Construction And Evaluation Of Targeted Or Responsive Codelivery Systems Of Chemotherapeutic And MiRNA Based On Aptamers

Chemotherapy is a systemic treatment for tumors.It has a common therapeutic effect on primary tumors,metastases,and subclinical metastases,and has become one of the most important methods for clinical treatment of tumors.However,chemotherapeutic drugs lack selectivity and have unavoidable side effects on normal tissues and organs.In addition,the long-term use of chemotherapeutic drugs could easily induce tumor cells to produce multidrug resistance,which has brought great obstacles to the following treatment.In order to solve the above-mentioned drawbacks of chemotherapeutic drugs,targeted and responsive nucleic acid aptamers were used to construct smart drug delivery systems for the combined delivery of chemotherapeutic drugs and therapeutic genes.Firstly,we linked the aptamer AS1411 targeting the necleolin on the membrane of tumor cellsto the biodegradable PLA nanoparticles,and constructed a novel delivery system with active targeted capability.Using this system,combined delivery of chemotherapeutic drug Dox and gene miR-519 c could be convinetly realized.The ability of miR-519 c to inhibit the expression of ABCG2,a drug-resistance-related protein,reduced the efflux effect of tumor cells on Dox,thereby increasing the effective intracellular concentration of Dox and increasing the killing effect of chemotherapeutic drugs on tumor cells.The results showed that this targeted drug/gene co-delivery system could efficiently load chemotherapeutic drugs,facilitate the tumor-targeted ability and further achieve the efficient enrichment of Dox in the nucleus.Through the synergistic action of Dox and miR-519 c,the co-delivery system can effectively achieve the killing of tumor cells,significantly inhibit the proliferation of 3D tumor spheres and tumor growth at an in vivo level.In addition,based on the significant difference in ATP concentration between cytosol and tumor environment,a nucleic aptamer complex with ATP response release capability namely Duplex was designed to load the chemotherapeutic drug Dox.Using PEI25 K as the carrier,Dox-Duplex and the therapeutic gene miR-34 a were assembled to construct nanocomplex.In the system,miR-34 a could inhibit the tumor migration,invasion and proliferation of tumor cells,and thus synergistic anti-tumor functions were exerted through different action pathways of genes and chemotherapeutic drugs.This responsive drug/gene co-delivery system can stably deliver the loaded drugs into tumor cells and rapidly release the drugs in an environment with high intracellular ATP concentration through its favorable responsive release capability.Through the synergy of Dox and miR-34 a,the co-delivery system can effectively inhibit the proliferation,migration and invasion of tumor cells.In conclusion,these two smart drug/gene co-delivery systems could compensate the obstacles of the lack of selectivity of chemotherapeutic drugs,the susceptibility to systemic toxicity and the multidrug resistance.Thus,it provided a new insight into the design of delivery systems achieving the co-delivery of drugs and genes which will be of great significance for the future effective and safe tumor therapy.