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

聚乙二醇被认为是一种无毒、无免疫原性的物质，用它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，我们报道了已批准临床使用的聚乙二醇化脂质体（SL），当在同一动物中以一定的间隔给药两次（加速血液清除（ABC）现象）时，失去了其长循环特性。我们阐明了抗peg IgM，在第一剂量SL的反应中分泌，通过启动补体激活负责第二剂量的快速清除。我们进一步阐明了这种抗peg IgM的产生是在裸鼠（没有T细胞）中引起的，而在SCID小鼠（没有B细胞和T细胞）和脾切除小鼠（没有脾脏）中没有引起。这表明脾脏B细胞以不依赖于t细胞的方式产生抗peg IgM。SL似乎像t细胞独立抗原一样激活脾脏免疫。我们的研究清楚地表明，任何聚乙二醇化制剂，如果这种制剂诱导抗peg IgM的产生，在重复注射时可能会表现出意想不到的药代动力学行为，从而可能表现出较低的治疗效果，甚至引起不良的副作用。因此，在不显著影响其体内性能的情况下取消聚乙二醇化制剂的免疫原性的策略对于有前途的聚乙二醇化制剂的进一步开发是非常可取的。

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.