Rancan Fiorenza, Helmreich Matthias, Mölich Andreas, Ermilov Eugeny A, Jux Norbert, Röder Beate, Hirsch Andreas, Böhm Fritz
Universitätsklinikum Charité, Hautklinik, Photobiologisches Labor, Berlin, Germany.
Bioconjug Chem. 2007 Jul-Aug;18(4):1078-86. doi: 10.1021/bc0603337. Epub 2007 Jun 6.
The employment of carriers to enhance drug selectivity is one of the strategies to increase the efficacy and reduce the side effects of antitumor therapy. The concept of a modular carrier system (MCS) was developed to construct a complex drug having a high efficacy and selectivity. An MCS employs diverse units or modules: beside the therapeutic unit, an addressing unit (e.g., an antibody) serves to direct the drug to its target, and a multiplying unit has the role of increasing the number of biological active moieties the system can carry. In this paper, we report on the synthesis of a modular carrier system in which the role of multiplying unit is given to a [5:1]fullerene hexakis adduct. This fullerene hexaadduct has five malonate spacers which can bind two therapeutic units (the photosensitizer pyropheophorbide-a) each, for a total of ten, and a longer malonate spacer which serves for the conjugation to the addressing unit, the monoclonal antibody rituximab. Confocal microscopy studies using Epstein-Barr virus-transformed B-lymphocytes and Jurkat cells showed that the antibody conjugate conserves the affinity for its receptor (CD20) and its selectivity toward CD20 positive B-lymphocytes. On the contrary, the antibody-free complex did not show any bounding or intracellular uptake.
利用载体提高药物选择性是提高抗肿瘤治疗疗效和降低副作用的策略之一。模块化载体系统（MCS）的概念旨在构建一种高效且具有选择性的复合药物。MCS采用多种单元或模块：除治疗单元外，寻址单元（如抗体）用于将药物导向其靶点，倍增单元则起到增加系统可携带生物活性部分数量的作用。在本文中，我们报道了一种模块化载体系统的合成，其中倍增单元的作用由[5:1]富勒烯六加成物承担。这种富勒烯六加成物有五个丙二酸间隔基，每个间隔基可结合两个治疗单元（光敏剂焦脱镁叶绿酸-a），总共可结合十个，还有一个较长的丙二酸间隔基用于与寻址单元——单克隆抗体利妥昔单抗偶联。使用爱泼斯坦-巴尔病毒转化的B淋巴细胞和Jurkat细胞进行的共聚焦显微镜研究表明，抗体偶联物保留了对其受体（CD20）的亲和力及其对CD20阳性B淋巴细胞的选择性。相反，无抗体复合物未显示任何结合或细胞内摄取。
