Ethylenediaminetetraacetic acid conjugated with polyethylene glycol is a safe chelator for colonic epithelial denudation and intestinal epithelial replacement therapy.

Colonic epithelia can be replaced with small intestinal (SI) epithelia through de-epithelialization of the colon using ethylenediaminetetraacetic acid (EDTA), followed by SI organoid transplantation, to treat short bowel syndrome and intestinal failure. However, the low molecular weight (MW) of EDTA results in hypocalcemia, consequently hindering the clinical application of this bivalent cation chelator. Therefore, we aimed to synthesize a non-absorbable chelator for potential application in regenerative medicine. We conjugated polyethylene glycols (PEGs) of different MWs to EDTA to synthesize EDTA-PEGs with higher MWs. NMR and LC-TOF/MS analyses demonstrated the stability and chelating ability of EDTA-PEGs. Moreover, EDTA-PEGs mitigated hypocalcemia in mice. This effect was more pronounced in EDTA-PEGs with a higher MW than in EDTA. Furthermore, EDTA-PEGs de-epithelialized a targeted region of the mouse colon, replacing it with SI organoids to preserve SI features. This study provides a basis for the development of safe regenerative medicine utilizing EDTA-PEG.