Targeted And Sustained Co-release Of Chemotherapeutics And Gene By Injectable Supramolecular Hydrogel For Drug-Resistant Cancer Therapy

Multidrug resistance of tumors can easily leads to failure of chemotherapy.It has been reported that the overexpression of anti-apoptotic Bcl-2 protein in tumor cells is one of the key causes of multi-drug resistance in tumors.Recent research showed that orphan nuclear receptor Nur77 lacking its DNA binding domain(Nur77/?DBD)plasmid can translocate the expressed Nur77 protein out of cell nucleus,and interact with the Bcl-2 protein in the mitochondria,reverse its conformation and convert it from an anti-apoptotic protein into a pro-apoptotic protein.But how to realize high transfection efficiency of Nur77/ADBD plasmid in drug-resistant tumors,the design of gene vector requires high requirements.This project aim at taking advantage of this"enemy to friend"strategy,and design a suitable carrier to load Nur77/?DBD gene for the therapy of Bcl-2 over-expressed drug-resistant tumors.In this paper,we first designed and synthesized a multi-block cationic copolymer,methoxy-poly(ethylene glycol)-poly(?-caprolactone)-polyethyleneimine(MPEG-PCL-PEI),and folic acid(FA)targeting ligand was introduced in this copolymer to synthesize MPEG-PCL-PEI-FA with tumor targeting ability as an efficient non-viral gene vector.The multi-block cationic copolymer MPEG-PCL-PEI-FA has good biocompatibility,and can effectively bind with plasmid by electrostatic attraction to form nano-complexes w ith particle size at around 200 nm and zeta potential at around+35 mV and further,achieve high gene transfection efficiency.In order to achieve synergistic therapy against drug-resistant tumor,the multi-block cationic copolymer was designed to co-load chemotherapeutics paclitaxel(PTX)and Bcl-2 conversion gene Nur77/?DBD plasmid.The cationic copolymer with co-load of PTX and Nur77/?DBD plasmid was used in the established Bcl-2 protein overexpressed tumor cell line to verify in vitro growth inhibition of co-loading against drug-resistant tumor cells.On this basis,?-CD was further introduced to form injectable supramolecular hydrogel with multi-block copolymer MPEG-PCL-PEI-FA by host-guest recognition.This supramolecular hydrogel can achieve local sustained release of chemotherapeutics and genes for up to 7 days,and can realize long-term inhibition of drug-resistant mice tumor growth.To the best of our knowledge,this is a pioneer report on injectable supramolecular hydrogel formed by polymer and cyclodextrin with the ability to codeliver and sustainedly release PTX and Nur77/?DBD gene to combat Bcl-2 overexpressed therapeutic-resistant tumors in a targeted manner.This project will provide a new idea for the therapy of drug-resistant tumors.