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Heparin-based hydrogels with tunable sulfation & degradation for anti-inflammatory small molecule delivery.

ABSTRACT: Sustained release of anti-inflammatory agents remains challenging for small molecule drugs due to their low molecular weight and hydrophobicity. Therefore, the goal of this study was to control the release of a small molecule anti-inflammatory agent, crystal violet (CV), from hydrogels fabricated with heparin, a highly sulfated glycosaminoglycan capable of binding positively-charged molecules such as CV. In this system, both electrostatic interactions between heparin and CV and hydrogel degradation were tuned simultaneously by varying the level of heparin sulfation and varying the amount of dithiothreitol within hydrogels, respectively. It was found that heparin sulfation significantly affected CV release, whereby more sulfated heparin hydrogels (Hep and Hep(-N)) released CV with near zero-order release kinetics (R-squared values between 0.96-0.99). Furthermore, CV was released more quickly from fast-degrading hydrogels than slow-degrading hydrogels, providing a method to tune total CV release between 5-15 days while maintaining linear release kinetics. In particular, N-desulfated heparin hydrogels exhibited efficient CV loading (?90% of originally included CV), near zero-order CV release kinetics, and maintenance of CV bioactivity after release, making this hydrogel formulation a promising CV delivery vehicle for a wide range of inflammatory diseases.

SUBMITTER: Peng Y

PROVIDER: S-EPMC4987208 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Heparin-based hydrogels with tunable sulfation & degradation for anti-inflammatory small molecule delivery.

Peng Yifeng Y Tellier Liane E LE Temenoff Johnna S JS

Biomaterials science 20160801 9

Sustained release of anti-inflammatory agents remains challenging for small molecule drugs due to their low molecular weight and hydrophobicity. Therefore, the goal of this study was to control the release of a small molecule anti-inflammatory agent, crystal violet (CV), from hydrogels fabricated with heparin, a highly sulfated glycosaminoglycan capable of binding positively-charged molecules such as CV. In this system, both electrostatic interactions between heparin and CV and hydrogel degradat ...[more]

PMID: 27447003

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Project description:The activation of nuclear factor (NF)?B pathway and its transducing signaling cascade has been associated with the pathogenesis of many inflammatory diseases. The central role that I?B? and p65 phosphorylation play in regulating NF?B signalling in response to inflammatory stimuli made these proteins attractive targets for therapeutic strategies. Although several chemical classes of NF?B inhibitors have been identified, it is only for a few of those that a safety assessment based on a comprehensive understanding of their pharmacologic mechanism of action has been reported. Here, we describe the specific anti-inflammatory effect of bindarit, an indazolic derivative that has been proven to have anti-inflammatory activity in a variety of models of inflammatory diseases (including lupus nephritis, arthritis and pancreatitis). The therapeutic effects of bindarit have been associated with its ability to selectively interfere with monocyte recruitment and the "early inflammatory response," although its specific molecular mechanisms have remained ill-defined. For this purpose, we investigated the effect of bindarit on the LPS-induced production of inflammatory cytokines (MCP-1 and MCPs, IL-12?/p40, IL-6 and IL-8/KC) in both a mouse leukaemic monocyte-macrophage cell line and bone marrow derived macrophages (BMDM). Bindarit inhibits the LPS-induced MCP-1 and IL-12?/p40 expression without affecting other analyzed cytokines. The effect of bindarit is mediated by the downregulation of the classical NF?B pathway, involving a reduction of I?B? and p65 phosphorylation, a reduced activation of NF?B dimers and a subsequently reduced nuclear translocation and DNA binding. Bindarit showed a specific inhibitory effect on the p65 and p65/p50 induced MCP-1 promoter activation, with no effect on other tested activated promoters. We conclude that bindarit acts on a specific subpopulation of NF?B isoforms and selects its targets wihtin the whole NF?B inflammatory pathway. These findings pave the way for future applications of bindarit as modulator of the inflammatory response.

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Heparin-based hydrogels with tunable sulfation & degradation for anti-inflammatory small molecule delivery.

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Heparin-based hydrogels with tunable sulfation & degradation for anti-inflammatory small molecule delivery.

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