Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, China.
Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
J Control Release. 2023 Dec;364:23-36. doi: 10.1016/j.jconrel.2023.10.023. Epub 2023 Oct 25.
PEGylated cholesterol-containing liposomes (Chol-PEG-lipo) have been widely used as a drug carrier for their good stealth property in blood circulation where cholesterol maintains the stability of the liposomal lipid bilayer and PEGylation endows liposomes with long circulation capability. However, cholesterol-related disadvantages and the accelerated blood clearance (ABC) phenomenon caused by PEGylation greatly limit the application of conventional stealth liposomes in clinic. Herein, ginsenoside Rg3 was selected to substitute cholesterol and PEG for liposomes preparation (Rg3-lipo). Rg3 was proved with similar liposomal membrane regulation ability to cholesterol and comparable long circulation effect to PEG. In addition, repeated administrations of Chol-PEG-lipo and Rg3-lipo were performed. The circulation time of the second dose of Chol-PEG-lipo was substantially reduced accompanied by a greatly increased accumulation in the liver due to the induction of anti-PEG IgM and the subsequent activated complement system. In contrast, no significantly increased level of relative plasma cells, IgM secretion and the complement activation in blood circulation was observed after the second injection of Rg3-lipo. As a result, Rg3-lipo showed great stealth property without ABC phenomenon. Therefore, developing liposomes utilizing Rg3 instead of PEG and cholesterol presents a promising strategy to prolong the blood circulation time of liposomes without triggering the ABC phenomenon and activated immune responses.
聚乙二醇化含胆固醇脂质体（Chol-PEG-lipo）因其在血液循环中良好的隐身特性而被广泛用作药物载体，其中胆固醇维持脂质体双层的稳定性，而聚乙二醇化则赋予脂质体长循环能力。然而，胆固醇相关的缺点和聚乙二醇化引起的加速血液清除（ABC）现象极大地限制了常规隐身脂质体在临床上的应用。在此，选择人参皂苷 Rg3 替代胆固醇和聚乙二醇用于脂质体的制备（Rg3-lipo）。Rg3 被证明具有与胆固醇相似的调节脂质体膜的能力和与聚乙二醇相当的长循环效果。此外，还进行了 Chol-PEG-lipo 和 Rg3-lipo 的重复给药。由于抗聚乙二醇 IgM 的诱导和随后激活的补体系统，第二剂 Chol-PEG-lipo 的循环时间大大缩短，同时肝脏中的积累显著增加。相比之下，第二次注射 Rg3-lipo 后，血液中相对浆细胞、IgM 分泌和补体激活水平没有明显增加。因此，Rg3-lipo 表现出良好的隐身特性，没有 ABC 现象。因此，开发利用 Rg3 替代 PEG 和胆固醇的脂质体，是一种延长脂质体血液循环时间而不引发 ABC 现象和激活免疫反应的有前途的策略。
