Degradable Copper-based Fenton-like Chemodynamic Agents For Efficient Cancer Therapy

Chemodynamic therapy（CDT）broadens the ways to fight malignant tumors with great promises for clinical translation.Compared with traditional cancer treatment methods,CDT owns high tumor specificity,depth independence,endogenous activation with no need for external energy input,and minimal systemic side-effects.The high catalytic efficiency of copper-based Fenton-like chemdynamic agent makes it capable of highly efficient CDT.The major hurdles of CDT are non-degradability and low-efficiency utilization of chemodynamic agents,and intracellular glutathione（GSH）-induced rapid scavenging of hydroxyl radicals（·OH）.Therefore,it is highly imperative to develop body-clearable,tumor microenvironment（TME）-degradable chemodynamic agents without compromising the therapeutic efficacy for efficient anticancer treatment.Taking all these issues into accounts,this thesis has done the following work:（1）Biodegradable amorphous Cu_xFe_y（Te O₃）_1.6 nanoparticles（a-CFT NPs）with amorphous nanostructures were reported.After structural and compositional analysis,the a-CFT NPs with equal molar content of copper and iron were surface modified for further CDT application.The a-CFT@IP6@BSA NPs agent were prepared by encapsulating a-CFT NPs into inositol hexaphosphate（IP6）and bovine serum albumin（BSA）.（2）The biggest merits of this agent are the GSH responsive degradation and amorphous structure,allowing the tumor-specific release of plenty of Cu⁺ions and their high-efficiency utilization for·OH production via the Fenton-like reaction.Besides,the released Cu⁺ions can deplete the intracellular GSH and thereby protect·OH from scavenging,greatly improving the CDT efficiency.Further,it is found that the a-CFT@IP6@BSA NP treatment down-regulates the levels of glutathione peroxidase 4（GPX-4）and B-cell lymphoma/Leukemia-2（BCL-2）,indicating GSH depletion-associated ferroptosis and IP6-induced apoptotic death of cancer cells.Utilizing the T₁/T₂ dual-modal magnetic resonance imaging capability,the a-CFT@IP6@BSA NPs are demonstrated with excellent in vivo anticancer efficiency and have great potential for imaging-guided cancer treatment.