A mouse model for studying the effect of blood anti-PEG IgMs levels on the in vivo fate of PEGylated liposomes
A mouse model for studying the effect of blood anti-PEG IgMs levels on the in vivo fate of PEGylated liposomes
复制标题
用于研究血液抗 PEG IgM 水平对 PEG 化脂质体体内命运影响的小鼠模型
DOI：
10.1016/j.ijpharm.2022.121539
复制
发表时间：
2022
影响因子：
5.8
通讯作者：
Tatsuhiro Ishida
中科院分区：
文献类型：
--
作者：
Marwa M. El Sayed;Taro Shimizu;Amr S. Abu Lila;Nehal E. Elsadek;Sherif E. Emam;Eman Alaaeldin;Amal Kamal;Hatem A. Sarhan;Hidenori Ando;Yu Ishima;Tatsuhiro Ishida
体循环中抗聚乙二醇（PEG）抗体的存在可能对PEG化产物在临床中的治疗活性具有潜在意义。为了研究预先存在的抗PEG抗体对体内脂肪酸的影响和PEG化治疗剂的治疗效率，我们通过腹膜内（i. p.）接种分泌单克隆抗PEG IgM的杂交瘤细胞（HIK-M09和HIK-M11），模拟血液中预先存在的抗PEG抗体。在该模型中，血液中抗PEG IgM的滴度随着腹膜内接种后杂交瘤细胞数量和时间的增加而增加。静脉注射空PEG化脂质体后，抗PEG IgM的体内水平以剂量依赖性方式降低。与没有可测量的抗PEG IgM的C26荷瘤小鼠相比，具有可测量水平的抗PEG IgM的C26荷瘤小鼠接受DiR标记的空聚乙二醇化脂质体的静脉内注射，显示出较低水平的脂质体肿瘤蓄积和较高水平的肝脏和脾脏蓄积。这说明鼠循环中抗PEG IgM的存在诱导了PEG化脂质体的加速血液清除并减少了其肿瘤蓄积。在抗PEG IgM小鼠模型中仔细检查市售含多柔比星（DXR）的PEG化脂质体Doxil®的生物分布和抗肿瘤功效。在具有循环抗PEG IgM的C26荷瘤小鼠中，与不具有循环抗PEG IgM的荷瘤小鼠相比，在注射后24小时，在血液和肿瘤中几乎没有观察到DXR，并且在脾脏和肝脏中观察到增加的DXR蓄积。在存在抗PEG IgM的情况下，Doxil®的抗肿瘤功效在C26荷瘤小鼠中显著受损。这些结果表明，抗PEG IgM小鼠模型可以是临床前研究中PEG化治疗剂的不同制剂的治疗有效性的有用预后指标。
The presence of anti-polyethylene glycol (PEG) antibodies in the systemic circulation might have potential implications for the therapeutic activity of PEGylated productsin vivoin the clinic. In order to study the effect of pre-existing anti-PEG antibodies on thein vivofate and the therapeutic efficiency of PEGylated therapeutics, we developed a BALB/c mouse model by virtue of the intraperitoneal (i.p.) inoculation of hybridoma cells (HIK-M09 and HIK-M11), secreting monoclonal anti-PEG IgM, mimicking the presence of pre-existing anti-PEG antibodies in the blood. In the model, the titers of anti-PEG IgM in the blood increased as a function of hybridoma cells numbers and time after i.p. inoculation. Thein vivolevels of anti-PEG IgM decreased in a dose-dependent manner, following i.v. administration of empty PEGylated liposomes. C26 tumor-bearing mice with measurable levels of anti-PEG IgM, receiving i.v. injection of DiR-labeled empty PEGylated liposomes, showed lower levels of liposomal tumor accumulation and higher levels of liver and spleen accumulation, compared to C26 tumor-bearing mice without measurable anti-PEG IgM. This specifies that the presence of anti-PEG IgM in the murine circulation induced accelerated blood clearance of PEGylated liposomes and reduced their tumor accumulation. The biodistribution and antitumor efficacy of commercially available doxorubicin (DXR)-containing PEGylated liposomes, Doxil®, were scrutinized in the anti-PEG IgM mouse model. In C26 tumor-bearing mice having circulating anti-PEG IgM, at 24 h after injection almost no DXR was observed in blood and tumor, and increased DXR accumulation was observed in spleen and liver, compared to tumor-bearing mice with no circulating anti-PEG IgM. The antitumor efficacy of Doxil® was significantly compromised in the C26 tumor-bearing mice in the presence of anti-PEG IgM. These results demonstrate that the anti-PEG IgM mouse model could be a useful prognostic indicator for the therapeutic effectiveness of different formulations of PEGylated therapeutics in pre-clinical studies.