Induction of a higher-ordered architecture in glatiramer acetate improves its biological efficiency in an animal model of multiple sclerosis.
Induction of a higher-ordered architecture in glatiramer acetate improves its biological efficiency in an animal model of multiple sclerosis.
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DOI：
10.1039/d0bm00957a
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发表时间：
2020-09-30
影响因子：
6.6
通讯作者：
Inoue M
中科院分区：
文献类型：
--
作者：
Song Z;Khaw YM;Pacheco LA;Tseng KY;Tan Z;Cai K;Ponnusamy E;Cheng J;Inoue M
醋酸格拉替雷（GA）是一种线性无规共聚肽，是多发性硬化症（MS）的一线治疗药物。然而，一个主要的问题是，GA治疗与不良反应和由于需要频繁注射而导致的患者依从性差有关。在这里，我们描述了改进的性能的聚合物药物，即使在低剂量与较低频率的注射，通过修改其架构成一个星形的GA（sGA）。在sGA中，多个GA共价连接到一个核上，这极大地改变了它们的性质，如分子量、大小和形状。球形sGA在腹膜内注射后在体内保留更长时间，并且比GA更容易被RAW 264.7巨噬细胞和骨髓来源的树突状细胞内化。在用实验性自身免疫性脑炎诱导的C57 BL/6小鼠（MS的小鼠模型）中，sGA治疗发挥了显著优于GA的疾病改善效果，尽管剂量较低且注射频率较低。此外，与GA处理条件相比，在sGA处理条件下，脱髓鞘和白细胞浸润的脊髓病理显著地不太明显。因此，我们建议，sGA与高阶架构提供了一个有吸引力的和潜在的可行的治疗选择MS患者。
Glatiramer acetate (GA), a linear random copolypeptide, is a first-line treatment for multiple sclerosis (MS). A major concern, however, is that GA treatment is associated with adverse effects and poor patient adherence due to the need for frequent injections. Here we describe improved performance of the polymeric drug, even at low doses with less-frequent injections, through the modification of its architecture into a star-shaped GA (sGA). In a sGA, multiple GAs are covalently linked onto a core, which greatly changes their properties such as molecular weight, size, and shape. The spherical sGA is retained longer in the body after intraperitoneal injection, and is more readily internalized by RAW 264.7 macrophage cells and bone marrow-derived dendritic cells than GA. In C57BL/6 mice induced with experimental autoimmune encephalitis, a mouse model for MS, sGA treatment exerts disease amelioration effect that is significantly better than that of GA despite a lower dose and less frequent injection. Moreover, spinal cord pathologies of demyelination and leukocyte infiltration are dramatically less pronounced in the sGA treatment condition compared to the GA treatment condition. Thus, we propose that sGA with a higher-ordered architecture offers an attractive and potentially viable treatment option for MS patients.
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