pH‐dependent swellable hyaluronate nanogels targeting acidic tumors

Abstract In this study, we have developed pH‐dependent nanogels based on hyaluronic acid (HA) to specifically target acidic tumors. Our initial approach involved modifying HA through the grafting of 3‐(diethylamino)propylamine (DEAP), a molecule known for its responsiveness to changes in pH. This modified HA was termed as HDEA. Subsequently, we performed chemical crosslinking of HDEA using adipic acid dihydrazide (ADH), a crosslinking molecule, resulting in the formation of nanogels referred to as cHDEA. Importantly, the non‐ionized DEAP molecules (with a pK b value of ~pH 7.0) at pH 7.4 support the formation of deswellable cHDEA. This property enables the encapsulation of a photodynamic model drug, chlorin e6 (Ce6), into cHDEA. However, when the DEAP molecules become protonated at pH 6.8, they induce a change in the nanogel structure, causing it to swell due to electrostatic repulsion. As a result, Ce6 is rapidly released from the nanogels. By modulating the pH, we can continuously control the nanogel structure, alternating between swelling and deswelling states. We anticipate that this system offers the advantage of facilitating drug release specifically under acidic tumor conditions while inhibiting drug release under normal pH conditions (i.e., pH 7.4). This approach will serve as an effective strategy for mitigating side effects by efficiently controlling drug release in specific disease areas.