title: Polysaccharide-based biomaterials with on-demand nitric oxide releasing property regulated by enzyme catalysis.
abstract: The regulatory role of nitric oxide (NO) in cell signaling has been well recognized. Clinically, NO deficiency is known to be associated with severe vascular disorders, especially in patients with long-term diabetes. Exogenous compensation of NO is a promising therapeutic strategy, although the lack of stable NO compounds often lead to unsatisfactory clinical outcomes. In the present study, we report a stable comb-shaped polymer (CS-NO) using glycosylated NO compound as pendent chains and chitosan (CS) as backbone for controlled NO release. The on-demand release of NO is achieved by controlling the decomposition process of the CS-NO polymer, which is blocked by galactose and only occurs in the presence of glycosidase, making the NO releasing kinetic closely correlate with the glycosidase concentration. In addition, due to its high stability, the CS-NO polymers can also be processed into supportive membrane or injectable hydrogel, further demonstrating its clinical potential. Indeed, we report that the NO-releasing membrane inhibited platelet adhesion, prolonged activated partial thromboplastin time (APTT) as shown in the platelet-rich-plasma (PRP) assay. We also observe enhanced human umbilical vein endothelial cell growth yet suppressed vascular smooth muscle cell proliferation on the NO-contained membrane in vitro. Furthermore, in vivo administration of CS-NO solution significantly enhanced angiogenesis in diabetic mice with hind-limb ischemia. Protective effect of CS-NO was also observed against limb necrosis. Given the physiological importance of NO, the CS-NO polymer may be considered a promising option in therapeutic development against vascular disorders and diabetic feet.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071, PR China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhao
authors.forename: Jimin
authors.initials: J
authors.lastname: Zhang
authors.forename: Lijie
authors.initials: L
authors.lastname: Song
authors.forename: Qing
authors.initials: Q
authors.lastname: Ji
authors.forename: Yao
authors.initials: Y
authors.lastname: Yao
authors.forename: Yun
authors.initials: Y
authors.lastname: Cui
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Peng George
authors.initials: PG
authors.lastname: Wang
authors.forename: Deling
authors.initials: D
authors.lastname: Kong
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D048271:Chitosan / Q000737:chemistry; D057930:Click Chemistry; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy; D006801:Humans; D051379:Mice; D009569:Nitric Oxide / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D010973:Platelet Adhesiveness / Q000187:drug effects; D011134:Polysaccharides / Q000737:chemistry*
chemical_list: D001672:Biocompatible Materials; D011134:Polysaccharides; D009569:Nitric Oxide; D048271:Chitosan
keywords: Cardiovascular biomaterials; Chitosan; Controlled release; Nitric oxide; β-galactosidase