Dual-aptamer-modified-mesoporous Silica Nanoparticles Loading Doxorubicin For Cancer Metastasis Prevention

Purpose:Cancer is one of the most terrible public health problems in the world,and cancer metastasis is the leading causes of death of cancer patients.Circulating tumor cells(CTCs)are considered to be responsible for metastasis.It dissociated from primary tumors,circulated around the body through the blood and lymph vessels and adhered to new sites then leading to metastasis.To overcome this threaten,we designed a kind of dual-aptamer-modified-mesoporous silica nanoparticles(EC-MSN),which can efficiently capture and restrain CTCs.Then EC-MSN was loaded with doxorubicin(DOX),which made the EC-MSN-D have the capability of simultaneously restraining the activities of CTCs.Method:Firstly,we synthesized an amine-modified mesoporous silica nanoparticles(MSN-NH2),then we modified the MSN-NH2 with two specific aptamers(anti-EpCAM and anti-CD44).Then the Dual-aptamer-modified EC-MSN was loaded with DOX.The physicochemical properties of EC-MSN-D were characterized by using transmission electron microscope,dynamic light scattering,infrared spectra,UV-Vis spectra,and fluorescent spectra.Furthermore,we use MTT assay to explore the cytotoxicity of MSN-D,E-MSN-D,C-MSN-D and EC-MSN-D to HT29 and SW620 cells.The effects of nanoparticles to cycle distribution,expression of proteins,adhesive ability to human umbilical vein endothelial cells(HUVECs),invasion ability of colon cancer cells were also measured.The nude mice were used to verify the effect of nanoparticles on inhibition of tumor metastasis in vivo.Results:A series of physicochemical characterization of nanoparticles proved that we successfully synthesized the dual-aptamer-modified nanoparticles.Results from flow cytometry analysis demonstrated that EC-MSN could capture and down-regulate the activities of CTCs in cancer patients' blood with high-efficiency.The recognition specificity of EC-MSN was much higher than E-MSN or C-MSN.The cytotoxicity experiment showed that aptamer-modified nanoparticles had toxic effects to cells with high EpCAM and CD44 expression.The adhesion assay proved that the adhesion of SW620 cells to HUVECs could be inhibited by bi-aptamer-modified nanoparticles.The invasion ability of colon cancer cells also could be down-regulated by bi-aptamer-modified nanoparticles.The in vivo experiments in nude mice provided the strong evidence that the bi-aptamer-modified nanoparticles could effectively restrain cancer metastasis.Conclusion:The bi-aptamer-modified nanoparticles loaded with DOX could control-release the DOX in acid environment which mimic the condition in cancer cells.The in vitro experiments demonstrated the inhibition of nanoparticles to the expression of EpCAM and CD44 on colon cancer cells.The adhesion and invasion ability of cancer cells also could be restrained by bi-aptamer-modified nanoparticles.Moreover,the bi-aptamer-modified nanoparticles could capture and down-regulate the tumor cells in blood.Therefore,the bi-aptamer-modified nanoparticles may provide a potential for cancer metastasis prevention.