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：

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通过具有治疗潜力的双重机制控制小的生物活性蛋白的释放

响应生物相关刺激的可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。在此，报道了独特聚合物的设计和合成，用于创建原位形成并响应于临床相关的内源性和外源性刺激而降解的水凝胶，特别是减少了微环境和外部施加的光。水凝胶由聚乙二醇和肝素基聚合物通过迈克尔型加成反应形成。研究了所得水凝胶的低分子量蛋白质（例如，生长因子和细胞因子）的局部控制释放，这对于调节体内的各种细胞功能和脂肪很重要，但仍然难以递送。在还原剂谷胱甘肽或光照下，还原敏感性键和光可降解键的结合可显着改变成纤维细胞生长因子-2（FGF-2）的释放曲线。释放的FGF-2的生物活性与原始的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，体内研究表明降解介导的FGF-2释放。总体而言，我们的研究表明，这些独特的刺激响应化学方法可响应临床相关刺激来控制低分子量蛋白质的局部释放。分别。释放的FGF-2的生物活性与原始的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，体内研究表明降解介导的FGF-2释放。总体而言，我们的研究表明，这些独特的刺激响应化学方法可响应临床相关刺激来控制低分子量蛋白质的局部释放。分别。释放的FGF-2的生物活性与原始的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，体内研究表明降解介导的FGF-2释放。总体而言，我们的研究表明，这些独特的刺激响应化学方法可响应临床相关刺激来控制低分子量蛋白质的局部释放。