Moghimi Majid, Moghimi S Moein
School of Chemistry, University of Guilan, Rasht, Iran.
J Drug Target. 2008 Aug;16(7):586-90. doi: 10.1080/10611860802228905.
Interstitially injected immuno-poly(ethyleneglycol)-liposomes (immuno-PEG-liposomes) can penetrate the thin-walled and fenestrated lymphatic microvessels and are subsequently conveyed to the regional lymph nodes. The exposed Fc region of coupled antibodies on the liposome surface facilitates vesicular recognition and clearance by lymph node macrophages via the Fc receptor. This limits immuno-PEG-liposome targeting to non-macrophage elements of the lymph nodes. We have evaluated the effect of antibody-coupling procedures to surface-exposed PEG chains with the aim of designing immuno-PEG-liposomes that avoid capture by the lymph node macrophages following interstitial injection. Non-specific IgG was oxidized through the addition of sodium periodate for coupling to hydrazine-PEG(2000)-phospholipid incorporated into liposomal bilayer. For comparison, IgG was also coupled to N-(4'-(4''-maleimidophenyl)butyroyl)-phosphatidylethanolamine (MPB-PE) or MPB-PEG(2000)-DSPE-bearing liposomes. The lymphatic fate of the engineered vesicles was followed following interstitial injection. Antibody coupling to MPB-PE and MPB-PEG(2000)-DSPE-bearing liposomes generated random exposure of IgG and favoured macrophage recognition. In IgG-hydrazine-PEG(2000)-liposomes, the antibody is coupled via its Fc portion. Although, this was expected to diminish Fc segment exposure to macrophages, rapidly drained IgG-hydrazine-PEG(2000)-liposomes were susceptible to extraction by lymph node macrophage as confirmed by macrophage elimination experiments with clodronate incorporated vesicles. Further studies with peritoneal macrophages have established a role for the scavenger receptor class A-I/II in recognition of the IgG-hydrazine-PEG(2000)-liposomes. Therefore, for efficient targeting of immuno-PEG-liposomes to non-macrophage elements of the regional lymph nodes, other strategies for antibody coupling must be sought and these are discussed.
间质注射免疫聚乙二醇脂质体（免疫PEG脂质体）可穿透薄壁且有窗孔的淋巴微血管，并随后被转运至局部淋巴结。脂质体表面偶联抗体暴露的Fc区域有助于囊泡通过Fc受体被淋巴结巨噬细胞识别和清除。这限制了免疫PEG脂质体对淋巴结非巨噬细胞成分的靶向作用。我们评估了抗体偶联程序对表面暴露的PEG链的影响，目的是设计间质注射后可避免被淋巴结巨噬细胞捕获的免疫PEG脂质体。通过添加高碘酸钠氧化非特异性IgG，以偶联掺入脂质体双层的肼基-PEG(2000)-磷脂。为作比较，IgG也偶联至含N-(4'-(4''-马来酰亚胺基苯基)丁酰基)-磷脂酰乙醇胺（MPB-PE）或MPB-PEG(2000)-DSPE的脂质体。间质注射后追踪工程化囊泡的淋巴命运。将抗体偶联至含MPB-PE和MPB-PEG(2000)-DSPE的脂质体导致IgG随机暴露，并有利于巨噬细胞识别。在IgG-肼基-PEG(2000)-脂质体中，抗体通过其Fc部分偶联。尽管预期这会减少Fc片段对巨噬细胞的暴露，但通过用含氯膦酸盐的囊泡进行的巨噬细胞清除实验证实，快速引流的IgG-肼基-PEG(2000)-脂质体易被淋巴结巨噬细胞提取。对腹膜巨噬细胞的进一步研究确定了A-I/II类清道夫受体在识别IgG-肼基-PEG(2000)-脂质体中的作用。因此，为使免疫PEG脂质体有效靶向局部淋巴结的非巨噬细胞成分，必须寻求其他抗体偶联策略，并对此进行了讨论。
