Thirumamagal B T S, Zhao Xiaobin B, Bandyopadhyaya Achintya K, Naranyanasamy Sureshbabu, Johnsamuel Jayaseharan, Tiwari Rohit, Golightly Danold W, Patel Vimalkumar, Jehning Brian T, Backer Marina V, Barth Rolf F, Lee Robert J, Backer Joseph M, Tjarks Werner
Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University, Columbus, 43210, USA.
Bioconjug Chem. 2006 Sep-Oct;17(5):1141-50. doi: 10.1021/bc060075d.
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.
脂质体一直是硼中子俘获疗法（BNCT）中肿瘤选择性硼递送策略的主要焦点，BNCT是一种基于硼原子与低能热中子之间的核反应来治疗癌症的二元方法。制备了三种新型碳硼烷胆固醇衍生物作为脂质双层成分，用于构建用于BNCT的非靶向和受体靶向硼化脂质体。这些新型硼化胆固醇模拟物的一个主要结构特征是用碳硼烷簇取代胆固醇的B环和C环。计算分析表明，所有三种硼化化合物都具有与胆固醇非常相似的结构特征和物理化学性质。其中一种合成的硼化胆固醇模拟物被稳定地掺入非靶向、叶酸受体（FR）靶向和血管内皮生长因子受体2（VEGFR-2）靶向的脂质体中。在传统的二棕榈酰磷脂酰胆碱（DPPC）/胆固醇脂质体、这种碳硼烷胆固醇衍生物的非靶向和FR靶向脂质体制剂之间，在外观、大小分布和片层结构上未发现重大差异。FR靶向硼化脂质体在体外FR过表达的KB细胞中被大量摄取，并且在游离叶酸存在下摄取被有效阻断。相比之下，掺入非靶向脂质体中的硼化胆固醇模拟物显示出明显较低的细胞摄取。当分别用硼化FR靶向和（VEGFR-2）靶向脂质体孵育时，在FR过表达的KB细胞和VEGFR-2过表达的293/KDR细胞中没有明显的体外细胞毒性，尽管前者在KB细胞中大量积累，后者通过引起自磷酸化并保护293/KDR细胞免受志贺样毒素（SLT）-VEGF细胞毒性的影响而有效地与VEGFR-2相互作用。
