Preparation Of Endogenous Stimulus-responsive Nanocarriers For Overcoming Chemoresistance Of Colorectal Cancer Induced By Fusobacterium Nucleatum

Colorectal cancer(CRC)is a serious threat to human life and health.Chemotherapy plays a key role in the control and treatment of advanced CRC.However,studies have shown that Fusobacterium nucleatum(Fn)carried in tumor tissues of colorectal cancer patients can lead to chemotherapy resistance in colorectal cancer,and then lead to chemotherapy failure.Based on this,two endogenous stimulus-responsive nanodrug delivery systems with both antibacterial and antitumor functions were designed to reduce the resistance of colorectal cancer to chemotherapeutic drugs.OEI-LA-PBA/PG-Pt nanoparticles with endogenous response were prepared by combining polyethylenimines(OEI)modified by lauric acid(LA)and phenylboric acid(PBA)with polyglycidyl ether(PG)grafted with oxaliplatin.The antibacterial and antitumor properties of OEI-LA-PBA/PG-Pt were investigated.The results showed that the borate ester bond in OEI-LA-PBA/PG-Pt could dissociate in acidic environment,and Pt(IV)could be reduced to toxic Pt(II)by glutathione to achieve responsive drug release.In vitro cell experiments showed that Fn could promote chemoresistance of HT29 cells.The addition of OEI-LA-PBA/PG-Pt could effectively reduce the chemoresistance via killing Fn.Meanwhile,PBA in OEI-LA-PBA/PG-Pt could specifically recognize overexpressed sialic acid groups onto the surface of CRC cells to increase cellular uptake.In vivo anti-tumor results showed that OEI-LA-PBA/PG-Pt could significantly inhibit tumor growth and effectively reduce chemoresistance induced by Fn.PBA and LA were grafted onto the quaternary ammonium polyaspartic acid(Q-PAsp),which was then combined with dextran to prepare the cationic polymer nanocarrier Q-PAsp-LA-PBA@Dextran.Phenylborate-alizarin red experiment showed that dextran could form dynamic borate ester bond with Q-PAsp-LA-PBA,which was beneficial for endogenous environmental stimulus-response.The antibacterial experiments showed that Q-PAsp-LA-PBA@Dextran could kill Fn effectively.The dissociation of Q-PAsp-LA-PBA@Dextran occurred under acidic or glucanase conditions,which promoted the adhesion of nanoparticles on bacterial surface.In vitro cytotoxicity test results showed that Q-PAsp-LA-PBA@Dextran nanoparticles had good biocompatibility due to the addition of dextran.