Development of specific delivery system for anti-oxidant enzymes to inflammatory lesions

近年来研究表明，活化的中性粒细胞通过产生羟自由基和过氧化亚硝酸盐，参与了缺血再灌注后炎性病变的诱导和发展，并导致多种组织损伤。本研究的目的是防止这些物质的产生，通过清除超氧化物的抗氧化酶传递到inflammatorylesions.Activated白细胞诱导急性组织损伤，使这些细胞可能会释放活性氧物种，包括超氧化物后不久，附着到内皮细胞衬里。为了将超氧化物歧化酶（SOD）歧化为氧分子和过氧化氢，我们首先合成了超氧化物歧化酶（SOD）与聚乙二醇（PEG; MW，5 kDa）的偶联物和硝酰基自旋探针SOD模拟物与PEG的偶联物。其次，我们合成了抗炎症细胞表面透明质酸受体（CD 44）的硝酰基自旋探针，并对这些抗氧化物质的体内行为进行了研究，阐明了这些物质具有在血管内滞留和在炎症病变部位聚集的特性。此外，我们将这些物质应用于小鼠短暂性局灶性脑缺血损伤。结果，它们显著抑制了脑水肿的形成。通过这些事实，功能性抗氧化聚合物被认为在清除炎性损伤中的自由基中起作用。

Recently, it was generally demonstrated that activated neutrophils are responsible for the induction and development of inflammatory lesions accompanied with ischemia-reperfusion and several types of tissue damages, through the generation of hydroxyl radical and peroxynitrite from superoxide. The purpose of the present study is to prevent the generation of these substances via scavenging superoxide by anti-oxidant enzymes delivered to inflammatory lesions.Activated leukocytes induce acute tissue damage, so that these cells may release reactive oxygen species including superoxide just after attachment to the endothelial cell-lining. To dismutate superoxide into oxygen molecule and hydrogen peroxide, at first, we synthesized a conjugate of superoxide dismutase (SOD) with polyethylene glycol (PEG; MW, 5 kDa), and a conjugate of nitroxyl spin probes, SOD mimics, with PEG. Secondly, we synthesized nitroxyl spin probes conjugated with hyaluronan, which is a legand against the hyaluronan receptor (CD 44) on the cell surface of inflammatory cells.When these anti-oxidant substances, were subjected to the study for their in vivo behaviors, it was elucidated that these substances possess characters, remaining in the intravascular compartment and accumulating in the inflammatory lesion. Furthermore, we applied these substances to transient focal cerebral ischemia injury in mice. As a result, they significantly suppressed brain edema formation. Through these fact, the functional anti-oxidant polymers is thought to play a role in scavenging free radicals in inflammatory lesions.