Controlled release of dexamethasone from peptide nanofiber gels to modulate inflammatory response.
Controlled release of dexamethasone from peptide nanofiber gels to modulate inflammatory response.
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DOI：
10.1016/j.biomaterials.2012.06.003
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发表时间：
2012-10
期刊：
影响因子：
14
通讯作者：
Stupp, Samuel I.
中科院分区：
文献类型：
--
作者：
Webber, Matthew J.;Matson, John B.;Tamboli, Vibha K.;Stupp, Samuel I.
关键词：
具有局部抑制免疫应答能力的新生物材料可在治疗以急性或慢性炎症为特征的疾病中具有广泛的治疗用途，或作为促进改善细胞或组织移植功效的策略。我们在这里报告的模块化肽两亲物（PA）的制备能够释放抗炎药物，地塞米松（Dex），通过共轭通过一个不稳定的腙连接。当与缺乏药物缀合物的类似PA混合时，该分子在水中自组装成长的超分子纳米纤维，并且添加钙盐以屏蔽纳米纤维之间的静电排斥促进凝胶形成。这些凝胶显示在生理介质中持续释放可溶性Dex超过一个月。从这些凝胶中释放的Dex保持其抗炎活性时，在体外评估使用人类炎症报告细胞系，并进一步保存心肌细胞的活力诱导氧化应激。使用悬浮在凝胶中的细胞替代聚苯乙烯微粒，然后将其皮下注射到小鼠中，评价该凝胶减轻细胞移植策略中炎症反应的能力。使用荧光报告分子鲁米诺的活体动物发光成像显示，与相同动物中对照PA内的颗粒的注射部位相比，在用Dex-PA注射颗粒的部位处炎症显著减少。组织学证据表明，当在Dex-PA凝胶内递送颗粒时，浸润炎性细胞的数量显著减少，并且在植入后3天或21天观察到非常少的炎症。Dex-PA的使用可以促进局部抗炎活性，作为再生医学中各种应用的生物材料的组成部分，并且可以特别是基于PA的治疗的有用模块。更广泛地说，这些研究定义了一种通用的策略，用于容易合成具有控制药物释放能力的基于自组装肽的材料。
New biomaterials that have the ability to locally suppress an immune response could have broad therapeutic use in the treatment of diseases characterized by acute or chronic inflammation or as a strategy to facilitate improved efficacy in cell or tissue transplantation. We report here on the preparation of a modular peptide amphiphile (PA) capable of releasing an anti-inflammatory drug, dexamethasone (Dex), by conjugation via a labile hydrazone linkage. This molecule self-assembled in water into long supramolecular nanofibers when mixed with a similar PA lacking the drug conjugate, and the addition of calcium salt to screen electrostatic repulsion between nanofibers promoted gel formation. These nanofiber gels demonstrated sustained release of soluble Dex for over one month in physiologic media. The Dex released from these gels maintained its anti-inflammatory activity when evaluated in vitro using a human inflammatory reporter cell line and furthermore preserved cardiomyocytes viability upon induced oxidative stress. The ability of this gel to mitigate the inflammatory response in cell transplantation strategies was evaluated using cell-surrogate polystyrene microparticles suspended in the nanofiber gel that were then subcutaneously injected in a mouse. Live animal luminescence imaging using the chemiluminescent reporter molecule luminol showed a significant reduction in inflammation at the site where particles were injected with Dex-PA compared to the site of injection for particles within a control PA in the same animal. Histological evidence suggested a marked reduction in the number of infiltrating inflammatory cells when particles were delivered within Dex-PA nanofiber gels and very little inflammation was observed at either 3 days or 21 days post-implantation. The use of Dex-PA could facilitate localized anti-inflammatory activity as a component of biomaterials designed for various applications in regenerative medicine and could specifically be a useful module for PA-based therapies. More broadly, these studies define a versatile strategy for facile synthesis of self-assembling peptide-based materials with the ability to control drug release.
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