Synthesis and Optimization of Ethylenediamine-Based\nZwitterion on Polymer Side Chain for Recognizing Narrow Tumorous pH\nWindows

Polyzwitterions that\nshow the alternation of net charge in response\nto external stimuli have attracted great attention as a new class\nof surface-polymers on nanomedicines. However, the correlation between\ntheir detailed molecular structures and expression of antifouling\nproperties under physiological condition remain controversial. Herein,\nwe synthesized a series of ethylenediamine-based polyzwitterions with\ncarboxy groups/sulfonic groups and ethylene, propylene, and butylene\nspacers as potential surface-polymers for nanomedicines, allowing\nsensitive recognition of tumor acidic environments (pH = 6.5–5.5).\nThen, we evaluated their structure-based characteristics, including\npH-dependent cellular uptakes and intracellular distributions. Additionally,\nthe role of conformation stability, <i>i.e.</i>, Gibbs free\nenergy changes, was to induce an intramolecular electrostatic interaction\nin the zwitterionic moieties. These results highlight the practicality\nof fine-tuning the design of zwitterionic moieties on polymers for\nthe future development of nanomedicines that can recognize the narrow\npH window in tumor acidic environments.