Harada A, Togawa H, Kataoka K
Department of Materials Science, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8656, Tokyo, Japan.
Eur J Pharm Sci. 2001 Apr;13(1):35-42. doi: 10.1016/s0928-0987(00)00205-0.
In this study, the physicochemical properties of polyion complex (PIC) micelles formed from antisense-oligodeoxynucleotides (antisense-ODN) and poly(ethylene glycol)-poly(L-lysine) block copolymers (PEG-PLL) were investigated to utilize them as a novel formulation for antisense-ODN delivery. Angular and concentration dependences of the diffusion coefficient of PIC micelles were evaluated by dynamic light scattering. Results suggested that the formed PIC micelles may have spherical shape with core-shell structure, in which the PIC core formed from antisense-ODN and PLL segment was surrounded by a PEG shell. The average radius of PIC micelles was dependent on the chain length of the PLL segment and was not influenced by the change in the length of ODN molecules at least in the range between 15 and 20 base pairs. Critical association concentration (cac) of PIC micelles was then determined from a profile of light scattering intensity versus concentration (Debye plots). Cac is ca. 0.20 mg/ml, which is low enough to ensure the micelle stability in very diluted condition as is the case with systemic injection into the blood compartment for antisense-ODN therapy. Furthermore, the stability of antisense-ODN against deoxyribonuclease I (DNase I) attack was evaluated using capillary gel electrophoresis, revealing that the complexation of antisense-ODN with PEG-PLL effectively prohibited DNase I attack. These characteristics of the PIC micelle system highlight its promising feature as ODN carrier used in the field of targeting therapy.
在本研究中，对由反义寡脱氧核苷酸（反义ODN）和聚（乙二醇）-聚（L-赖氨酸）嵌段共聚物（PEG-PLL）形成的聚离子复合物（PIC）胶束的物理化学性质进行了研究，以将其用作反义ODN递送的新型制剂。通过动态光散射评估了PIC胶束扩散系数的角度和浓度依赖性。结果表明，形成的PIC胶束可能具有核壳结构的球形形状，其中由反义ODN和PLL片段形成的PIC核被PEG壳包围。PIC胶束的平均半径取决于PLL片段的链长，并且至少在15至20个碱基对的范围内不受ODN分子长度变化的影响。然后根据光散射强度与浓度的关系曲线（德拜图）确定PIC胶束的临界缔合浓度（cac）。cac约为0.20 mg/ml，这足够低，以确保在非常稀释的条件下胶束的稳定性，就像在反义ODN治疗中全身注射到血液腔室的情况一样。此外，使用毛细管凝胶电泳评估了反义ODN对脱氧核糖核酸酶I（DNase I）攻击的稳定性，结果表明反义ODN与PEG-PLL的络合有效地阻止了DNase I的攻击。PIC胶束系统的这些特性突出了其作为靶向治疗领域中使用的ODN载体的有前景的特征。
