Iron–Doxorubicin Hyaluronan Nanogel as an Effective Targeted Chemotherapy with Modulated Cardiotoxicity

The complex of doxorubicin (Dox) and intracellular iron in cardiomyocytes generates reactive oxygen species (ROS), contributing to commonly observed cardiotoxicity. To enhance the anticancer potency and minimize the cardiotoxicity, here Dox was formulated into a hyaluronan (HA) nanogel using ferric ion (Fe³⁺) coordination to control the intracellular distribution and release of Dox. Taking advantage of the paramagnetic properties of iron and the fluorescence of Dox, we conveniently monitored the targeted delivery of the HA@Dox nanogel in murine breast tumors through both T1-weighted magnetic resonance imaging and fluorescence imaging. Compared with free Dox, HA@Dox nanogel affords a CD44-targeted delivery, lysosomal distribution, pH-responsive release, and significant tumor inhibition. Mechanistically, the lysosome-enriched HA@Dox produces ROS, causing lysosomal membrane permeabilization, which further promotes the intracellular Dox distribution. This HA@Dox nanogel not only provides a facile cancer-targeted delivery but also successfully relieves Dox toxicity, representing a potent delivery system for Dox.