Design of Poly(ethylene Glycol)-Functionalized Hydrophilic Carbon Clusters for Targeted Therapy of Cerebrovascular Dysfunction in Mild Traumatic Brain Injury
Design of Poly(ethylene Glycol)-Functionalized Hydrophilic Carbon Clusters for Targeted Therapy of Cerebrovascular Dysfunction in Mild Traumatic Brain Injury
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DOI：
10.1089/neu.2011.2301
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发表时间：
2013-05-01
影响因子：
4.2
通讯作者：
Tour, James M.
中科院分区：
文献类型：
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作者：
Marcano, Daniela C.;Bitner, Brittany R.;Tour, James M.
创伤性脑损伤是指氧化应激导致脑血管功能障碍，包括脑血流自动调节功能障碍。目前，还没有临床上有效的抗氧化剂治疗这些疾病。目前大多数可用的抗氧化剂的作用机制是抗氧化剂要么转移自由基，要么需要再生，这两种机制在创伤后的有毒环境中都会受到损害。我们以前报道过单壁碳纳米管和超短碳纳米管具有抗氧化活性，它们的特性表明自由基湮灭是其主要机制。我们现在已经开发了一类生物相容的基于碳的纳米载体，聚乙二醇化的亲水性碳簇(PEGHC)，可以通过抗体进一步功能化，从而显示出作为靶向药物输送平台的前景。在此，我们报道了聚乙二醇-羟基喜树碱具有天然的抗氧化活性，并且可以通过P-选择素抗原的抗体在损伤的培养脑内皮细胞模型中被快速靶向。这种疗法的一个直接应用是治疗伴随脑外伤并在面临全身低血压时恶化预后的血管功能障碍。这些体外结果支持了在动物模型中进行进一步研究的必要性。
Traumatic brain injury (TBI) involves the elaboration of oxidative stress that causes cerebrovascular dysfunction, including impairment of autoregulation of cerebral blood flow. Currently, there is no clinically effective antioxidant treatment for these pathologies. Most currently available antioxidants act through mechanisms in which the antioxidant either transfers the radical or requires regeneration, both of which are impaired in the toxic post-TBI environment. We previously reported that single-walled carbon nanotubes (SWCNTs) and ultrashort SWCNTs possess antioxidant activity, and their characteristics suggest that radical annihilation is the major mechanism. We have now developed a biologically compatible class of carbon-based nanovectors, poly(ethylene glycol)-functionalized hydrophilic carbon clusters (PEG-HCCs) that can be further functionalized with antibodies, and hence show promise as targeted drug delivery platforms. Here we report that PEG-HCCs possess innate antioxidant activity and can be rapidly targeted via an antibody to the P-selectin antigen in a model of injured cultured brain endothelial cells. One immediate application of this therapy is to vascular dysfunction that accompanies TBI and worsens outcome in the face of systemic hypotension. These in vitro results support the need for further investigation in animal models.