由于与其带电对应物相比，非离子水凝胶在长期治疗植入方面具有较小的免疫原性，因此引起了特别关注。然而，在生理条件下原位形成非离子超分子水凝胶一直是一项具有挑战性的任务。在这方面，我们报道了通过Hofmeister效应自组装类药物水凝胶剂（SAPH）形成的非离子超分子聚合物（SPs）的盐诱导胶化的发现。设计的SAPH由两个SN-38单元（一种抗癌药物伊立替康的活性代谢物）和一个短肽嵌合的两个或四个寡乙二醇（OEG）段组成。在水中自组装后，所得的非离子SPs可在磷酸盐添加后被触发胶化。我们的1H-NMR研究揭示了添加的磷酸盐导致了亚甲基质子的化学偏移改变，暗示了水-醚氢键的破坏以及SPs周围水合壳的重组。与添加的盐量相一致的这种脱盖效应可能促进了SAPH丝束之间的关联相互作用，形成了一个三维网络。形成的水凝胶表现出对癌细胞具有强效的SN-38水凝胶剂持续释放特性。© 2023 Wiley-VCH GmbH.

Nonionic hydrogels are of particular interest for long-term therapeutic implantation due to their minimal immunogenicity relative to their charged counterparts. However, in-situ formation of nonionic supramolecular hydrogels under physiological conditions has been a challenging task. In this context, we report on our discovery of salt-triggered hydrogelation of nonionic supramolecular polymers (SPs) formed by self-assembling prodrug hydrogelators (SAPHs) through the Hofmeister effect. The designed SAPHs consist of two SN-38 units, which is an active metabolite of the anticancer drug irinotecan, and a short peptide grafted with two or four oligoethylene glycol (OEG) segments. Upon self-assembly in water, the resultant nonionic SPs can be triggered to gel upon addition of phosphate salts. Our 1H-NMR studies revealed that the added phosphates led to a change in the chemical shift of the methylene protons, suggestive of a disruption of the water-ether hydrogen bonds and consequent reorganization of the hydration shell surrounding the SPs. This deshielding effect, commensurate with the amount of salt added, likely promoted associative interactions among the SAPH filaments to percolate into a 3D network. The formed hydrogels exhibited a sustained release profile of SN-38 hydrogelator that acted potently against cancer cells.© 2023 Wiley-VCH GmbH.