Asai Tomohiro, Oku Naoto
Department of Medical Biochemistry and Global COE, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
Methods Mol Biol. 2010;605:335-47. doi: 10.1007/978-1-60327-360-2_23.
Liposomal oligopeptides are one of the promising nanocarriers to deliver a drug, DNA or siRNA to target tissues. In this chapter, we describe our methodology to develop liposomal oligopeptides targeting to tumor angiogenic vessels. At first, we introduce our strategies to identify objective peptides. We performed in vivo biopanning using a phage-displayed peptide library and identified Ala-Pro-Arg-Pro-Gly (APRPG) peptide as a ligand for angiogenic vessels. To modify APRPG peptide on the surface of PEGylated liposomes, we synthesized a novel lipid derivative of the peptide, distearoylphosphatidylethanolamine-polyethyleneglycol-APRPG (DSPE-PEG-APRPG). The lipid derivative of APRPG peptide is expected to be readily incorporated into liposomal membrane and enables to present the peptides on the surface of PEGylated liposomes. We next describe how to evaluate the advantages of liposomal oligopeptides using specific examples; (1) Intratumoral distribution of APRPG-PEG-modified liposomes, (2) Therapeutic efficacy of adriamycin encapsulated in APRPG-PEG-modified liposomes, (3) Preparation of 5'-O-dipalmitoylphosphatidyl 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine (DPP-CNDAC) liposomes modified with APRPG-PEG, and (4) Therapeutic experiment with APRPG-PEG-modified liposomal DPP-CNDAC.
脂质体寡肽是将药物、DNA或小干扰RNA递送至靶组织的有前景的纳米载体之一。在本章中，我们描述了开发靶向肿瘤血管生成血管的脂质体寡肽的方法。首先，我们介绍了鉴定目标肽的策略。我们使用噬菌体展示肽库进行体内淘选，并鉴定出丙氨酸-脯氨酸-精氨酸-脯氨酸-甘氨酸（APRPG）肽作为血管生成血管的配体。为了在聚乙二醇化脂质体表面修饰APRPG肽，我们合成了一种新型的肽脂质衍生物，二硬脂酰磷脂酰乙醇胺-聚乙二醇-APRPG（DSPE-PEG-APRPG）。APRPG肽的脂质衍生物有望易于掺入脂质体膜中，并能够在聚乙二醇化脂质体表面呈现这些肽。接下来，我们将通过具体实例描述如何评估脂质体寡肽的优势；（1）APRPG-PEG修饰脂质体的瘤内分布，（2）APRPG-PEG修饰脂质体中封装的阿霉素的治疗效果，（3）用APRPG-PEG修饰的5'-O-二棕榈酰磷脂酰2'-C-氰基-2'-脱氧-1-β-D-阿拉伯呋喃糖基胞嘧啶（DPP-CNDAC）脂质体的制备，以及（4）用APRPG-PEG修饰的脂质体DPP-CNDAC进行的治疗实验。
