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Supramolecular Aptamers on Graphene Oxide for Efficient Inhibition of Thrombin Activity.

ABSTRACT: Graphene oxide (GO), a two-dimensional material with a high aspect ratio and polar functional groups, can physically adsorb single-strand DNA through different types of interactions, such as hydrogen bonding and ?-? stacking, making it an attractive nanocarrier for nucleic acids. In this work, we demonstrate a strategy to target exosites I and II of thrombin simultaneously by using programmed hybrid-aptamers for enhanced anticoagulation efficiency and stability. The targeting ligand is denoted as Supra-TBA_15/29 (supramolecular TBA_15/29), containing TBA₁₅ (a 15-base nucleotide, targeting exosite I of thrombin) and TBA₂₉ (a 29-base nucleotide, targeting exosite II of thrombin), and it is designed to allow consecutive hybridization of TBA₁₅ and TBA₂₉ to form a network of TBAs (i.e., supra-TBA_15/29). The programmed hybrid-aptamers (Supra-TBA_15/29) were self-assembled on GO to further boost anticoagulation activity by inhibiting thrombin activity, and thus suppress the thrombin-induced fibrin formation from fibrinogen. The Supra-TBA_15/29-GO composite was formed mainly through multivalent interaction between poly(adenine) from Supra-TBA_15/29 and GO. We controlled the assembly of Supra-TBA_15/29 on GO by regulating the preparation temperature and the concentration ratio of Supra-TBA_15/29 to GO to optimize the distance between TBA₁₅ and TBA₂₉ units, aptamer density, and aptamer orientation on the GO surfaces. The dose-dependent thrombin clotting time (TCT) delay caused by Supra-TBA_15/29-GO was >10 times longer than that of common anticoagulant drugs including heparin, argatroban, hirudin, and warfarin. Supra-TBA_15/29-GO exhibits high biocompatibility, which has been proved by in vitro cytotoxicity and hemolysis assays. In addition, the thromboelastography of whole-blood coagulation and rat-tail bleeding assays indicate the anticoagulation ability of Supra-TBA_15/29-GO is superior to the most widely used anticoagulant (heparin). Our highly biocompatible Supra-TBA_15/29-GO with strong multivalent interaction with thrombin [dissociation constant (K _d) = 1.9 × 10^-11 M] shows great potential as an effective direct thrombin inhibitor for the treatment of hemostatic disorders.

SUBMITTER: Lin TX

PROVIDER: S-EPMC6532589 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Supramolecular Aptamers on Graphene Oxide for Efficient Inhibition of Thrombin Activity.

Lin Ting-Xuan TX Lai Pei-Xin PX Mao Ju-Yi JY Chu Han-Wei HW Unnikrishnan Binesh B Anand Anisha A Huang Chih-Ching CC

Frontiers in chemistry 20190516

Graphene oxide (GO), a two-dimensional material with a high aspect ratio and polar functional groups, can physically adsorb single-strand DNA through different types of interactions, such as hydrogen bonding and π-π stacking, making it an attractive nanocarrier for nucleic acids. In this work, we demonstrate a strategy to target exosites I and II of thrombin simultaneously by using programmed hybrid-aptamers for enhanced anticoagulation efficiency and stability. The targeting ligand is denoted a ...[more]

PMID: 31157200

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Project description:BACKGROUND:Graphene holds great promise for potential use in next-generation electronic and photonic devices due to its unique high carrier mobility, good optical transparency, large surface area, and biocompatibility. The aim of this study was to investigate the antibacterial effects of graphene oxide (GO) and reduced graphene oxide (rGO) in Pseudomonas aeruginosa. In this work, we used a novel reducing agent, betamercaptoethanol (BME), for synthesis of graphene to avoid the use of toxic materials. To uncover the impacts of GO and rGO on human health, the antibacterial activity of two types of graphene-based material toward a bacterial model P. aeruginosa was studied and compared. METHODS:The synthesized GO and rGO was characterized by ultraviolet-visible absorption spectroscopy, particle-size analyzer, X-ray diffraction, scanning electron microscopy and Raman spectroscopy. Further, to explain the antimicrobial activity of graphene oxide and reduced graphene oxide, we employed various assays, such as cell growth, cell viability, reactive oxygen species generation, and DNA fragmentation. RESULTS:Ultraviolet-visible spectra of the samples confirmed the transition of GO into graphene. Dynamic light-scattering analyses showed the average size among the two types of graphene materials. X-ray diffraction data validated the structure of graphene sheets, and high-resolution scanning electron microscopy was employed to investigate the morphologies of prepared graphene. Raman spectroscopy data indicated the removal of oxygen-containing functional groups from the surface of GO and the formation of graphene. The exposure of cells to GO and rGO induced the production of superoxide radical anion and loss of cell viability. Results suggest that the antibacterial activities are contributed to by loss of cell viability, induced oxidative stress, and DNA fragmentation. CONCLUSION:The antibacterial activities of GO and rGO against P. aeruginosa were compared. The loss of P. aeruginosa viability increased in a dose- and time-dependent manner. Exposure to GO and rGO induced significant production of superoxide radical anion compared to control. GO and rGO showed dose-dependent antibacterial activity against P. aeruginosa cells through the generation of reactive oxygen species, leading to cell death, which was further confirmed through resulting nuclear fragmentation. The data presented here are novel in that they prove that GO and rGO are effective bactericidal agents against P. aeruginosa, which would be used as a future antibacterial agent.

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Supramolecular Aptamers on Graphene Oxide for Efficient Inhibition of Thrombin Activity.

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Supramolecular Aptamers on Graphene Oxide for Efficient Inhibition of Thrombin Activity.

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