Sustained dual drug delivery of anti-inhibitory molecules for treatment of spinal cord injury.
Sustained dual drug delivery of anti-inhibitory molecules for treatment of spinal cord injury.
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DOI：
10.1016/j.jconrel.2015.06.031
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发表时间：
2015-09-10
期刊：
影响因子：
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通讯作者：
Sakiyama-Elbert SE
中科院分区：
文献类型：
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作者：
Wilems TS;Sakiyama-Elbert SE
髓鞘相关抑制物(MAI)和硫酸软骨素蛋白多糖(CSPGs)是脊髓损伤后轴突生长抑制和限制功能恢复的主要因素。NEP1-40肽竞争性地结合Nogo受体并部分阻断MAI的抑制作用，而软骨素酶ABC(ChABC)则酶促消化损伤部位上调的CSPG。体外研究表明，当将分离的胚胎背根神经节接种到同时含有MAIS和CSPG的抑制底物上时，ChABC和NEP1-40的组合比单独使用任何一种处理都能增加轴突的延伸。此外，通过将ChABC装载到脂质微管中，将Np1-40装载到聚乳酸-乙醇酸(PLGA)微球中，从而实现了从生物材料支架中提供生物活性ChABC和Np1-40的持续输送的能力，从而消除了对鞘内侵入性泵或导管的需要。以PLGA微球和脂质微管为载体的纤维蛋白支架在体外能释放活性ChABC长达一周，释放活性NEP1-40达两周以上。此外，纤维蛋白支架中的载药系统减少了CSPG的沉积和胶质瘢痕的形成，同时也促进了体内脊髓损伤后轴突的生长。因此，ChABC和NEP1-40在损伤脊髓内持续的局部传递可能会阻断髓鞘和CSPG相关的抑制，并允许改善轴突生长。
Myelin-associated inhibitors (MAIs) and chondroitin sulfate proteoglycans (CSPGs) are major contributors to axon growth inhibition following spinal cord injury and limit functional recovery. The NEP1-40 peptide competitively binds the Nogo receptor and partially blocks inhibition from MAIs, while chondroitinase ABC (ChABC) enzymatically digests CSPGs, which are upregulated at the site of injury. In vitro studies showed that the combination of ChABC and NEP1-40 increased neurite extension compared to either treatment alone when dissociated embryonic dorsal root ganglia were seeded onto inhibitory substrates containing both MAIs and CSPGs. Furthermore, the ability to provide sustained delivery of biologically active ChABC and NEP1-40 from biomaterial scaffolds was achieved by loading ChABC into lipid microtubes and NEP1-40 into poly (lactic-co-glycolic acid) (PLGA) microspheres, obviating the need for invasive intrathecal pumps or catheters. Fibrin scaffolds embedded with the drug delivery systems (PLGA microspheres and lipid microtubes) were capable of releasing active ChABC for up to one week and active NEP1-40 for over two weeks in vitro. In addition, the loaded drug delivery systems in fibrin scaffolds decreased CSPG deposition and development of a glial scar, while also increasing axon growth after spinal cord injury in vivo. Therefore, the sustained, local delivery of ChABC and NEP1-40 within the injured spinal cord may block both myelin and CSPG-associated inhibition and allow for improved axon growth.