Controlling the Release of Small, Bioactive Proteins via Dual Mechanisms with Therapeutic Potential,Advanced Healthcare Materials

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Controlling the Release of Small, Bioactive Proteins via Dual Mechanisms with Therapeutic Potential
Advanced Healthcare Materials ( IF 10.0 ) Pub Date : 2017-10-12 , DOI: 10.1002/adhm.201700713
Prathamesh M Kharkar ₁ , Rebecca A Scott _{1,

2} , Laura P Olney ₃ , Paige J LeValley ₄ , Emanual Maverakis ₃ , Kristi L Kiick _{1,

5} , April M Kloxin _{1,

4}

Affiliation

Injectable delivery systems that respond to biologically relevant stimuli present an attractive strategy for tailorable drug release. Here, the design and synthesis of unique polymers are reported for the creation of hydrogels that are formed in situ and degrade in response to clinically relevant endogenous and exogenous stimuli, specifically reducing microenvironments and externally applied light. Hydrogels are formed with polyethylene glycol and heparin‐based polymers using a Michael‐type addition reaction. The resulting hydrogels are investigated for the local controlled release of low molecular weight proteins (e.g., growth factors and cytokines), which are of interest for regulating various cellular functions and fates in vivo yet remain difficult to deliver. Incorporation of reduction‐sensitive linkages and light‐degradable linkages affords significant changes in the release profiles of fibroblast growth factor‐2 (FGF‐2) in the presence of the reducing agent glutathione or light, respectively. The bioactivity of the released FGF‐2 is comparable to pristine FGF‐2, indicating the ability of these hydrogels to retain the bioactivity of cargo molecules during encapsulation and release. Further, in vivo studies demonstrate degradation‐mediated release of FGF‐2. Overall, our studies demonstrate the potential of these unique stimuli‐responsive chemistries for controlling the local release of low molecular weight proteins in response to clinically relevant stimuli.

中文翻译：

通过具有治疗潜力的双重机制控制小生物活性蛋白质的释放

对生物相关刺激作出反应的注射递送系统为可定制的药物释放提供了一种有吸引力的策略。在这里，报告了独特聚合物的设计和合成，用于创建水凝胶，该水凝胶在原位形成并响应临床相关的内源性和外源性刺激而降解，特别是减少微环境和外部施加的光。水凝胶是由聚乙二醇和肝素基聚合物通过迈克尔型加成反应形成的。研究所得水凝胶的低分子量蛋白质（例如生长因子和细胞因子）的局部受控释放，这些蛋白质对于调节体内各种细胞功能和命运很有意义，但仍然难以递送。在还原剂谷胱甘肽或光存在的情况下，还原敏感键和光可降解键的结合分别使成纤维细胞生长因子-2 (FGF-2) 的释放曲线发生显着变化。释放的 FGF-2 的生物活性与原始 FGF-2 相当，表明这些水凝胶在封装和释放过程中保留货物分子的生物活性的能力。此外，体内研究证明降解介导的 FGF-2 释放。总的来说，我们的研究证明了这些独特的刺激响应化学物质在控制低分子量蛋白质的局部释放以响应临床相关刺激方面的潜力。

更新日期：2017-10-12

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