Institute of Drug Discovery and Development, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai 200062, PR China.
Colloids Surf B Biointerfaces. 2013 May 1;105:31-6. doi: 10.1016/j.colsurfb.2012.12.046. Epub 2013 Jan 7.
This research is aimed to develop a nano-sized supramolecular micelle delivery system of cis-dichlorodiammine platinum (II) (CDDP) in order to achieve the passive tumor targeting. Firstly, star-shaped poly (γ-benzyl-L-glutamate) was synthesized by the ring-opening polymerization of γ-benzyl-L-glutamate-N-carboxyanhydride initiated with per-6-amino-β-cyclodextrin. After removal of benzyl groups, β-cyclodextrin based seven-armed poly (L-glutamic acid) (β-CD-7PLGA) was obtained. β-CD-7PLGA/CDDP complexes were prepared by the complex reaction between the carboxylic groups of β-CD-7PLGA and CDDP. Further inclusion of β-CD-7PLGA/CDDP complexes with adamantine terminated mPEG (mPEG-Ad) gave CDDP supramolecular micelles (mPEG-Ad@β-CD-7PLGA/CDDP). The formation of mPEG-Ad@β-CD-7PLGA/CDDP supramolecular micelles was confirmed by fluorescence spectrophotoscopy and particle size measurements. All the micelles showed spherical shape, and their sizes increased from 100 to 135 nm with the increase of PLGA arm molecular weight. mPEG-Ad@CD-7PLGA/CDDP micelles showed sustained drug release profiles over 50h in PBS. Compared with CDDP, mPEG-Ad@β-CD-7PLGA/CDDP supramolecular micelles showed essential decreased cytotoxicity to KB cells, suggesting their great potential as the delivery carriers of CDDP.
本研究旨在开发一种顺式二氯二氨合铂(II)（CDDP）的纳米级超分子胶束递药系统，以实现被动肿瘤靶向。首先，通过用六氨基-β-环糊精引发γ-苄基-L-谷氨酸-N-羧酸酐开环聚合合成星形聚（γ-苄基-L-谷氨酸）。除去苄基后，得到基于β-环糊精的七臂聚（L-谷氨酸）（β-CD-7PLGA）。通过β-CD-7PLGA 与 CDDP 之间的羧酸基团的复合反应制备β-CD-7PLGA/CDDP 配合物。进一步将β-CD-7PLGA/CDDP 配合物与金刚烷封端的 mPEG（mPEG-Ad）包载，得到 CDDP 超分子胶束（mPEG-Ad@β-CD-7PLGA/CDDP）。荧光分光光度法和粒径测量证实了 mPEG-Ad@β-CD-7PLGA/CDDP 超分子胶束的形成。所有胶束均呈球形，随着 PLGA 臂分子量的增加，其粒径从 100nm 增加到 135nm。mPEG-Ad@CD-7PLGA/CDDP 胶束在 PBS 中表现出超过 50h 的持续药物释放曲线。与 CDDP 相比，mPEG-Ad@β-CD-7PLGA/CDDP 超分子胶束对 KB 细胞的细胞毒性显著降低，表明其作为 CDDP 递送载体具有巨大潜力。
