Simulation study of the pH sensitive directed self-assembly of rheins for sustained drug release hydrogel

The hydrogel formed by the directed self-assembled rhein molecules at an appropriate pH value for sustained drug release has been reported recently. Although the application in drug therapy has been experimentally verified, the research on the mechanism of the self-assembly by rhein is still incomplete. In this study, we provide a new insight of the pH-induced self-assembly mechanism employing the dissipative particle dynamics (DPD) as well as multiscale molecular simulations. It comes to the conclusion that protonated rheins incline to aggregate, so spherical, columnar, and membrane-shaped aggregated micelles can be observed with the mounting drug concentrations. However, the thermodynamic solubility of these structures is relatively weak, which ultimately causes the system to precipitate. While, driven by the better hydrophilicity and charge effect of the deprotonated rheins, the self-assembly conformation of deprotonated rheins grows through a sphere, wormlike, long wormlike manner, resulting in a host of discontinuous and highly dispersive morphologies. Those structures, having good thermodynamic solubility though, cannot provide the required mechanical properties, thus the rhein system can only exist in the aqueous solution state. Only when the value of pH is moderate (the corresponding degree of deprotonation is 36 %-60 %), could a continuous network self-assembled structure be obtained, leading to the formation of hydrogel to meet the clinical requirements.