Multifunctional nanogel engineering with redox-responsive and AIEgen features for the targeted delivery of doxorubicin hydrochloride with enhanced antitumor efficiency and real-time intracellular imaging

Nanogels exhibit potential application values in drug delivery systems because of their tunable properties and biocompatibility. In this study, multifunctional hyaluronic-based nanogels (HNPs), all-trans retinoid acid (ATRA)/aggregation-induced emission luminogen (AIEgen) fluorophores (TPENH2)-grafted hyaluronic acid (HA) with disulfide bonds as linkers of (HA-ss-ATRA/TPENH2), were successfully developed for doxorubicin hydrochloride (DOX) delivery. Besides, the controls of HA-ATRA/TPENH2 were also developed for comparison. The HNPs with nanoscale particle sizes possessed an excellent DOX-loading capacity. As expected, the DOX-loaded HNPs exhibited the higher stability in a normal physiological environment (10 mu M GSH), but rapidly disintegrated in the cancer microenvironment (20mM GSH) according to an in vitro drug release study. The intracellular observation of HNPs by the fluorescence microscopy indicated that the self-fluorescent DOX-loaded HNPs with unique AIEgen characteristic transported DOX into the cancer cells and visibly accumulated within the cytoplasm. Importantly, the accumulation of DOX-loaded HNPs was largely increased due to the targeted reorganization of CD44 or LYCE-1 receptors by HA moieties on the surface of HNPs. Based on in vitro cytotoxicity analyses, the DOX-loaded HNPs displayed dramatically enhanced virulence to cancer cells compared to the controls and free DOX. This is the first study to achieve combined functionalities of targeted delivery, controllable release and real-time intracellular imaging on HA-base nanogels with enhanced antitumor efficiency. Therefore, the multifunctional HA-ss-ATRA/TPENH2 HNPs have good potential to develop a novel drug delivery platform for the targeted delivery and controlled release of DOX to achieve enhanced antitumor efficiency as well as real-time intracellular imaging.