水凝胶已被证明是智能药物载体，可以识别肿瘤微环境以进行癌症治疗。水凝胶网络中的动态交联既有助于刺激响应特性，也导致水凝胶的稳定性和机械性能较差。在这里，通过使用苯硼酸接枝的聚乙烯亚胺（PBA-PEI）修饰明胶（PPG），将PPG用缩醛交联胶原酸酯（ADA）进行亚胺键和硼酸酯键交联，然后加入钙离子（Ca2+），在网络中引入第三种钙-羧酸盐交联，形成三重交联的PPG/ADA + Ca2+水凝胶。由于网络中三种动态键的存在，PPG/ADA + Ca2+水凝胶具有自修复性、刺激响应性和良好的机械性能，相比于单交联或双交联水凝胶。PPG/ADA + Ca2+水凝胶也表现出控制释放能力，表明在氧化氢存在下，包埋分子可以从水凝胶网络中迅速释放出来，而在酸性pH值下，释放速率可以减慢。此外，由于细胞微环境的调控降解，PPG/ADA + Ca2+水凝胶对癌细胞展示出选择性毒性和药物传递。综上所述，PPG/ADA + Ca2+水凝胶已被证明是具有多种理想性能和动态特性的有前景的生物材料，可用于生物医学应用中的控制分子释放。版权所有 © 2023. Elsevier B.V.出版。

Hydrogels have been demonstrated as smart drug carriers to recognize the tumor microenvironment for cancer treatment, where the dynamic crosslinks in the hydrogel network contribute to the stimuli-responsive features but also result in poor stability and weak mechanical property of the hydrogels. Here, phenylboronic acid-grafted polyethyleneimine (PBA-PEI)-modified gelatin (PPG) was synthesized to crosslink alginate dialdehyde (ADA) through imine bonds and boronate ester bonds, and then calcium ions (Ca2+) were added to introduce the third calcium-carboxylate crosslinking in the network to form the triple-crosslinked PPG/ADA + Ca2+ hydrogels. Given the three types of dynamic bonds in the network, PPG/ADA + Ca2+ hydrogels possessed a self-healing manner, stimuli-responsiveness, and better mechanical properties compared to single- or double-crosslinked hydrogels. The controlled release capability of PPG/ADA + Ca2+ hydrogels was also demonstrated, showing the encapsulated molecules can be rapidly released from the hydrogel network in the presence of hydrogen peroxide while the release rate can be slowed down at acidic pH. Furthermore, PPG/ADA + Ca2+ hydrogels presented selected cytotoxicity and drug delivery to cancer cells due to the regulated degradation by the cellular microenvironment. Taken together, PPG/ADA + Ca2+ hydrogels have been demonstrated as promising biomaterials with multiple desirable properties and dynamic features to perform controlled molecule release for biomedical applications.Copyright © 2023. Published by Elsevier B.V.