Regilation Of Gulation Of Tumor Cell Repair Ability Bu Nucleic Acid Nano Engineering And Overcoming Platinum

Nowadays,chemotherapy is the main treatment for malignant tumors.Cisplatin,as a representative of bivalent platinum drugs,is a common clinical chemotherapy drug.While it can effectively kill tumor cells,its serious side effects and drug resistance become a bottleneck problem.The way of action of cisplatin based bivalent platinum drugs is to cross link with DNA in the nucleus,resulting in abnormal transcription and cell death.Apurinic/pyrimidine endonuclease(APE1)is an essential key enzyme in the base excision repair(BER)pathway.It is responsible for the repair of DNA damage caused by oxidation and alkylation,which can protect tumor cells from the toxic effects of endogenous and exogenous agents,and enhance the drug resistance of tumor cells.By inhibiting the expression of APE1,the self resistance of tumor cells can be reduced,which is helpful to enhance the efficacy of drugs interacting with nucleic acids.Inspired by this project,we combined small molecule platinum drugs with gene drug APE1 siRNA to construct a novel smart nucleic acid nano drug carrier.Based on the verification that the inhibition of APE1 protein expression can effectively overcome platinum drug resistance,we designed a rigid nucleic acid nanostructure as the drug carrier skeleton.A small interfering RNA(siRNA)that inhibits APE1 protein expression is attached to the structure;And a nucleic acid probe for real-time detection of APE1 expression level;At the same time,as 1411 aptamer targeting high expression of nucleolin in tumor cells was linked.After that,the small molecule platinum drugs(bivalent platinum drug cisplatin and tetravalent platinum prodrug C8 cispt)were incubated with the prepared nucleic acid nanoparticles to connect them and complete the preparation.Gel electrophoresis and atomic force microscopy showed that the synthesis was stable and stable.In vitro fluorescence experiments confirmed that the nucleic acid probe had good sensitivity in detecting APE1 and was not easy to be degraded by nuclease in cells.Furthermore,the co localization of APE1 siRNA and APE1 protein probe in nucleic acid nano drug carrier was verified by cell fluorescence experiment,and the Pearson coefficient was 0.77.The APE1 protein probe showed that APE1 had different inhibitory effect at different time.The half inhibitory concentration(IC50)of C8 cisptpt was as low as 0.74 μM。Finally,we further verified its good therapeutic effect and high safety through the anti-tumor experiment in mice.Finally,we further verified its good therapeutic effect and high safety through the anti-tumor experiment in mice.This new type of intelligent nucleic acid nano drug delivery system not only overcomes the problem of platinum drug resistance,but also uses nucleic acid nano carrier to improve its drug loading capacity and target tumor cells for precise release,showing real-time monitoring of specific treatment in vitro and in vivo,which brings great hope for overcoming tumor recurrence and treatment escape.