Monoclonal Antibody-functionalized Mesoporous Silica Nanoparticles Loaded With Mifepriston For Cancer Metastasis Prevention

OBJECTIVE:Tumor metastasis and recurrence is considered to be closely related to the circulating tumor cells(CTCs)in the peripheral blood.We hypothesized that the adhesion of CTCs to vascular endothelial bed might be a crucial point in metastatic cascade.Mesoporous silica nanoparticles(MSN)were widely applied in biomedical fields as the vector because of its good chemical and thermal stability and biocompatibility.We used carboxyl modified MSN modified with monoclonal antibody(aEpCAM)and loaded with mifepriston(MIF)to serve as a cancer metastatic preventive nanomedicine(aE-MSN-M)which can down-regulate the activity of CTCs and interrupt the adhesion of CTCs to the intima of microvasculature for purpose of prevention of tumor metastasis from the source.METHOD:Firstly,based on carboxy-modified mesoporous silica nanoparticles(MSN-COOH),we synthesised MSN-M,aE-MSN and aE-MSN-M by modified with monoclonal antibody(aEpCAM)or loaded with mifepriston(MIF).Physicochemical properties of MSN-M,aE-MSN and aE-MSN-M were characterized by using transmission electron microscope(TEM),dynamic light scattering(DLS),fluorescent imaging,infrared spectra,and U-V-Vis spectra.Furthermore,MTT assay was used to compare MSN,MSN-M,aE-MSN and aE-MSN-M in the cytotoxicity to colon cancer cells(HT-29 and SW620).The cell cycle distributions and cellular uptake efficiencies were analyzed by flow cytometry.The capability of intervention of the colon cancer cells adhered to human umbilical vein endothelial cells(HUVECs)was studied by fluorescence-photographed methods.Inhibition of expression of cell adhesion molecules of HUVECs were also investigated by flow cytometry.Moreover,nude mice bearing human colorectal cancer cells SW620 were used as the model animals to evaluate the anti-metastasis effects of aE-MSN-M.RESULTS:The successfully synthesized nanoparticles which have uniform particle size and good dispersity could be demonstrated through a variety of characterization methods.MTT assay showed aE-MSN and aE-MSN-M had toxic effects to colon cancer cells and arrested the cell cycle distribution in G0/G1 phase.Cellular uptake study showed that aE-MSN had targeting ability due to the coupling of aEpCAM.The adhesion assay demonstrated that the adherence of colon cancer cells to HUVECs could be inhibited and the expression of CD54 and CD62E on HUVECs could be down-regulated by MIF and aEpCAM in the aE-MSN-M synergistically.The in vivo experiment demonstrated that aE-MSN-M could have inhibiting effect on tumor metastasis.CONCLUSION:The functionalized aE-MSN-M could recognized and down-regulate the activities of colon cancer cells,arrested the cell cycle distribution in G0/G1 phase,down-regulated the expression of CD54 and CD62E of HUVECs,and had inhibiting effect on tumor metastasis in vivo.Therefore,these studies may provide the important theory basis and the reference for the R&D of new drug for tumor metastasis prevention and inhibition.