Synthesis and Optimization of Ethylenediamine-Based Zwitterion on Polymer Side Chain for Recognizing Narrow Tumorous pH Windows

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