Theranostic Copolymers Neutralize Reactive Oxygen Species and Lipid Peroxidation Products for the Combined Treatment of Traumatic Brain Injury.
Theranostic Copolymers Neutralize Reactive Oxygen Species and Lipid Peroxidation Products for the Combined Treatment of Traumatic Brain Injury.
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治疗诊断共聚物中和活性氧和脂质过氧化产物用于创伤性脑损伤的联合治疗。
DOI：
10.1021/acs.biomac.1c01635
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发表时间：
2022-04-11
影响因子：
6.2
通讯作者：
Convertine, Anthony J.
中科院分区：
文献类型：
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作者：
Priester, Aaron;Waters, Richard;Abbott, Ashleigh;Hilmas, Krista;Woelk, Klaus;Miller, Hunter A.;Tarudji, Aria W.;Gee, Connor C.;McDonald, Brandon;Kievit, Forrest M.;Convertine, Anthony J.
创伤性脑损伤（TBI）导致活性氧（ROS）和脂质过氧化产物（LPOx）的产生，包括丙烯醛和4-羟基壬烯醛（4 HNE）。这些生物化学紊乱的存在导致在损伤的第二阶段的神经变性。快速中和多种物种的能力可以显著改善TBI患者的预后。然而，创建同时靶向多种生物化学紊乱的疗法的困难极大地限制了治疗功效。因此，我们的目标是设计一种在TBI后可以快速结合和中和ROS和LPOx的材料。为此，制备了一系列基于硫辛酸甲基丙烯酸酯（LIPOMA）和聚乙二醇单甲醚甲基丙烯酸酯（FW ~ 950 Da）（O 950）的硫醇官能化生物相容性共聚物。还从cyclen开始合成可聚合的钆-DOTA甲基丙烯酸酯单体（Gd-MA），以促进直接磁共振成像（MRI）和体内追踪累积。这些神经保护性共聚物（NPC）显示出快速且有效地中和ROS和LPOx两者。辣根过氧化物酶（HRPO）的吸光度测定表明，NPC有效地中和H2 O2，而R-藻红蛋白保护试验表明，它们能够保护荧光蛋白免受氧化损伤。1H NMR研究表明，硫醇官能的NPC与丙烯醛迅速形成共价键，有效地将其从溶液中除去。在体外细胞研究与SH-SY 5 Y分化的神经元表明，NPC提供独特的保护，对有毒浓度的H2 O2和丙烯醛。NPC快速积累并保留在受控皮质撞击小鼠的受损脑中，并减少创伤后氧化应激。因此，这些材料显示出改善多种生物化学紊乱的靶结合的希望，希望改善TBI治疗结果。
Traumatic brain injury (TBI) results in the generation of reactive oxygen species (ROS) and lipid peroxidation product (LPOx) including acrolein and 4-hydroxynonenal (4HNE). The presence of these biochemical derangements results in neurodegeneration during the secondary phase of the injury. The ability to rapidly neutralize multiple species could significantly improve outcomes for TBI patients. However, difficulty in creating therapies that target multiple biochemical derangements simultaneously has greatly limited therapeutic efficacy. Therefore, our goal was to design a material that could rapidly bind and neutralize both ROS and LPOx following TBI. To do this, a series of thiol-functionalized biocompatible copolymers based on lipoic acid methacrylate (LIPOMA) and polyethylene glycol monomethyl ether methacrylate (FW ~ 950 Da) (O950) were prepared. A polymerizable gadolinium-DOTA methacrylate monomer (Gd-MA) was also synthesized starting from cyclen to facilitate direct magnetic resonance imaging (MRI) and in vivo tracking of accumulation. These neuroprotective copolymers (NPCs) were shown to rapidly and effectively neutralize both ROS and LPOx. Horseradish peroxidase (HRPO) absorbance assays showed that the NPCs efficiently neutralized H2O2 while R-phycoerythrin protection assays demonstrated their ability to protect the fluorescent protein from oxidative damage. 1H NMR studies indicated the thiol-functional NPCs rapidly form covalent bonds with acrolein, efficiently removing it from solution. In vitro cell studies with SH-SY5Y-differentiated neurons showed that NPCs provide unique protection against toxic concentrations of both H2O2 and acrolein. NPCs rapidly accumulate and are retained in injured brain in controlled cortical impact mice and reduce post-traumatic oxidative stress. Therefore, these materials show promise for improved target engagement of multiple biochemical derangements in hopes of improving TBI therapeutic outcomes.
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通讯作者：
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