The Effect And Mechanism Of NO Donor Combined With Nanozyme Targeted Treatment Of Breast Cancer

As a major killer of women’s health,breast cancer is a serious threat to women’s life and health,thus receiving more and more attention.Currently,although conventional chemotherapy can prolong the survival time of patients,its systemic toxic side effects often limit the use of chemotherapeutic drugs.In recent years,chemodynamic therapy(CDT)based on the catalytic activity of nanozymes has great potential for breast cancer treatment due to its unique advantage of non-toxic treatment.However,the current selectivity and specificity of nanozymes are low and there is off target "toxicity".Moreover,the complex breast tumor microenvironment limits the effectiveness of single CDT for breast cancer treatment.Therefore,the development of efficient combined strategy based on specific targeting nanozymes is of great importance for breast cancer treatment.In this study,we proposed a research strategy for the targeted treatment of breast cancer using CD44 antibody-functionalized modified nanozymes carrying NO donors.The study uses superparamagnetic ferric tetroxide as the core,encapsulated with manganese dioxide capable of in situ oxygen generation;the chemotherapeutic drug NO donor is adsorbed within the pore channel using physical adsorption method.Then,gold nanoparticles were used to plug the pore channel by in situ growth method to prevent drug leakage.Finally,a CD44 antibody capable of specifically targeting breast cancer was coupled,i.e.,a CD44antibody-functionalized modified nanozyme therapeutic system was constructed.The highly toxic ·OH produced by the nanozyme-catalyzed reaction induces apoptosis of breast cancer cells,and the efficiency of the nanozyme-catalyzed therapy is further enhanced by the combination of NO donors,which finally achieves a synergistic enhancement of the therapeutic effect of breast cancer.Firstly,the nanocarriers were characterized by TEM,XRD,FTIR,XPS,BET,and indirect immunofluorescence analysis for their morphology,elemental composition,atomic valence,pore size,specific surface area,and other properties,and it was clear that the CD44 antibody functionalized modified nanocarriers were successfully synthesized.The colorimetric analysis of TMB clarified that the nanocarrier had enhanced peroxidase-like activity and was highly active over a wider p H and temperature range compared to the natural enzyme.Secondly,the results of cellular and molecular level analysis showed that the CD44 antibody functionalized modified nanocarriers were able to be specifically taken up by MDA-MB-231 cells.The CD44 antibody targeted nanozyme combined with NO donor was able to cause a significant decrease in intracellular glutathione content,a severe imbalance in redox status,a significant decrease in mitochondrial membrane potential,a severe disruption of cytoskeletal morphology,a rupture and crumpling,and the expression level of apoptotic protein cleaved caspase 3 was significantly increased.The above results indicated that the CD44 antibody-targeted nanosystem combined with NO donor could synergistically increase apoptosis and death of breast cancer MDA-MB-231 cells.A nude mouse breast cancer transplantation tumor model was used to study the effect of CD44 antibody-targeted nanosystem combined with NO donor on breast cancer targeting therapy at the animal level.The results showed that the synergistic effect of the two could significantly inhibit the growth of breast tumors with good biosafety on normal tissues.In summary,CD44 antibody-targeted nanoparticles combined with NO donor can produce synergistically enhanced effects of inhibiting MDA-MB-231 cell proliferation and breast tumor growth.This study provides a new research model and research basis for breast cancer targeted therapy,which has important guiding significance for clinical targeted therapy of breast cancer.