Carrier-free metal-organic nanodrugs via coordination-driven self-assembly for synergistic anti-angiogenesis and oxidative-stress oncotherapy

Although nanodrugs based on antiangiogenic and oxidative stress have received widespread attention in oncotherapy, low delivery efficiency and drug payload have greatly hindered their further applications. The self-targeting carrier-free metal-organic nanodrugs are constructed via the dynamic ligand-driven self-assembly of anti-angiogenesis pseudolaric acid B (PAB), Fenton-like agent copper ion, and the chemo-drug pemetrexed (PEM) to enhance anti-angiogenic-oxidative stress oncotherapy. After intravenous injection, it is found that such nanodrugs can be efficiently accumulated in tumor site and internalized into tumor cells by folate receptors-mediated self-targeting. After that, nanodrugs are disassembled to achieve the burst release of drugs under stimuli of acidic lysosome and endogenous glutathione (GSH). Interestingly, the released Cu^[II] can efficiently decompose the endogenous hydrogen peroxide (H₂O₂) into hydroxyl radicals (·OH) and significantly weaken reactive oxygen species (ROS) elimination by downregulating endogenous GSH to self-amplify intracellular oxidative stress. Meanwhile, the released PAB can obviously inhibit the secretion of vascular endothelial growth factor (VEGF), block the formation of new blood vessels, and regulate the conformation of VEGF receptor 2 (VEGFR2) to inhibit the angiogenesis signaling pathway. After two weeks of treatment, PEM-Cu^[II]-PAB (PCP) nanodrugs achieved a 95% tumor inhibition rate and 100% survival rate in tumor-bearing mice. Taken together, our study can expect to provide a promising method for targeted oncotherapy based on the synergistic therapy of antiangiogenic or oxidative stress.