An Intelligent and Tumor-Responsive Fe2+ Donor and Fe2+-Dependent Drugs Cotransport System.

Fe2+ plays an essential role for artemisinin (ART)-based drugs in anticancer therapy. As a result, it is important to realize these two agents' cotransport for improving antitumor efficacy. We utilized a kind of alternating magnetic field (AMF) and tumor-responsive material-mesoporous Fe3O4 (mFe3O4)-to encapsulate ART. After that, the outer surface of mFe3O4 was capped with multifunctional hyaluronic acid (HA), which was used not only as a smart gatekeeper but also as a tumor targeting moiety. In vitro and in vivo studies proved that ART can be encapsulated in HA-mFe3O4 and protected by HA coating which could effectively avoid premature release during in vivo circulation. HA-mFe3O4/ART could be taken up by MCF-7 tumor cells via CD44 receptor-mediated endocytosis and locate at acidic lysosome. Subsequently, "HA gate" could be degraded by acidity and hyaluronidase. Then this system synchronously released Fe2+ and ART at the same site. Fe2+ can nonenzymatically convert ART to ROS for killing cancer cells. Under AMF irradiation, HA-mFe3O4 could not only effectively convert electromagnetic wave into heat for tumor thermal therapy but also generate high levels of reactive oxygen species (ROS) for tumor dynamic therapy. These results demonstrated that the antitumor efficacy of HA-mFe3O4/ART in vivo significantly enhanced 3.7 times compared with free ART. Combining with AMF, it further improved 3.9 times (V/V0 of 0.11), suggesting the successful combined application of HA-mFe3O4/ART and AMF for tumor treatment. It is believed that HA-mFe3O4/ART is a promising system for Fe2+-dependent drugs to improve their therapeutic effect.