Study for Interaction of Biological Milieu with Nano-drug Carrier system

聚乙二醇是一种无毒、无免疫原性的材料，对其进行表面修饰可以提高纳米载体的免疫原性和药代动力学。然而，我们报道了已被批准用于临床使用的聚乙二醇化脂质体（SL），当它们以一定间隔在同一动物中施用两次时失去其长循环特性（加速血液清除（ABC）现象）。我们阐明，响应于SL的第一剂量而分泌的抗PEG IgM负责通过启动补体激活快速清除第二剂量。我们进一步阐明了这种抗PEG IgM的产生是在裸鼠（无T细胞）中引起的，而在SCID小鼠（无B和T细胞）和脾切除小鼠（无脾）中不引起。这表明脾B细胞以T细胞非依赖性方式产生抗PEG IgM。SL与非T细胞依赖性抗原一样激活脾脏免疫。我们的研究清楚地表明，如果任何PEG化制剂诱导抗PEG IgM产生，则这种制剂在重复注射时可能显示出意外的药代动力学行为，因此可能显示出较低的治疗功效或甚至引起不期望的副作用。因此，消除聚乙二醇化制剂的免疫原性而不显著损害其体内性能的策略对于有前景的聚乙二醇化制剂的进一步开发是高度期望的。

PEG is considered as non-toxic and non-immunogenic material, and surface modification with it can improve the immunogenicity and pharmacokinetics of nanocarriers. However, we reported that PEGylated liposome (SL), which has been approved for clinical use, loses their long circulating properties when they are administered twice in same animal with certain interval (accelerated blood clearance (ABC) phenomenon). We elucidated that anti-PEG IgM, secreted in response to the first dose of SL, is responsible for the rapid clearance of the second dose via initiation of complement activation. We further elucidated that such anti-PEG IgM production is caused in nude mice (no T-cells), while it was not caused in SCID mice (no B and T cells) and splenectomized mice (no spleen). These suggest that spleen B cells produce the anti-PEG IgM in a T-cell independent manner. It appears that SL activates the immunity in spleen as T-cell independent antigens do. Our studies clearly demonstrate that any PEGylated formulations may display unexpected pharmacokinetic behavior upon repeated injection if such formulation induce anti-PEG IgM production and, as a consequence, may show less therapeutic efficacy or even cause undesirable side-effects. Therefore, a strategy to abrogate the immunogenicity of PEGylated formulations without significant compromising their in vivo performance would be highly desirable for the further development of promising PEGylated formulations.