Institute of Materials Research and Engineering (IMRE), Agency for Science, Technology and Research (A*STAR) #08-03, 2 Fusionopolis Way, Singapore, Singapore, 138634, Republic of Singapore.
Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Dr, Proteos, Singapore, Singapore, 138673, Republic of Singapore.
Chem Asian J. 2024 Sep 2;19(17):e202400453. doi: 10.1002/asia.202400453. Epub 2024 Jul 25.
Temperature-responsive hydrogels, or thermogels, have emerged as a leading platform for sustained delivery of both small molecule drugs and macromolecular biologic therapeutics. Although thermogel properties can be modulated by varying the polymer's hydrophilic-hydrophobic balance, molecular weight and degree of branching, varying the supramolecular donor-acceptor interactions on the polymer remains surprisingly overlooked. Herein, to study the influence of enhanced hydrogen bonding on thermogelation, we synthesized a family of amphiphilic polymers containing urea and urethane linkages using quinuclidine as an organocatalyst. Our findings showed that the presence of strongly hydrogen bonding urea linkages significantly enhanced polymer hydration in water, in turn affecting hierarchical polymer self-assembly and macroscopic gel properties such as sol-gel phase transition temperature and gel stiffness. Additionally, analysis of the sustained release profiles of Aflibercept, an FDA-approved protein biologic for anti-angiogenic treatment, showed that urea bonds on the thermogel were able to significantly alter the drug release mechanism and kinetics compared to usage of polyurethane gels of similar composition and molecular weight. Our findings demonstrate the unrealized possibility of modulating gel properties and outcomes of sustained drug delivery through judicious variation of hydrogen bonding motifs on the polymer structure.
温度响应水凝胶（thermogels）或温敏水凝胶已成为小分子药物和大分子生物治疗药物持续释放的主要平台。尽管可以通过改变聚合物的亲水-亲脂平衡、分子量和支化度来调节温敏水凝胶的性质，但对聚合物上的超分子供体-受体相互作用的变化却出人意料地被忽视了。在此，为了研究增强氢键对温敏水凝胶形成的影响，我们使用奎宁环作为有机催化剂合成了一系列含有脲和氨酯键的两亲性聚合物。我们的研究结果表明，强氢键脲键的存在显著增强了聚合物在水中的水合作用，进而影响了聚合物的分级自组装和宏观凝胶性质，如溶胶-凝胶相转变温度和凝胶硬度。此外，对已获 FDA 批准的用于抗血管生成治疗的蛋白质生物制剂阿柏西普（Aflibercept）的持续释放曲线进行分析表明，与使用具有相似组成和分子量的聚氨酯凝胶相比，温敏水凝胶上的脲键能够显著改变药物释放机制和动力学。我们的研究结果表明，通过合理改变聚合物结构上的氢键模式，有可能调节凝胶性质和持续药物释放的结果。
