Interactions of Alginate-Deferoxamine Conjugates With Blood Components and Their Antioxidation in the Hemoglobin Oxidation Model.

Tong Sun,Rui Zhong,Chao You,Hao Liu,Chengwei Wang,Meng Tian,Hao Li,Lu Ma,Junwen Guan,Xi Guo

doi:10.3389/fbioe.2020.00053

Abstract

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 in vitro. 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.

Highlights

Deferoxamine (DFO) has long been used as an FDA-approved intravenously injected iron chelator in clinic for half a century in the treatment of iron overload diseases, while in the recent years, a great deal of attention was given to the important applications of DFO in the growing field of tissue regeneration as a result of its unique properties to inhibit inflammation and promote vascularization (Guo et al, 2019; Holden and Nair, 2019)
alginate-DFO conjugates (ADs) were synthesized through a two-step process in which alginate was oxidized to ADA firstly, and the conjugates were prepared by Schiff-base reaction through the terminal amine groups in DFO and reactive aldehyde groups in ADA and followed by reduction with NaBH3CN and NaBH4 (Figure 1A)
Hemolysis is characterized as the rupture of red blood cells (RBCs) and the release of the cytoplasm, and the evaluation of hemolysis is essential regarding the biosafety of exogenous materials

Summary

Introduction

Deferoxamine (DFO) has long been used as an FDA-approved intravenously injected iron chelator in clinic for half a century in the treatment of iron overload diseases, while in the recent years, a great deal of attention was given to the important applications of DFO in the growing field of tissue regeneration as a result of its unique properties to inhibit inflammation and promote vascularization (Guo et al, 2019; Holden and Nair, 2019). The application of DFO is still of much limitation owing to its drawbacks, like other small molecular drugs, including short plasma half-life and toxicity (Cassinerio et al, 2014). In this regard, polymer-drug conjugation strategy is appropriate for DFO to overcome these obstacles (Yan et al, 2016). The reasons why these conjugates with fine-tuned structures do not function as intended need to be elucidated in order to advance the therapy in clinic (Feng et al, 2019)

Methods

Results

Conclusion