Abstract Tannic acid (TA) forms a highly dispersible supramolecular network with aza-18-crown-6 ether (Aza18C6), enabling efficient encapsulation of an anionic protein, FITC-labeled bovine serum albumin (F-BSA) under physiologically relevant Mg²+ concentrations. Unlike 18-crown-6, Aza18C6 carries protonatable secondary amines that provide an intrinsic positive charge, allowing direct association with TA without relying on K+. Density functional theory (DFT) calculations support a sandwich-like structure in which protonated Aza18C6 is stabilized between 2 galloyl-rich TA units through cooperative noncovalent interactions. Job plot and ¹H NMR analyses indicate an Aza18C6:TA ratio of ∼2:1 to 2.5:1, consistent with the formation of a cross-linked network in which each Aza18C6 bridges multiple TA molecules. In the presence of Mg²+, the TA–Aza18C6 networks incorporate F-BSA efficiently in an Mg²+-dependent manner and remain colloidally stable for 24 h, while rapidly disassembling at mildly acidic pH (∼5). In contrast, TA complexes formed with monoamine-terminated PEG show progressive aggregation, highlighting the superior stability and pH-responsive behavior of the TA–Aza18C6 platform for protein delivery.
Nakaji et al. (Wed,) studied this question.