Cho Seojung, Hori Miyuki, Ueki Ryosuke, Saito Yutaro, Nagai Yukiko, Iki Haruka, Tsuchiya Akira, Konno Tomohiro, Owari Kensuke, Piao Haishun, Futami Kazunobu, Sando Shinsuke
Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
TAGCyx Biotechnologies Inc. Komaba Open Laboratory, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-0041, Japan.
Biomater Sci. 2025 Feb 25;13(5):1347-1353. doi: 10.1039/d4bm01541j.
Overcoming poor pharmacokinetics is a critical challenge in developing therapeutic aptamers, and conjugation to poly(ethylene glycol) (PEG) is a well-established technique for aptamers to prolong blood circulation. However, the existence of antibodies that specifically recognize PEG and their adverse effects on behaviors have been increasingly reported, highlighting the necessity of alternative modification strategies for aptamers. To address this issue, we focused on a zwitterionic polymer, particularly poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), as a PEG alternative to modify DNA aptamers. We conjugated PMPC to a DNA aptamer targeting IFN-gamma and investigated the properties of the PMPC-conjugated DNA aptamer as a therapeutic agent. PMPC modification did not affect the neutralizing activity of the aptamer. PMPC demonstrated lower reactivity against anti-PEG antibodies than PEG-like aptamer modifiers previously reported to exhibit low reactivity against PEG antibodies. In addition, PMPC extended the blood circulation time of the aptamer as long as or longer than PEG with a similar molecular size. In the LPS-induced inflammation animal model, the survival rate after treatment with the PMPC-aptamer conjugate was significantly superior to that with unmodified aptamer. These results indicate that PMPC has potential as an aptamer or other nucleic acid drug modifier to replace or be compatible with PEG.
克服不佳的药代动力学是开发治疗性适配体的一项关键挑战，而与聚乙二醇（PEG）偶联是一种成熟的用于延长适配体血液循环时间的技术。然而，越来越多的报道指出存在特异性识别PEG的抗体及其对行为的不良影响，这凸显了适配体替代修饰策略的必要性。为解决这一问题，我们聚焦于一种两性离子聚合物，特别是聚（2-甲基丙烯酰氧乙基磷酰胆碱）（PMPC），作为修饰DNA适配体的PEG替代物。我们将PMPC与靶向干扰素-γ的DNA适配体偶联，并研究了PMPC偶联的DNA适配体作为治疗剂的性质。PMPC修饰不影响适配体的中和活性。与先前报道的对PEG抗体反应性较低的类PEG适配体修饰剂相比，PMPC对抗PEG抗体的反应性更低。此外，PMPC将适配体的血液循环时间延长至与分子大小相似的PEG相同或更长。在脂多糖诱导的炎症动物模型中，用PMPC-适配体偶联物治疗后的存活率显著高于未修饰的适配体。这些结果表明，PMPC有潜力作为一种适配体或其他核酸药物修饰剂来替代PEG或与PEG兼容。
