Geraniin-Based Self-Assemble Nanoplatform for Antioxidation Reduced Cardiotoxicity and Tumor Synergistic Therapy

Reducing the cardiotoxicity caused by DOX is a difficult problem in clinical cancer therapy. The small hydrophobic polyphenolic compound geraniin (GE) was designed as a DOX nanocarrier to coordinate with Fe3+, forming DOX-Fe-3+@GE-PEG (GDFP) nanoparticles (NPs). DOX-induced cardiotoxicity mediated by the Nrf2/HO-1 pathway was studied in vitro and in vivo. The targeting ability of GDFP NPs toward tumor cells or tissues was assessed using NIR imaging and pharmacokinetics studies. The synergistic therapeutic efficacy of the DOX and GE-based GDFP NPs was evaluated in vitro and in vivo. GE-based GDFP NPs promoted SOD and GSH-Px activities, inhibited Nrf2 protein expression, and enhance HO-1 protein expression, which contributed to the reduction of DOX-induced cardiotoxicity. The blood-circulation half-life of GDFP NPs was longer than 20 h determined by the NIR imaging and DOX plasma level calculations. The results indicated that high tumor accumulation of GDFP NPs could be achieved by retention (EPR) effect. The GDFP NPs showed an improved synergistic antitumor effect. Our work has explored a novel approach for overcoming DOX-induced cardiotoxicity and achieving synergistic chemotherapy, which holds great potential for future clinical application.