Sun Tong, Guo Xi, Zhong Rui, Wang Chengwei, Liu Hao, Li Hao, Ma Lu, Guan Junwen, You Chao, Tian Meng
Neurosurgery Research Laboratory, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China.
Front Bioeng Biotechnol. 2020 Feb 11;8:53. doi: 10.3389/fbioe.2020.00053. eCollection 2020.
While deferoxamine (DFO) has long been used as an FDA-approved iron chelator, its proangiogenesis ability attracts increasing number of research interests. To address its drawbacks such as short plasma half-life and toxicity, polymeric conjugated strategy has been proposed and shown superiority. Owing to intravenous injection and application in blood-related conditions, however, the blood interactions and antioxidation of the DFO-conjugates and the mechanisms underlying these outcomes remain to be elucidated. In this regard, incubating with three different molecular-weight (MW) alginate-DFO conjugates (ADs) red blood cells (RBCs), coagulation system, complement and platelet were investigated. To prove the antioxidant activity of ADs, we used hemoglobin oxidation model . ADs did not cause RBCs hemolysis while reversible aggregation and normal deformability ability were observed. However, the coagulation time, particularly APTT and TT, were significantly prolonged in a dose-dependent manner, and fibrinogen was dramatically decreased, suggesting ADs could dominantly inhibit the intrinsic pathways in the process of coagulation. The dose-dependent anticoagulation might be related with the functional groups along the alginate chains. The complements, C3a and C5a, were activated by ADs in a dose-dependent manner through alternative pathway. For platelet, ADs slightly suppressed the activation and aggregation at low concentration. Based on above results, the cross-talking among coagulation, complement and platelet induced by ADs was proposed. The antioxidation of ADs through iron chelation was proved and the antioxidant activity was shown in a MW-dependent manner.
尽管去铁胺（DFO）长期以来一直作为美国食品药品监督管理局（FDA）批准的铁螯合剂使用，但其促血管生成能力吸引了越来越多的研究兴趣。为了解决其诸如血浆半衰期短和毒性等缺点，人们提出了聚合物共轭策略并显示出优越性。然而，由于静脉注射以及在血液相关病症中的应用，DFO共轭物的血液相互作用和抗氧化作用以及这些结果背后的机制仍有待阐明。在这方面，研究了三种不同分子量（MW）的藻酸盐-DFO共轭物（ADs）与红细胞（RBCs）、凝血系统、补体和血小板的孵育情况。为了证明ADs的抗氧化活性，我们使用了血红蛋白氧化模型。ADs未引起RBCs溶血，同时观察到可逆聚集和正常的变形能力。然而，凝血时间，尤其是活化部分凝血活酶时间（APTT）和凝血酶时间（TT），以剂量依赖的方式显著延长，并且纤维蛋白原显著降低，这表明ADs在凝血过程中可主要抑制内源性途径。剂量依赖性抗凝作用可能与藻酸盐链上的官能团有关。补体C3a和C5a通过替代途径被ADs以剂量依赖的方式激活。对于血小板，ADs在低浓度时轻微抑制其活化和聚集。基于上述结果，提出了ADs诱导的凝血、补体和血小板之间的相互作用。通过铁螯合证明了ADs的抗氧化作用，并且抗氧化活性以分子量依赖的方式呈现。
