Targeted Delivery Of MiR-34a To Inhibit Tumor Proliferation And Migration

Knowledge that were gained about molecular mechanisms of cancer in the last decades promoted the application of tumor-targeted gene carriers in cancer therapy.For example,some nano medicines have already been adopted in clinical use;many other nanomedicines have enrolled in clinical trials.In order to unblock the disadvantages like drug safety,side effects,drug solubility,drug stability,and drug permeability,it is important to achieve the active targeting activity of the nanomedicines during the drug design by reducing the capture of nano-carrier from reticuloendothelial system(RES)making it available for the targeted drug delivery system to enter the cells through the interaction with the receptors on cell surface.In this study,PEN was modified with the single domain antibody which can selectively combine with carcinoembryonic receptor 6(CEAC AM 6)via EDC/N HS method,and developed a tumor-targeted polymer carrier PEN-Nb with high selectivity.PEN-Nb has shown a good binding capacity with miR-34 a.PEN-Nb was demonstrated to achieve an efficient cellular uptake of miR-34 a in a CEACAM 6-dependent endocytosis.PEN-Nb showed great biological stability and high transfection efficiency.Through the miR-34 a delivery,PEN-Nb can exhibit obvious inhibition of the proliferation,which was attributed to the enhancement cell apoptosis and cell cycle arrest.Meanwhile the cell migration and invasion has also been observed to be inhibited.In order to further study the efficiency of active targeting carrier in vivo,we the n modified chondroitin sulfate(CS)on the surface of PAMAM to construct a CD44-targeted carrier CS-PAMAM for miR-34 a delivery.CS-PAMAM/miR-34 a nanoparticles were intravenously injected into mice bearing human lung adenocarcinoma cell A549 xenografts.CS-PAMAM showed good biocompatibility and CD44-targeting selectivity.Furthermore,CS-PAMAM/miR-34 a could efficiently inhibit the tumor growth and induce the situ apoptosis in tumor tissue.In addition,there was no side effect on other organs of mice after injection.The enhanced accumulation of CS-PAMAM in tumor side could make it available for miR-34 a to perform its function.In conclusion,these two types of tumor-targeted carriers can effic iently deliver miR-34 a in to cells through the ligend-receptor interaction,and achieve the enhancement inhibition of the proliferation and migration in vitro and in vivo.This study provided new strategies and methods for the cons truction of tumor targeted gene carrier,which demonstrated the potential of tumor treatment,and laid a foundation in clinical.