The Polyethyleneglycol Dilemma: Advantage and Disadvantage of PEGylation of Liposomes for Systemic Genes and Nucleic Acids Delivery to Tumors
The Polyethyleneglycol Dilemma: Advantage and Disadvantage of PEGylation of Liposomes for Systemic Genes and Nucleic Acids Delivery to Tumors
复制标题
DOI：
10.1248/bpb.b13-00059
复制
发表时间：
2013-06-01
影响因子：
2
通讯作者：
Harashima, Hideyoshi
中科院分区：
文献类型：
--
作者：
Hatakeyama, Hiroto;Akita, Hidetaka;Harashima, Hideyoshi
基因和核酸治疗有望在下一代癌症治疗药物中发挥重要作用。我们最近开发了一种多功能的嵌入式纳米器件（MEND）作为一种新型的非病毒基因传递系统。聚乙二醇（PEG）的改性，即，PEG化是一种通过增强的渗透性和保留（EPR）效应实现更长的循环时间以将MEND递送至肿瘤的有用方法。然而，PEG化强烈抑制细胞摄取和内体逃逸，这导致递送系统活性的显著损失。对于用于癌症治疗的成功核酸递送，与PEG的使用相关的关键问题，即，必须解决“PEG困境”。在这篇综述中，我们描述了MEND的发展和应用，并讨论了各种策略，克服PEG困境的基础上操纵的药代动力学和细胞内运输的细胞摄取和内体释放。为了增加细胞摄取，首先引入靶配体，包括识别肿瘤上特异性表达的分子的蛋白质、肽、抗体和适体。其次，描述了可裂解的PEG系统。PEG从载体上的裂解是响应于细胞内环境以及肿瘤微环境而实现的，这改善了细胞摄取和内体逃逸。然后，内体融合肽进行了讨论。最后，描述了使用pH敏感脂质的pH敏感脂质体。
Gene and nucleic acid therapy is expected to play a major role in the next generation of agents for cancer treatment. We have recently developed a multifunctional envelope-type nano device (MEND) for use as a novel nonviral gene delivery system. The modification of polyethyleneglycol (PEG), i.e., PEGylation, is a useful method for achieving a longer circulation time for the delivery of MEND to a tumor via the enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits cellular uptake and endosomal escape, which results in significant loss of activity of the delivery system. For successful nucleic acid delivery for cancer treatment, the crucial problem associated with the use of PEG, i.e., the "PEG dilemma" must be resolved. In this review, we describe the development and applications of MEND and discuss various strategies for overcoming the PEG dilemma based on the manipulation of both pharmacokinetics and intracellular trafficking of cellular uptake and endosomal release. To increase cellular uptake, target ligands including proteins, peptides, antibodies and aptamers that recognize molecules specifically expressed on tumors are first introduced. Second, cleavable PEG systems are described. The cleavage of PEG from carriers was achieved in response to the intracellular environment as well as the tumor microenvironment, which improvs cellular uptake and endosomal escape. Then, endosomal fusogenic peptides are discussed. Finally, pH-sensitive liposomes using pH-sensitive lipids are described.