表明，所有三个硼化合物的结构特征和物理化学性质，是非常相似的胆固醇。合成的硼化胆固醇模拟物之一被稳定地掺入非叶酸受体（FR）和血管内皮生长因子受体-2（VEGFR-2）靶向脂质体中。常规二棕榈酰磷脂酰胆碱（DPPC）/胆固醇脂质体、该碳硼烷胆固醇衍生物的非靶向和FR靶向脂质体制剂之间的外观、粒度分布和层状结构没有发现重大差异。FR靶向的硼化脂质体在体外FR过表达的KB细胞中被广泛摄取，并且在游离叶酸存在下，摄取被有效地阻断。相比之下，掺入非靶向脂质体的硼化胆固醇模拟物显示出显著较低的细胞摄取。有没有明显的体外细胞毒性在FR过表达KB细胞和VEGFR-2过表达293/KDR细胞时，这些与硼化FR-和（VEGFR-2）-靶向脂质体孵育，分别，虽然前者广泛积累在KB细胞和后者有效地与VEGFR-2相互作用，引起自磷酸化和保护293/KDR细胞从志贺样毒素（志贺样毒素）-VEGF细胞毒性。
Liposomes have been a main focus of tumor-selective boron delivery strategies in boron neutron capture therapy (BNCT), a binary method for the treatment of cancer that is based on the nuclear reaction between boron atoms and low-energy thermal neutrons. Three novel carboranyl cholesterol derivatives were prepared as lipid bilayer components for the construction of nontargeted and receptor-targeted boronated liposomes for BNCT. A major structural feature of these novel boronated cholesterol mimics is the replacement of the B and the C ring of cholesterol with a carborane cluster. Computational analyses indicated that all three boronated compounds have structural features and physicochemical properties that are very similar to those of cholesterol. One of the synthesized boronated cholesterol mimics was stably incorporated into non-, folate receptor (FR)-, and vascular endothelial growth factor receptor-2 (VEGFR-2)-targeted liposomes. No major differences were found in appearance, size distribution, and lamellarity between conventional dipalmitoylphosphatidylcholine (DPPC)/cholesterol liposomes, nontargeted, and FR-targeted liposomal formulations of this carboranyl cholesterol derivative. FR-targeted boronated liposomes were taken up extensively in FR overexpressing KB cells in vitro, and the uptake was effectively blocked in the presence of free folate. In contrast, a boronated cholesterol mimic incorporated into nontargeted liposomes showed significantly lower cellular uptake. There was no apparent in vitro cytotoxicity in FR overexpressing KB cells and VEGFR-2 overexpressing 293/KDR cells when these were incubated with boronated FR- and (VEGFR-2)-targeted liposomes, respectively, although the former accumulated extensively in KB cells and the latter effectively interacted with VEGFR-2 by causing autophosphorylation and protecting 293/KDR cells from SLT (Shiga-like toxin)-VEGF cytotoxicity.