Glu‐derived Zwitterionic Micelles Conquering the Intestinal Mucosal Barrier toward Oral Delivery

Abstract Amino acid transporters with different categories are highly expressed in intestinal epithelial cells for maintaining the essential metabolism of body. The zwitterionic property of amino acid with α‐amino and α‐carboxyl also has tremendous potential to conquer the mucus barrier. Therefore, Glu‐derived amphiphilic block polymers [i. e., poly(lactic acid)‐b‐poly(glutamine)₂₅ (PPQ) and poly(lactic acid)‐b‐poly(glutamate)₂₅ (PPD)] were rational designed and Glu‐derived zwitterionic micelles (PPQ‐M and PPD‐M) were further prepared toward oral delivery. In comparison with PEGylated micelles (PEG‐M), PPD‐M and PPQ‐M possessed superior mucus permeability. In addition, enhanced cellular internalization capacity was also detected in both zwitterionic micelles, which was mainly mediated by multiple amino acid transporters. The cellular uptake efficiency of PPQ‐M was obviously higher than that of PPD‐M due to the glutamine constitutional unit of PPQ‐M with higher affinity to amino acid transporters. Furthermore, the retrograde pathway played an important role in the intracellular transport (including transcytosis) of both zwitterionic micelles. Excellent villi absorption of zwitterionic micelles was observed in situ, which gave a convincing evidence for oral delivery application prospect. The results of this research demonstrated that Glu‐derived zwitterionic micelles with distinguished capacity of conquering intestinal mucosal barrier, have promising potential toward oral delivery.