Department of Chemistry and Biochemistry and ‡Department of Cell Biology and Molecular Genetics, University of Maryland , College Park, Maryland 20742, United States.
J Am Chem Soc. 2016 Nov 2;138(43):14488-14496. doi: 10.1021/jacs.6b09504. Epub 2016 Oct 20.
Self-assembly of ligand 1 and Pd(NO) delivers Fujita-type metal-organic polyhedron (MOP) 3 which bears 24 covalently attached methyl viologen units on its external surface, as evidenced by H NMR, diffusion-ordered spectroscopy NMR, electrospray mass spectrometry, transmission electron microscopy, and atomic force microscopy measurements. MOP 3 undergoes noncovalent complexation with cucurbit[n]urils to yield MOPs 4-6 with diameter ≈5-6 nm. MOP 5 can be fully loaded with doxorubicin (DOX) prodrug 2 via hetero-ternary complex formation to yield 7. The MOPs exhibit excellent stability toward neutral to slightly acidic pH in 10 mM sodium phosphate buffer, mitigating the concern of disassembly during circulation. The results of MTS assays show that MOP 7 is 10-fold more cytotoxic toward HeLa cells than equimolar quantities of DOX prodrug 2. The enhanced cytotoxicity can be traced to a combination of enhanced cellular uptake of 7 and DOX release as demonstrated by flow cytometry and confocal fluorescence microscopy. The confluence of properties imparted by the polycationic MOP architecture and plug-and-play CB[n] complexation provides a potent new platform for drug delivery application.
配体 1 和 Pd(NO) 的自组装提供了 Fujita 型金属有机多面体 (MOP) 3，其外部表面带有 24 个共价连接的甲紫单元，这一点可以通过 1H NMR、扩散有序光谱 NMR、电喷雾质谱、透射电子显微镜和原子力显微镜测量得到证明。MOP 3 与瓜环[n]发生非共价络合，生成直径约为 5-6nm 的 MOPs 4-6。MOP 5 可以通过杂三元络合形成完全负载多柔比星（DOX）前药 2，得到 7。在 10mM 磷酸钠缓冲液中，MOPs 对中性到略酸性 pH 表现出优异的稳定性，减轻了在循环过程中解组装的担忧。MTS 测定结果表明，MOP 7 对 HeLa 细胞的细胞毒性比等摩尔量的 DOX 前药 2 高 10 倍。这种增强的细胞毒性可以追溯到 7 的细胞摄取增强和 DOX 释放的综合作用，这一点可以通过流式细胞术和共聚焦荧光显微镜得到证明。多阳离子 MOP 结构和即插即用 CB[n]络合赋予的特性的融合为药物输送应用提供了一个强大的新平台。
