Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, Tokushima, 770-8505, Japan; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
J Pharm Sci. 2014 Feb;103(2):557-66. doi: 10.1002/jps.23823. Epub 2013 Dec 17.
Cationic liposomes (CLs) have shown promise as nonviral delivery systems. To achieve in vivo stability and long circulation, most liposomes are modified with hydrophilic polymer polyethylene glycol (PEG). However, we have reported that repeated administration of PEG-coated CLs containing plasmid DNA (pDNA; PEGylated lipoplexes) induces what is referred to as "the accelerated blood clearance (ABC) phenomenon" and, consequently, subsequently administered lipoplexes lose their prolonged circulation characteristics. Anti-PEG IgM produced in response to the first dose of PEG-coated pDNA-lipoplexes (PEG-DCL) has proven to be a major cause of the ABC phenomenon. In this study, to evade and/or attenuate this unexpected immune response, we modified the surface of a lipoplex with polyglycerol (PG)-derived lipid. The PG-coated pDNA-lipoplex (PG-DCL) attenuated the production of anti-polymer IgM, whereas PEG-coated pDNA-lipoplex (PEG-DCL) did not. In addition, a second dose of PG-DCL maintained the accumulation level in the tumor tissue of a tumor-bearing mouse model, comparable to that of the first dose, whereas the tumor accumulation level of a second dose of PEG-DCL was significantly compromised, compared with the first dose of PEG-DCL. Our results indicate that surface modification of lipoplex with PG represents a viable means for the attenuation, and/or evasion, of the ABC phenomenon that is encountered upon repeated administrations of nucleic acids containing PEG-coated nanocarriers.
阳离子脂质体 (CL) 已被证明是一种很有前途的非病毒递送系统。为了实现体内稳定性和长循环，大多数脂质体都用亲水性聚合物聚乙二醇 (PEG) 进行修饰。然而，我们已经报道，重复给予含有质粒 DNA (pDNA; PEGylated lipoplexes) 的 PEG 修饰的 CL 会引起所谓的“加速血液清除 (ABC) 现象”，因此，随后给予的 lipoplexes 会失去其延长的循环特征。针对第一剂 PEG 修饰的 pDNA-脂质体 (PEG-DCL) 产生的抗 PEG IgM 已被证明是 ABC 现象的主要原因。在这项研究中，为了规避和/或减弱这种意外的免疫反应，我们用聚甘油 (PG) 衍生的脂质修饰了脂质体的表面。PG 修饰的 pDNA-脂质体 (PG-DCL) 减弱了抗聚合物 IgM 的产生，而 PEG 修饰的 pDNA-脂质体 (PEG-DCL) 则没有。此外，第二剂 PG-DCL 维持了荷瘤小鼠模型中肿瘤组织的积累水平，与第一剂相当，而第二剂 PEG-DCL 的肿瘤积累水平与第一剂相比显著降低。我们的结果表明，用 PG 对脂质体进行表面修饰是一种可行的方法，可以减弱和/或规避在重复给予含有 PEG 修饰的纳米载体的核酸时遇到的 ABC 现象。
