Maruyama Kazuo
School of Pharmaceutical Sciences, Teikyo University, Sagamiko, Tsukui-gun, Kanagawa, Japan.
Biosci Rep. 2002 Apr;22(2):251-66. doi: 10.1023/a:1020138622686.
This review deals with the current status of newly developed pendant-type PEG-immunoliposomes (Type C), carrying monoclonal antibodies or their fragments (Fab') at the distal ends of the PEG chains. In terms of target binding of Type C, two different anatomical compartments are considered. They are mouse lung endothelium as a readily accessible site via the intravascular route and the implanted solid tumor as a much less accessible target site reached via extravasation. Small unilamellar liposomes (90-130 nm in diameter) were prepared from phosphatidycholine and cholesterol (2:1, m/m) containing 6mol.% of DSPE-PEG-COOH or DPPE-PEG-Mal. For targeting to the vascular endothelial surface in the lung, 34A antibody, which is highly specific to mouse pulmonary endothelial cells, was conjugated to PEG-liposomes (34A-Type C). The degree of lung binding of 34A-Type C in BALB/c mouse was significantly higher than that of 34A-Type A, which is an ordinary type of immunoliposome (without PEG derivatives). For targeting to solid tumor tissue, 21 B2 antibody (anti-human CEA) and its Fab' fragment were used. The targeting ability of Fab'-Type C was examined by using CEA-positive human gastric cancer strain MKN-45 cells inoculated into BALB/c nu/nu mice. Fab'-Type C showed low RES uptake and a long circulation time, and enhanced accumulation of the liposomes in the solid tumor was seen. The small Fab'-Type C predominantly passed through the leaky tumor endothelium by passive convective transport. These studies offer important insights into the potential of Type C liposomes for target-specific drug delivery.
本综述涉及新开发的悬挂型聚乙二醇免疫脂质体（C型）的当前状况，其在聚乙二醇链的末端携带单克隆抗体或其片段（Fab'）。就C型的靶向结合而言，考虑了两个不同的解剖学区域。它们是小鼠肺内皮，其是通过血管内途径易于到达的部位，以及植入的实体瘤，其是通过外渗到达的难以到达得多的靶部位。由含有6mol.%的二硬脂酰磷脂酰乙醇胺-聚乙二醇-羧基（DSPE-PEG-COOH）或二棕榈酰磷脂酰乙醇胺-聚乙二醇-马来酰亚胺（DPPE-PEG-Mal）的磷脂酰胆碱和胆固醇（2:1，质量比）制备小单层脂质体（直径90-130nm）。为了靶向肺中的血管内皮表面，将对小鼠肺内皮细胞具有高度特异性的34A抗体偶联到聚乙二醇脂质体上（34A-C型）。34A-C型在BALB/c小鼠中的肺结合程度显著高于34A-A型，后者是普通类型的免疫脂质体（不含聚乙二醇衍生物）。为了靶向实体瘤组织，使用了21B2抗体（抗人癌胚抗原）及其Fab'片段。通过将CEA阳性的人胃癌细胞系MKN-45接种到BALB/c裸鼠中来检测Fab'-C型的靶向能力。Fab'-C型显示出低的网状内皮系统摄取和长的循环时间，并且在实体瘤中观察到脂质体的积累增强。小的Fab'-C型主要通过被动对流运输穿过渗漏的肿瘤内皮。这些研究为C型脂质体在靶向特异性药物递送方面的潜力提供了重要见解。
