Deoxycholic Acid‐Assisted, Highly Stable pH ‐Responsive Hyaluronated Nanoparticles

ABSTRACT

The pH‐responsive nanoparticles (NPs) were engineered to minimize drug release under physiological conditions by enhancing structural stability through incorporation of deoxycholic acid (DOCA). The NPs were prepared from hyaluronic acid‐deoxycholic acid (HA‐DOCA, HDOC _x ) conjugates with varying degrees of DOCA substitution ( x  = 0.40, 0.20, and 0.10) and further functionalized with the pH‐responsive moiety 3‐(diethylamino)propylamine (DEAP). As a result of pH‐induced NP destabilization, the NPs exhibited selective, triggered drug release in acidic tumor‐associated microenvironments while maintaining strongly suppressed drug release under physiological conditions. Experimental results demonstrated that increasing the degree of DOCA substitution in HDOC‐DEAP significantly enhanced NP stability, thereby highly suppressing premature doxorubicin (DOX) release at physiological pH, while enabling DEAP‐mediated, accelerated DOX release at pH 6.8. Consistent with these observations, in vitro studies revealed reduced cellular uptake and cytotoxicity at pH 7.4, in contrast to enhanced cellular uptake and increased cytotoxicity under tumor acidic conditions (pH 6.8). Collectively, these findings underscore the potential of HDOC‐DEAP NPs as a pH‐responsive platform for drug delivery under mildly acidic tumor‐associated conditions.