中文摘要：神经营养因子3生长因子可以改善耳蜗神经元的存活，将该蛋白定点递送到中耳圆窗膜，有可能逆转感音神经性听力损失。本研究旨在开发一种可注射的水凝胶给药系统，能够以可控和持续的方式定点释放神经营养因子3。选择使用硫醇-乙烯基砜迈克尔加成交联的PEG水凝胶制剂，它与目前临床研究用于治疗听力损失的Poloxamer水凝胶相比，具有更高的机械刚性、更好的生物粘附性和更长的停留时间。在体内，PEG水凝胶诱导的局部免疫反应可与生物相容性Poloxamer水凝胶媲美，但它在皮下区域释放有效载荷的速度却比后者慢5倍。基于这一可注射水凝胶制剂，利用神经营养因子3蛋白亲和肽修饰PEG水凝胶，设计了基于亲和肽的蛋白释放系统；并验证了由于肽和蛋白质之间的可逆相互作用，使肽偶联PEG水凝胶可持续释放神经营养因子3。亲和控释的速率取决于聚合物浓度、肽的亲和度及肽蛋白比。可见，本研究开发的定点递送神经营养因子3的可注射水凝胶制剂，与Poloxamer水凝胶相比，可以做到亲和控释和更长的给药时间。
外文摘要：Neurotrophin-3 growth factor can improve cochlear neuron survival, and localized delivery of this protein to the round window membrane in the middle ear may be able to reverse sensorineural hearing loss. Thus, the goal of this work was to develop an injectable hydrogel delivery system that can allow localized release of neurotrophin-3 in a controlled and sustained manner. We identified a PEG hydrogel formulation that uses thiol-vinyl sulfone Michael addition for crosslinking. This injectable formulation provides elastic hydrogels with higher mechanical rigidity, better bio-adhesion and longer residence time than Poloxamer hydrogels currently being investigated clinically for hearing loss. In vivo, PEG hydrogels induce local immune responses comparable to biocompatible Poloxamer hydrogels, yet they released payloads at a similar to 5-fold slower rate in the subcutaneous area. Based on this injectable hydrogel formulation, we designed an affinity-based protein release system by modifying PEG hydrogels with affinity peptides specific to neurotrophin-3 proteins. We verified the sustained release of neurotrophin-3 from peptide-conjugated PEG hydrogels resulting from the reversible interaction between peptides and proteins. The rate of affinity-controlled release depends on the polymer concentrations, the affinity of peptides and the peptide-to-protein ratios. Collectively, we developed an injectable hydrogel formulation for localized delivery of neurotrophin-3, which provides affinity-controlled release and longer delivery time compared to Poloxamer hydrogels.
外文关键词：Injectable hydrogel；Michael addition；Affinity-controlled release；Phage display；Neurotrophin-3；Round window membrane
作者：Wang, J；Youngblood, R；Cassinotti, L；Skoumal, M；Corfas, G；Shea, L
作者单位：Univ Michigan
期刊名称：JOURNAL OF CONTROLLED RELEASE
期刊影响因子：7.727
出版年份：2021
出版刊次：330
点击下载：一种通过亲和肽控释神经营养因子3的可注射PEG水凝胶