Codelivery For Paclitaxel And Bcl-2 Conversion Gene By PHB-PDMAEMA For Effective Drug Resistant Cancer Therapy

In modern society,the number of cancer patients is growing rapidly.Cancer has become a major threat to human health and life.The current clinical treatment of cancer is surgical therapy combined with chemotherapy.However,chemotherapeutic drugs are often difficult to kill cancer cells with drug resistance,resulting in the enrichment of cancer cells,tumor recurrence and metastasis,and malignization of tumors,which often lead to poor clinical chemotherapy efficacy.Therefore,overcoming the multidrug resistance of tumor has become the focus of current clinical treatment.Previous studies have found that multidrug resistant tumor cells would pump chemotherapeutic drugs out of the cells and reduce the enrichment of chemotherapeutic drugs in the cells.On the other hand,Bcl-2 protein,which can stabilize the membrane voltage of mitochondria and prevent mitochondria from releasing Cyt C(cytochrome C)to inhibit cell apoptosis,is overexpressed in multidrug resistant tumor cells.In this paper,we designed a series of biodegradable amphiphilic block copolymers PHB-PDMAEMA(poly[(R)-3-hydroxybutyrate]-poly(2-(dimethylamino)ethyl methacrylate).The hydrophobic PHB segment possesses the ability of loading hydrophobic chemotherapeutic drug paclitaxel.PHB is a biosynthetic polyhydroxyalkanoate,which degrades to ?-hydroxybutyrate(HB),a natural component of human blood.Thus,PHB is suitable for various biomedical applications.The hydrophilic cationic fragment PDMAEMA can adsorb negatively charged plasmid Nur77/?DBD(Nur77 lacking DNA binding domain).This plasmid expresses the nuclear receptor protein Nur77,which interact with Bcl-2 protein on the mitochondria and convert the structure of Bcl-2 protein,so that reverse Bcl-2 protein from anti-apoptotic proteins into pro-apoptotic proteins to reduced drug-resistance of tumor cells.The experimental results showed that PHB-PDMAEMA amphiphilic block copolymers have the ability to self-assemble into nanomicelles and jointly carry paclitaxel and Nur77/?DBD to form drug-gene-polymer polyplex micelles.After the drug-gene-polymer complex micelles entering the tumor cells,Nur77 protein will change the Bcl-2 protein structure,making it from the anti-apoptotic protein into a pro-apoptotic protein.On the other hand,the polyplex would also promote the enrichment and release of PTX in tumor cells compared to simply use of paclitaxel.In conclusion,drug-gene-polymer polyplex can effectively inhibit the proliferation of resistant tumor cells.This result results are encouraging for the further design of co-delivery platforms for combating drug resistant tumors.