Jeong Ji Hoon, Kim Sung Wan, Park Tae Gwan
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, South Korea.
Bioconjug Chem. 2003 Mar-Apr;14(2):473-9. doi: 10.1021/bc025632k.
An antisense oligonucleotide (ODN), c-myb, was covalently conjugated to poly(ethylene glycol) (PEG) via an acid-cleavable phosphoramidate linkage to form a diblock copolymer-like structure. The phosphoramidate linkage between ODN and PEG was completely cleaved within 5 h in an endosomal acidic condition (pH 4.7). When complexed with a cationic fusogenic peptide, KALA, the ODN/PEG conjugate self-associated to form polyelectrolyte complex micelles in an aqueous solution. The anionic ODN segments were ionically interacted with cationic KALA peptide to form an inner polyelectrolyte complex core, while the PEG segments constituted a surrounding corona. Effective hydrodynamic volume of the micelles was ca. 70 nm with a very narrow size distribution. The polyelectrolyte complex micelles, composed of c-myb ODN-PEG conjugate and KALA, were transported into cells far more efficiently than c-myb ODN itself. They also exhibited higher antiproliferative activity against smooth muscle cells. This study demonstrates that the DNA/PEG hybrid micelles system can be applied for the delivery of antisense oligonucleotide.
一种反义寡核苷酸（ODN），即c-myb，通过酸可裂解的氨基磷酸酯键与聚乙二醇（PEG）共价连接，形成类似二嵌段共聚物的结构。在酸性内体条件（pH 4.7）下，ODN与PEG之间的氨基磷酸酯键在5小时内完全裂解。当与阳离子融合肽KALA复合时，ODN/PEG共轭物在水溶液中自缔合形成聚电解质复合胶束。阴离子ODN片段与阳离子KALA肽发生离子相互作用，形成内部聚电解质复合核，而PEG片段构成周围的冠层。胶束的有效流体动力学体积约为70 nm，尺寸分布非常窄。由c-myb ODN-PEG共轭物和KALA组成的聚电解质复合胶束比c-myb ODN本身更有效地转运到细胞中。它们对平滑肌细胞也表现出更高的抗增殖活性。这项研究表明，DNA/PEG杂化胶束系统可用于反义寡核苷酸的递送。
