Supramolecular Cyclodextrin Nanocarriers For Chemo-and Gene Therapy Towards The Effective Treatment Of Drug Resistant Cancers

The resistance of tumor cells to anticancer agents remains a major cause of treatment failure in cancer patients.In order to overcome the multi-drug resistance strategy,nano-carrier-mediated drug administration is considered to provide a novel innovative ideas,promising to become a substitute for traditional chemotherapy agents.Supramolecular cyclodextrin(CD)-based drug carriers may be a versatile approach for materializing these aims due to its unique supramolecular structure,good biocompatibility and molecular recognition of self-assembly ability.Based on this,the first part of this paper is based on the pre-experimental synthesis of P-CD-OEI,and modified targeting ability of the nanocarrier(NC)to self-assemble into a multi-functional drug/gene delivery system(?-NC@Nano-polyplex),The delivery system can be paclitaxel embedded in the hydrophobic cavity,changing the water solubility of paclitaxel itself,enhancing the practical value of paclitaxel,and more importantly,the unique nature of the positive charge makes the gene well attached to the branched OEI.The reporter gene results show high load efficiency.In second part,we make use of the modified-nanocarrier to co-deliver chemotherapeutic drug and functional gene for overcoming tumor resistance by an "enemy to friend" strategy for potential drug resistant cancer therapy.Chemotherapy produces multidrug resistance,which divided into pump resistance and non-pump resistance.The main mechanism of non-pump resistance is to activate the intracellular anti-apoptotic protein defense system,mainly mediated by BCL-2 protein.While the nuclear receptor Nur77 protein can reverse the BCL-2 protein from the anti-apoptotic protein into pro-apoptotic protein.Based on these,the modified star-shaped cationic derivative ?-NC-OEI(p-NC-OEI-SS-FA)was conjugated to the target group Folic acid(FA),co-deliver chemotherapeutic paclitaxel and the Nur77 was effective in reversing the survival protein of BCL-2-mediated drug-resistant cells,and more importantly by constructing a drug-resistant animal tumor model to verify the co-deliver drug and gene nanocomposite's vivo function based on the effect of the system on anti-drug resistant tumors in living tissue.The results of the drug-resistant tumor model show that Nur77 gene can reverse BCL-2 from anti-apoptotic proteins into pro-apoptotic proteins,effectively overcoming the effects of medicinal anti-apoptotic protein activated-defense systems.So that chemotherapy drugs like paclitaxel can play its role in continuously treating the tumor,effectively inhibit tumor cell growth,and even reduce the tumor size.At the same time,this paper will provide new ideas and methods for exploring the effect of supramolecular selfassemble nano-carrier to co-deliver Nur77 gene and chemotherapeutic drugs.