Targeting MOFs Loaded With Fluorouracil Deoxynucleoside For Breast Cancer Treatment

Breast cancer is one of the serious threats to human health,which incidence rate is the highest in female tumors.The development of breast cancer is a complex process with many pathogenic factors.The overexpression of HER2 directly lead to the occurrence and metastasis of tumor,and predict the adverse prognosis.Antibody therapy of HER2 plays a leading role in clinical application,which can significantly improve the therapeutic effect and overall survival rate.However,due to the large molecular weight of antibody and the need for humanization,there are limitations in its application,such as poor permeability of tissues and cells,easy to cause immune response and drug resistance,and high production cost.In order to overcome these limitations,chemotherapy is often used as adjuvant therapy of antibody therapy to enhance the therapeutic effect and solve the antibody resistance.5-Fluorouracil?5-FU?,as an important component of adjuvant chemotherapy,has been widely used in the treatment of HER2 overexpressed breast cancer.However,there are still many bottlenecks in its clinical application,such as poor selectivity,poor stability,serious side effects and poor efficacy.Therefore,it is necessary to develop a new targeted nanodrug delivery system to transport 5-fluorouracil for systemic administration,so as to tackle the shortcomings of the drug itself.Metal-Organic Frameworks?MOFs?are crystalline porous materials that are self-assembled by metal ions or metal clusters and organic ligands.It has the characteristics of high porosity,large specific surface area,structure design,adjustable holes,and material modification.It is a class of potential drug carrier materials.Although MOFs-based drug carriers have good drug loading functions and drug sustained-release properties,the materials themselves lack targeting.To improve the active targeting ability of MOFs,the targeted ligand molecule?affbody?was attached to MOFs,and the targeted nano carrier affibody-MOFs was prepared to carry Fluorouracil deoxynucleoside?FUdR,one of the metabolites of 5-FU?-DNA strand for targeted therapy of breast cancer cells overexpressed by HER2.Firstly,the modified group?amino group?on MOFs and the sulfhydryl group on affibody were connected by linker to construct the target nano-carrier of affibody-MOFs.Through electrostatic adsorption,positively-charged affibody-MOFs adsorbed negatively-charged FUdR₁₅ strand composed of 15 consecutive FUdR synthesized by solid-phase synthesis,and the two spontaneously formed nano-drug particles FUdR₁₅@affi-MOFs.FUdR₁₅@affi-MOFs had nanometer size?80 nm?,irregular three-dimensional structure and good serum stability.The targeting and cytotoxicity of FUdR₁₅@affi-MOFs were evaluated by breast cancer cells with different expression levels of HER2.The results indicated that the drug showed high targeting and cytotoxicity to the cells with high expression of HER2.In addition,it was found that FUdR₁₅@affi-MOFs enhanced the expression and activity of apoptosis related proteins in Bcl-2/Bax-caspase 8,9-caspase 3 apoptosis pathway induced by FUdR.This study shows that the targeting vector affibody-MOFs establishes a promising delivery system platform for nucleoside analogues,and provides a new strategy for the development of cancer treatment methods.