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.