Poly(ethylene glycol) modification enhances penetration of fibroblast growth factor 2 to injured spinal cord tissue from an intrathecal delivery system
Poly(ethylene glycol) modification enhances penetration of fibroblast growth factor 2 to injured spinal cord tissue from an intrathecal delivery system
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DOI：
10.1016/j.jconrel.2010.01.029
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发表时间：
2010-05-21
影响因子：
10.8
通讯作者：
Shoichet, Molly S.
中科院分区：
文献类型：
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作者：
Kang, Catherine E.;Tator, Charles H.;Shoichet, Molly S.
目前尚无有效的治疗脊髓损伤的方法，临床给药技术受到血脊髓屏障的限制。我们实验室开发了一种可注射给药系统，由透明质酸和甲基纤维素(HAMC)的生物聚合物混合物组成，可以在鞘内持续药物释放长达24小时。成纤维细胞生长因子2(FGF2)具有血管生成和营养作用，在治疗脊髓损伤方面具有很大的潜力，但以往的研究表明局部给药不能渗透到脊髓组织中。已知与聚乙二醇(PEG)的偶联通过减少清除和提供免疫原性屏蔽来改善蛋白质对组织的渗透。我们研究了聚乙二醇与FGF2的偶联作用，并比较了从HAMC鞘内注射时，其相对于未修饰的FGF2在损伤脊髓组织中的分布。重要的是，当局部给药时，聚乙二醇偶联物几乎使损伤脊髓中的FGF2浓度增加了一倍，与以前的报道相反，我们使用更灵敏的检测技术证明了一些FGF2穿透到损伤脊髓中。我们的结果表明，FGF2的聚乙二醇化通过降低其消除速度来增强组织渗透。(C)2010爱思唯尔B.V.保留所有权利。
There is no effective treatment for spinal cord injury and clinical drug delivery techniques are limited by the blood-spinal cord barrier. Our lab has developed an injectable drug delivery system consisting of a biopolymer blend of hyaluronan and methylcellulose (HAMC) that can sustain drug release for up to 24 h in the intrathecal space. Fibroblast growth factor 2 (FGF2) has great potential for treatment of spinal cord injury due to its angiogenic and trophic effects, but previous studies showed no penetration into spinal cord tissue when delivered locally. Conjugation to poly(ethylene glycol) (PEG) is known to improve penetration of proteins into tissue by reducing clearance and providing immunogenic shielding. We investigated conjugation of PEG to FGF2 and compared its distribution relative to unmodified FGF2 in injured spinal cord tissue when delivered intrathecally from HAMC. Importantly, PEG conjugation nearly doubled the concentration of FGF2 in the injured spinal cord when delivered locally and, contrary to previous reports, we show that some FGF2 penetrated into the injured spinal cord using a more sensitive detection technique. Our results suggest that PEGylation of FGF2 enhanced tissue penetration by reducing its rate of elimination. (C) 2010 Elsevier B.V. All rights reserved.